Patients eligible for inclusion in this study have to meet all of the following criteria:

1. Age = 18 years.

2. Patients with diagnosis of relapsed or refractory AML (=5% bone marrow blasts, and/or =1% peripheral blood blasts, and/or histologically proven extramedul-lary disease) defined according to 2022 ICC criteria1 after at least one prior line of treatment who are ineli-gible for intensive salvage chemotherapy and/or al-logeneic hematopoietic cell transplantation or who de-cline standard treatment.
OR
Patients with diagnosis of relapsed/refracto-ryMDS/AML with 10-19% bone marrow blasts at initial diagnosis and =5%bone marrow blasts, and/or =1% peripheral blood blasts at screening defined accord-ing to 2022 ICC criteria1 after at least one prior line of treatment who are ineligible for intensive salvage chemotherapy and/or allogeneic hematopoietic cell transplantation or who decline standard treatment.

3. IDH1-mutated as determined by a validated assay at a specific site (IDH1 R132).

4. ECOG 0-2.

5. Adequate hepatic function as evidenced by:

- Serum total bilirubin = 3 x upper limit of normal (ULN) unless considered due to Gilbert’s syndrome, or leukemic involvement of the liver – following writ-ten approval by the coordinating investigator.

- Aspartate aminotransferase (AST) and alanine ami-notransferase (ALT), = 3.0 x ULN, unless consid-ered due to leukemic involvement of the liver - fol-lowing written approval by the coordinating investi-gator.

6. Adequate renal function as evidenced by creatinine clearance = 30 mL/min based on the CKD-EPI for-mula for glomerular filtration rate (GFR).

7. Able to understand and willing to sign an informed consent form (ICF).

8. Written informed consent.

9. Female patient must either:

- Be of non-childbearing potential:

- Postmenopausal prior to screening defined as:
- Age = 50 years and in postmeno-pausal state > 1 year or
- Age < 50 years and in postmenopausal state > 1 year with serum FSH > 40 IU/l and serum estrogen < 30 ng/l or a nega-tive estrogen test, both at screening
or
- Patient is documented surgically sterile by bilat-eral tubal ligation or bilateral oophorectomy or status post-hysterectomy or uterine agenesis (at least 1 month prior to screening).

- If of childbearing potential:
- Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
- And have a negative serum pregnancy test at screening
And, if heterosexually active, agree to consist-ently use highly effective* contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration.

* Highly effective forms of birth control include:

i. Established intrauterine device (IUD) or intrauter-ine system (IUS).

ii. Bilateral tubal occlusion.

iii. Vasectomy (a vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used).

iv. Male is sterile due to a bilateral orchiectomy.

v. Sexual abstinence is considered a highly effec-tive method only if defined as refraining from het-erosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in rela-tion to the duration of the clinical study and the preferred and usual lifestyle of the patient.

* List is not all inclusive. Prior to enroll-ment, the investigator is responsible for confirming patient will utilize highly ef-fective forms of birth control per the re-quirements of the CTFG Guidance document 'Recommendations related to contraception and pregnancy testing in clinical trials’, September 2020 (and any updates thereof) during the proto-col defined period. Since ivosidenib may decrease the concentrations of hormonal contraceptives, it is recom-mended to use alternative methods of contraception as mentioned above (see section 5.5).

- Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months after the final study drug administration.

- Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.

10. Male patient and their female partners who are of childbearing potential must use highly effective con-traception per locally accepted standards (see above *highly effective forms of birth control) in addition to a barrier method starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration.

11. Male patient must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug admin-istration.

12. Patient agrees not to participate in another interven-tional study while on treatment.

13. Ability to swallow and retain oral medication, no known malabsorption syndrome, adequate organ function for the study treatment in the opinion of the investigator.

Patients eligible for inclusion in this study must not meet any of the following criteria:

1. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA, or other translocations associated with APL.

2. AML with BCR-ABL translocation.

3. MDS with bone marrow blasts <10% at initial diagnosis (if patients progress from MDS to MDS/AML they should be treated with a hypomethylating agent first).

4. MDS with bone marrow blasts <5% at screening.

5. Prior treatment with ivosidenib, olutasidenib or a PHD inhibitor (e.g. roxadustat) within the last 6 months prior to screening (in the case of pre-treatment with ivosidenib, it is necessary to consult with the coordinating investigator before patient inclusion).

6. Persistence of toxicity of prior chemotherapy above grade 1.

7. Treatment with any investigational agent within two weeks before day one of study treatment or less than 5 half-lives of the compound.

8. CNS disease or other severe acute or chronic medical or psychiatric condition, or la-boratory abnormality that may increase the risk associated with study participation or study drug
administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.

9. Known allergy or suspected hypersensitivity to molidustat and/or ivosidenib and/or any excipients.

10. Taking medications with narrow therapeutic windows with potential interaction with in-vestigational medication (see Appendix I), unless the patient can be transferred to other medications prior to enrolling or unless the medications can be properly monitored dur-ing the study.

11. Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporter- sensitive substrate medications (see Appendix J) unless the patient can be transferred to other medications within = 5 half-lives prior to administration of molidustat and ivo-sidenib, or unless the medications can be properly monitored during the study.

12. Breast feeding at the start of study treatment.

13. Active infection, including hepatitis B or C or HIV infection that is uncontrolled at screen-ing. An infection controlled with an approved or closely monitored antibiotic/antiviral/an-tifungal treatment is allowed.

14. Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at < 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
- Basal or squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer

15. Significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure (Appendix H); myocardial infarction, unstable angina and/or stroke; or left ventricular ejection fraction (LVEF) < 40% by ultrasound obtained within 28 days prior to the start of study treatment.

16. Liver cirrhosis Child Pugh B or Child Pugh C or disorders of bilirubin metabolism, e.g. in patients with Crigler-Najjar syndrome or Rotor syndrome, with exception of Gilbert’s syndrome (see section 4.1 and 5.5).

17. QTc interval using Fridericia’s formula (QTcF) = 480 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the coordinating investigator.

18. Taking medications that are known to prolong the QT interval (see Appendix K), unless deemed critical and without a suitable alternative. In those cases, they may be admin-istered with proper monitoring.

19. Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the inges-tion or gastrointestinal absorption of orally administered drugs.

20. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screen-ing.

21. A known medical history of progressive multifocal leukoencephalopathy (PML).

22. Immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or severe disseminated intravascular coagulation.

23. Any other medical condition deemed by the Investigator to be likely to interfere with a patient’s ability to give informed consent or participate in the study.

24. Any psychological, familial, sociological or geographical condition potentially hamper-ing compliance with the study protocol and follow-up schedule.

1) Male or female participants, age >=18 years

2) HLA type of participant must match at HLA B and C loci, based on high resolution typing, to 4 digits (e.g., HLA-B*07*02), with Allo-RevCAR01-T batches.

3) a) For escalation part of the trial
Participants with CD123+ AML (defined as =20% of leukemic cells expressing CD123 at any point in the course of disease)

(1) for whom all standard or life-extending therapies have failed and for whom no potentially curative therapies are available or who are intolerant to such therapies.
b) For Phase 1b expansion part of the trial
Participants with CD123+ AML (defined as >=20% of leukemic cells expressing CD123 at any point in the course of disease

(1) up to 3rd relapse for whom all standard or life-extending therapies have failed and for whom no potentially curative therapies are available or who are intolerant to such therapies

(2) having up to 30% blasts in a Bone Marrow assessment at either screening or prescreening, or having between 30% and 40% blasts for two consecutive bone marrow assessments with a minimum of one month and no more than two months apart,

(3) without hyperproliferative disease requiring cytoreductive treatment,

(4) exceptions to BM blast criterion are only possible in minor deviations in timing and/or blast count in clinically stable patients, and only with written sponsor approval. Exceptions to minimum CD123 expression are not allowed.

c) For Phase 1a escalation and Phase 1b expansion part of the trial
Participants with MRD+ AML are potentially eligible but must meet the following criteria:

(1) MRD positivity must be based on assays and markers supported by consensus guidelines (Heuser 2021) ] and in the judgment of the investigator must confer negative prognostic risk highly likely to result in relapse.

(2) Must have received or be ineligible for allogeneic stem cell transplant.

(3) Must be approved by the Sponsor for inclusion in the study

4) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

5) Life expectancy of at least 3 months in the judgement of the investigator.

6) Adequate renal and hepatic laboratory assessments:

1 Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) <=2.5x upper limit of normal (ULN)
2 Total bilirubin <=1.5x ULN (unless related to Gilbert’s syndrome)
3 Serum creatinine clearance* >60mL/min.

7) Adequate cardiac function, i.e., left ventricular ejection fraction (LVEF) of >=50%**

8) Long-term central venous access existing (e.g., port-system) or willing to have such a
device inserted.

9) Able to give written informed consent.

10) Weight >=45 kg.

11) A woman of childbearing*** potential (WOCBP) may be enrolled if she has a negative serum pregnancy test at screening visit and is willing to use a highly effective method of birth control (pearl index of =1 required) resulting in a low failure rate (e.g., hormonal contraception, intrauterine device, total sexual abstinence, or sterilization)for at least 12 months after lymphodepletion therapy. Male participants must also practice a highly effective method of birth control and should not father a child or donate sperm for at least until 6 months after end of lymphodepletion therapy.

* Cockroft-Gault formula to be used:

CCr = ((140–age) x weight)/(72xSCr)) [x 0.85 (if female)]
CCr (creatinine clearance) = mL/minute; Age = years; Weight = kg; SCr (serum creatinine) = mg/dL
** Assessed primarily by transthoracal two-dimensional echocardiography (ECHO), but if ECHO is not possible, any locally available standard equivalent investigation for cardiac function, including LVEF, is acceptable.
*** Following the EU Heads of Medicines Agencies Clinical Trials Facilitation Group “Recommendations related to contraception and pregnancy testing in clinical trials , a woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. For the purpose of this document, a man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.

1. Acute promyelocytic leukemia (t15;17).

2. AML with only extramedullary manifestations (e.g., chloroma, primary myeloid sarcoma)

3. Acute manifestation of AML in the central nervous system.

4. Bone marrow failure syndromes (e.g., Fanconi anemia, Kostman syndrome, Shwachman syndrome).

5. Cardiac disease: heart failure (New York Heart Association III or IV); unstable coronary artery disease, myocardial infarction, or serious cardiac ventricular arrhythmias requiring
anti-arrhythmic therapy within the last 6 months prior to study entry.

6. Active pulmonary disease with clinically relevant hypoxia (need for oxygen inhalation).

7. Parkinson’s disease or epilepsy with clinical symptoms in the previous 12 months that may, in the Investigator's opinion, interfere with participation in the trial.

8. Stroke, seizure, or intracranial hemorrhage in the past 12 months.

9. History or presence of disseminated intravascular coagulation (DIC), deep vein thrombosis, or thromboembolism within 3 months prior to start of treatment. Patients with uncomplicated DVTs may be considered for participation in the study with written Sponsor approval.

10. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy (in individual cases, after consultation
with the Sponsor, this may not include past, non-acute, non-clinically significant infectious diseases for which there is still serological evidence).

11. Presence of hemorrhagic cystitis

12. Other toxicity from prior anticancer treatment has not resolved to Grade <=1 or baseline.

13. Allogeneic stem cell transplantation within last 2 months or GvHD requiring systemic immunosuppressive therapy.

14. Vaccination with live viruses <2 weeks prior to lymphodepletion therapy.

15. Major surgery within 28 days prior to start of R-TM123 infusion.

16. Prior malignancy in the past 3 years or any malignancy requiring ongoing active therapy other than adjuvant endocrine therapy. Participants with resected or ablated tumors, such
as basal cell carcinoma of skin, carcinoma-in-situ of the cervix, or other tumors considered cured may be considered for the study with Sponsor approval.

17. Treatment with any investigational drug substance or experimental therapy within 4 weeks or 5 half-lives (whatever is shorter) of the substance prior to lymphodepletion.

18. Treatment with anti-leukemic therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to lymphodepletion

19. Prior treatment with gene-modified cell products, unless written approval is obtained from the Sponsor.

20. Use of checkpoint inhibitors within 5 half-lives of the specific drug.

21. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants.
Note: Physiologic steroid replacement not exceeding 10 mg prednisolone equivalent per day is allowed.

22. Pregnant or breastfeeding women.

23. Psychologic disorders with treatment modifications required within the last 3 months, drug and/or significant active alcohol abuse as per investigator’s medical judgement. Depression or anxiety due to presence of the underlying malignancy may be exempted with Sponsor approval.

24. History of human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).

25. Presence of autoantibodies against La/SS-B or presence or history of autoimmune diseases associated with such antibodies (e.g., systemic lupus erythematosus, Sjögren's syndrome/systemic lupus erythematosus overlap syndrome, subacute cutaneous lupus erythematosus, neonatal lupus, primary biliary cirrhosis, Sjögren's syndrome).

26. Known hypersensitivity to cellular component (Allo-RevCAR01-T) and/or TM (R-TM123) excipients or to compounds of the lymphodepletion therapy or tocilizumab or corticosteroids.

27. Evidence that the participant is not likely to follow the study protocol (e.g., lacking compliance) in the judgement of the investigator.

28. Participant is unable to understand the informed consent and possible consequences of the participation in the clinical trial in the judgement of the investigator.

Patients must meet all the following inclusion criteria to be eligible to enroll in this trial:

1. Male or female, = 18 years old.

2. Willing and able to give written informed consent.

3. Have histologically confirmed R/R B-NHL or CLL, per WHO classification, expected to express CD19 and/or CD20 (confirmation of CD19 or CD20 expression required in EU only), have received, are deemed ineligible for, or have declined standard therapies reimbursed by their health care system, and have a clinical need for systemic treatment.
- LBCL (including e.g., DLBCL, HGBL, transformed LBCL from indolent lymphoma or CLL, PMBCL – but not PCNSL)
- FL
- MZL
- MCL
- CLL/SLL
Note: Eligible diagnoses may be narrowed during dose escalation Phase Ia or for expansion Phase Ib, and Phase II to DLBCL only, or to fewer indications based on accumulating data, (i.e., unacceptable safety profile, or no suitable patients or no responses in escalation).
Individuals with primary and secondary CNSL are eligible only on safe doses (backfill cohorts, dose expansion).

4. For lymphomas (including SLL), measurable disease with at least 1 bi-dimensional measurable lesion (CT/MRI), longest diameter > 1.5 cm for nodal, > 1 cm for extranodal within a month of the treatment start, and after any anti-lymphoma therapies.
Previously radiated lesions are eligible only if there is documented progression on the site after radiation therapy. Only MRD positivity is not considered eligible.

5. For CLL, indication for treatment per iwCLL 2018 guideline and objectively measurable disease (e.g., lymphocytosis or measurable lesion, including lymphadenopathy, splenomegaly, and extra-nodal lesions, but not e.g., autoimmune manifestations only, or MRD positivity).

6. Availability of fresh or archival biopsy sample (obtained after last CD19/CD20 targeting treatment line), or willingness to provide one. A patient may be included without biopsy material if the biopsy procedure would cause unacceptable safety risk or discomfort per careful investigator judgement including individual risk-benefit assessment.

7. HLA B and C types match 1 or more of the available IMP batches.

8. ECOG 0 to 1.

9. Adequate organ function:

- Calculated CrCl = 60 mL/min
Note: CrCl must be calculated using the Cockcroft-Gault Method:
CrCl = ((140 – age) x weight)/(72 x SCr)) [x 0.85 (if female)]
CrCl = mL/minute; Age = years; Weight = kg; SCr = mg/dL

- Direct bilirubin = 1.5 x ULN (unless Gilbert’s syndrome)

- AST/ALT = 2.5 x ULN (up to 5 x ULN if elevation directly caused by lymphoma
infiltration)

- LVEF = 45% (per local standard method, e.g., transthoracic echocardiography)

- Oxygen saturation = 92% on room air

- Blood counts:
- ANC = 1.0 x 10^9 L
- Platelets = 50 x 10^9 /L
- Hb = 7 g/dL

Note: Lower levels are allowed if cytopenia is directly caused by lymphoma/CLL infiltration, and participation is deemed safe per investigator judgement.

10. Life expectancy of = 3 months as assessed by the Investigator.

11. Central venous access or willingness to have one.

12. Weight is greater than the minimum weight required for a specific batch to ensure that the dose administered does not exceed 105 TCR+ cells/kg of patient weight.

13. Contraception:

a) Women NOT of childbearing potential can be enrolled: i.e., postmenopausal, or permanently sterilized women (e.g. bilateral tubal occlusion, hysterectomy, bilateral salpingectomy), or women who have not had menarche yet.

b) A woman of childbearing potential (WOCBP) may be enrolled if she has a negative serum pregnancy test at Screening visit and is willing to use, for at least 12 months after LD chemotherapy, a highly effective method of birth control (Pearl index of = 1% per year) resulting in a low failure rate:
- combined (oral, intravaginal, transdermal) or progestogen-only (oral, injectable, implantable) hormonal contraception associated with inhibition of ovulation.
- placement of an intrauterine device (IUD) or intrauterine system (IUS)
- total sexual abstinence if this corresponds to the participant´s way of life choice
- vasectomised partner provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success.

c) Male patients must either be willing to practice true abstinence (if this corresponds to the participant´s way of life choice), be sterilized (with appropriate postvasectomy documentation of the absence of sperm in the ejaculate) or be willing to use a condom with spermicide. Their female partner of childbearing potential (if not pregnant) must also use a highly effective contraceptive method during the study and for at least 6 months after the end of lymphodepletion chemotherapy.

Note: A specific gender allocation is not applied in this trial because the incidence of target indications is comparable across genders. Inclusion is in the same way limited to participants aged 18 years and older to ensure that the study population is representative of the target patient group (Pan et al., 2025).

Patients meeting any of the following exclusion criteria are not eligible to enroll in this trial.

1. Active CNS involvement (including PCNSL) is excluded from dose escalation cohorts.
However, these individuals may be enrolled to established safe dose cohorts (i.e., backfill cohorts, dose expansion).

2. Prior CAR-T treatment within 3 months of Screening, or = Grade 3 ICAHT associated with prior CAR-T treatment.

Note: ICAHT per EHA/EBMT recommendation, Grade 3: ANC = 0.1 x 10^9 /L for 7 days, or ANC = 0.5 x 10^9 /L for 14 days, or ANC = 0.5 x 10^9 /L 30 days after the CAR-T administration or later.

3. Hematological autologous hematopoietic stem cell transplantation within 3 months.

4. Prior allogeneic hematopoietic stem cell transplantation or solid organ transplant.

5. Prior therapy with dual CD19/CD20 targeting CAR-T.

6. Known severe hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in trial.

7. History of GvHD or post-transplant lymphoproliferative disorder.

8. Presence of autoantibodies against La/SS-B or presence or history of autoimmune diseases associated with such antibodies.

9. History of other malignancy that could affect compliance with the protocol or interpretation of results, excluding:
- History of curatively treated basal or squamous cell carcinoma of the skin, or in situ carcinoma of the cervix at any time prior to Screening.
- Low-grade, early-stage prostate cancer (Gleason score = 6, Stage 1 or 2) with no requirement for therapy at any time prior to Screening.
- Current adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer for 2 or more years prior to Screening.
- Any other malignancy treated with curative intent and in remission without treatment for 2 years prior to Screening.

10. Active viral infection within 1 week of Screening or ongoing bacterial or fungal infection requiring hospitalization or intravenous antimicrobials, or any other ongoing infection that would have a significant impact on safety or trial conduct per Investigator judgement.

11. Presence of hemorrhagic cystitis.

12. Active neuro-autoimmune diseases, including MS, Guillain-Barre, ALS.

13. Active or residual HBV, HCV, or syphilis.

14. Active HIV disease. Individuals with positive HIV history may be included after Phase Ia dose escalation if:
- Ongoing antiretroviral treatment for = 6 months
- Adherence to antiretroviral treatment per Investigator judgement and leading to good treatment response (as below)
- Good treatment response, defined by absence of clinical symptoms (including infectious and constitutional), normal blood CD4+ count (at least 500 cells /µL), and undetected HIV RNA (= 50 copies /mL).

15. Active or recent (within 6 months of Screening) cerebrovascular ischemia/hemorrhage, dementia, Parkinson’s disease, cerebellar disease, or autoimmune disease with CNS involvement that may impair ability to evaluate neurotoxicity or have an impact on trial safety per Investigator assessment.

16. History of MI, cardiac angioplasty or stenting, unstable angina or other clinically significant cardiac disease within 6 months of Screening with an impact on trial safety per Investigator assessment.

17. Primary immunodeficiency or history of autoimmune disease (e.g., Crohn’s disease, rheumatoid arthritis, systemic lupus) requiring systemic treatment within 1 year of Screening unless stable and not increasing safety risk per Investigator judgement.

18. Other non-hematological toxicity from prior anti-cancer treatment that has not resolved to Grade =1 or baseline, except for peripheral neuropathy which is eligible up to Grade 2.

19. Systemic immunosuppression within 28 days of Screening, including therapeutic doses of corticosteroids and other immunosuppressants (per section 7.4.2).

20. Any investigational therapy, systemic anti-lymphoma, anti-CLL or other anti-cancer treatment, including standard and investigational treatments (per section 7.4.2), within 28 days or within 5 half-lives of Screening, whichever is shorter.

21. Major surgery within 14 days of Screening.

22. Local radiation within 28 days of Screening.

23. Live vaccination within 28 days of Screening.

24. Pregnant or breastfeeding.

Note: Any period mentioned before Screening (i.e., within xx days/week “of Screening") means time before the last day of Screening period (eligibility confirmation date by the Sponsor or delegate). The investigator is solely responsible for determining and confirming participant eligibility in this study.

An individual is eligible for inclusion in the study if the individual meets all of the following criteria:

Type of Participant and Disease Characteristics

1. Confirmed diagnosis of CLL/SLL and active disease clearly documented to initiate therapy. At least 1 of the following criteria should be met:

- Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cutoff levels of Hb < 10g/dL or platelet counts < 100 x 10^9/L are generally regarded as indication for treatment; however, in some patients, platelet counts < 100 x 10^9/L may remain stable over a long period; this situation does not automatically require therapeutic intervention.

- Massive (ie, = 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.

- Massive nodes (ie, = 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.

- Progressive lymphocytosis with an increase of = 50% over a 2-month period, or LDT, < 6 months. LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; participants with initial blood lymphocyte counts < 30 x 10^9/L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (eg, infections, steroid administration) should be excluded.

- Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids, as deemed by the investigator.

- Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine).

- Disease-related symptoms as defined by any of the following:
- Unintentional weight loss = 10% within the previous 6 months.
- Significant fatigue (ie, up to ECOG performance status 2; cannot work or unable to perform usual activities).
- Fever of 100.5 Grad F or 38.0 Grad C for 2 or more weeks without evidence of infection.
- Night sweats for = 1 month without evidence of infection.

2. Del(17p) status, TP53 mutation status, and IGHV mutation status results required before
randomization for Part 2 participants only as determined by central testing:

- Del(17p) status, TP53 mutation status, IGHV mutation status.
For accurate prognostic stratification, each patient must have a known result for IGHV, del(17p), and TP53. In cases where del(17p) or TP53 results are indeterminate, eligibility may be determined with sponsor consultation and approval as follows: participants with an indeterminate del(17p) result are eligible only if a TP53 mutation is confirmed, and participants with an indeterminate TP53 result are eligible only if del(17p) is confirmed.

- Provision of peripheral blood sample (at screening for CLL participants). For SLL participants, peripheral blood and a bone marrow aspirate are required, and if available/preferrable a lymph node sample (if obtained up to 1 year before central laboratory submission if there was no intervening therapy). Further information is provided in Appendix 14.

NOTE: Tissue collection and submission to the central laboratory should only be performed once all other eligibility criteria have been collected and reviewed.

3. Relapsed or refractory to at least 1 prior available therapy.

NOTE: Participants refractory to venetoclax are excluded.

NOTE: There is no limit on the number of prior therapies.

NOTE: The definition of relapsed/refractory disease follows the iwCLL definition (see Appendix 10). Relapse is defined as evidence of disease progression in a patient who has previously achieved a CR or PR for =6 months. Refractory disease is defined as treatment failure (including SD, nonresponse, disease progression) or as progression within 6 months from the last dose of therapy.

4. Have at least 1 of the following markers of disease burden:

- Malignant lymph nodes attributable to CLL/SLL which are clearly and reproducibly measurable in 2 dimensions in the axial plane, and measure = 1.5 cm in longest diameter when assessed by CT/MRI scan

- Absolute lymphocyte count > 4 x 10^9/L

- Platelet count < 100 x 10^9/L

- Hemoglobin < 11 g/dL

5. An ECOG performance status of 0 to 2 within 7 days before randomization.

6. A life expectancy of at least 3 months, based on the investigator assessment.

7. The ability to swallow and retain oral medication.

NOTE: Administration of nemtabrutinib and venetoclax is not permitted through a J-PEG tube.

8. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV DNA viral load before randomization.

NOTE: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

Hepatitis B screening tests should include HBsAg and anti-HBc.

9. Participants with history of HCV infection are eligible if HCV RNA viral load is undetectable at screening.

NOTE: Participants must have completed curative antiviral therapy at least 4 weeks before randomization.

Hepatitis C screening tests are not required unless:

- Known history of HCV infection

- As mandated by local health authority (see Appendix 7 for country-specific requirements)

10. Participants with HIV are eligible if they meet ALL the following criteria:

- The CD4 count is =350 cells/µL at screening

- Achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening

- Are on a stable ART regimen for at least 4 weeks before study entry

NOTE: ART must include drugs that are not strong CYP3A4 inducers (participants receiving ART that are strong CYP3A4 inhibitors are not eligible to be included in the study).

- Are compliant with their ART

NOTE: If the participant has had an AIDS-defining opportunistic infection in the past 12 months before screening, they are not eligible to be included in the study.

HIV screening will follow local regulations. See Appendix 7 for country-specific requirements.

11. Adequate organ function as defined in Table 6. Specimens must be collected within 7 days before the start of study intervention.

Table 6: Adequate Organ Function Laboratory Values

System: Laboratory Value

Hematological

ANC: = 1,000 MikroL

Platelets: = 50,000/MikroL regardless of bone marrow involvement

Hemoglobin: = 8.0 g/dLa

Renal

Measured or calculated creatinine clearance using the Cockcroft-Gault equationb or a 24-hour urine test: = 30 mL/min

Hepatic

Total bilirubin: = 1.5 x ULN OR direct bilirubin = ULN for participants with total bilirubin levels >1.5 x ULN. In participants with documented liver metastases and/or Gilbert’s syndrome, total bilirubin of = 3 x ULN.

AST (SGOT) and ALT (SGPT): = 2.5 x ULN (= 5 x ULN for participants with liver metastases)

Coagulation

INR or PT aPTT: = 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

AIHA=autoimmune hemolytic anemia; ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); ANC=Absolute neutrophil count; aPTT=Activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CLL=chronic lymphocytic leukemia; INR=International normalized ratio; min=minutes; PT=prothrombin time; SLL=small lymphocytic lymphoma; ULN=upper limit of normal.

^a Criteria must be stable for =1 week, with the exception of AIHA for CLL/SLL
^b Measured or calculated creatinine clearance using Cockcroft-Gault:

((140-age [years]) x (weight [kg]) / Serum creatinine (mg/dL) x 72) (xF)*

*where F=0.85 for females and F=1 for males

Demographics

12. Is an individual of any sex/gender and aged at least 18 years at the time of providing documented informed consent.

Participants Assigned Male Sex at Birth

13. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:

- Nemtabrutinib: 12 days.
- Venetoclax: 1 month (30 days).
- Rituximab (rituximab biosimilar [see Appendix 13]): not applicable.

- Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent.

OR

- Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the
participant’s medical records, medical examination, or medical history interview):

- Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant and should also be advised of the benefit for that partner to use an additional method of contraception, as a condom may break or leak.

NOTE: Participants capable of producing ejaculate whose partner is pregnant or breastfeeding must agree to use a penile/external condom during each episode of sexual activity in which the partner is at risk of drug exposure via ejaculate.

- Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of ontraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.

Participants Assigned Female Sex at Birth

14. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:

- Is not a POCBP.

OR

- Is a POCBP and:
- Uses a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention.

The length of time required to continue contraception for each study intervention is:

- Nemtabrutinib: 1 month (30 days).

- Venetoclax: 1 month (30 days).

- Rituximab (or rituximab biosimilar [see Appendix 13]): 12 months (See Appendix 7 for country-specific requirements).

- The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCPBs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.

- Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours (for urine test) or 72 hours (for serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.7.

- Abstains from breastfeeding during the study intervention period and for at least 30 days after study intervention with nemtabrutinib, 1 month (30 days) after the last dose of venetoclax, and 6 months after the last dose of rituximab (or rituximab biosimilar [see Appendix 13]).

- Medical history, menstrual history, and recent sexual activity have been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.

Informed Consent

15. The participant (or legally acceptable representative) has provided documented informed consent for the study and the participant has provided documented assent, when applicable, for the study. The participant may also provide consent for FBR; however, the participant may participate in the study without participating in FBR.

16. Criterion was modified and moved to Section 10.7.11 EEA Appendix.

See Appendix 7 for EU-specific consenting requirements for participants who require a legally designated representative for consenting purposes.

An individual must be excluded from the study if the individual meets any of the following criteria:

Medical Conditions
1. Active HBV/HCV infection. See Inclusion Criteria 8 (HBV) and 9 (HCV) for requirements.

2. GI dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy).

3. Known additional malignancy that is progressing or has required active treatment within the past 2 years.

NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma ofskin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potential curative therapy are not excluded. Participants with low risk, earlystage prostate cancer (T1-T2a, Gleason score =6, and prostate-specific antigen < 10 ng/mL) either treated with definitive intent or untreated in active surveillance with SD are not excluded.

4. Diagnosis of Richter Transformation or active CNS involvement by CLL/SLL.

5. Active infection requiring systemic therapy, such as IV antibiotics, during screening.

NOTE: Participants may be rescreened following completion of IV antibiotic course.

6. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease and/or AIDS-defining opportunistic infection in the past 12 months before screening.

7. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

8. Clinically significant cardiovascular disease, including the following:

- Myocardial infarction within 6 months before screening.

Unstable angina within 6 months before screening.

- New York Heart Association Class III or IV congestive heart failure.

- History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade’s de pointes).

- QTcF > 470 msecs based on Fridericia’s formula (NOTE: QTcF value may be calculated as the numerical average of up to 3 separate readings for eligibility).

- History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.

- Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic blood pressure > 105 mm Hg at screening.

9. Known allergy/sensitivity (=Grade 3) to nemtabrutinib or contraindication to venetoclax/rituximab (or rituximab biosimilar [see Appendix 13]), or any of the excipients.

NOTE: Refer to the IB for details regarding excipients for nemtabrutinib and the current prescribing information for venetoclax/rituximab (or rituximab biosimilar [see Appendix 13]).

10. History of severe bleeding disorders (eg, hemophilia).

Prior/Concomitant Therapy

11. Received prior systemic anticancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before randomization.

12. Received prior:

- BCL2i within < 12 months before randomization.

- Prior radiotherapy within 2 weeks of start of study intervention, or radiation related toxicities, requiring corticosteroids.

NOTE: Participants refractory to venetoclax are excluded.

NOTE: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted.
The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.

13. Currently being treated with the following therapies:

- P-gp substrates with a narrow therapeutic index.

- CYP3A strong or moderate inducers.

- CYP3A strong inhibitors.

NOTE: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a participant to be eligible for study enrollment.
A list of examples of in vivo CYP3A strong inhibitors, CYP3A strong or moderate inducers, and P-gp substrates with narrow therapeutic index is provided in Appendix 8.
Refer to Sections 6.5.1, 6.5.2, 6.6.2, and Appendix 8 for information on prohibited concomitant medications, medications that require caution or dose adjustment when co-administered, and potential drug interactions post randomization.

14. Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention.

Refer to Section 6.5.1 for information on COVID-19 vaccines.

Prior/Concurrent Clinical Study Experience

15. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.

Diagnostic Assessments

16. Known psychiatric or substance use disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.

Other Exclusions

17. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

18. Participating Sites in EU Region only: Participants who are incapacitated are not eligible for this study.

See Appendix 7 for country-specific requirements.

Each patient eligible to participate in this study must meet all the applicable criteria:

1. Provision of signed and dated written informed consent prior to any study-specific procedures, sampling, or analyses

2. Age 18 years or older

3. Confirmed diagnosis of one of the following by 2016 World Health Organization criteria (Arber et al 2016; see Appendix 13):

a. AML, nonacute promyelocytic leukemia and meets one of the following disease activity criteria:
i. TN and unfit for intensive chemotherapy (TN unfit) as defined by one of the following:
(1) Age = 65 years
(2) Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction = 50%, or chronic stable angina)
(3) Severe pulmonary disorder (eg, diffusion capacity for carbon monoxide, [DLCO] = 65%, or forced expiratory volume in 1 second [FEV1] = 65%)
(4) Creatinine clearance between 30 and 49 mL/min
(5) Liver disease with bilirubin > 1.5 x upper limit of normal (ULN) and must be = 3 x ULN

Note: In the USA, TN unfit AML patients will not be enrolled in Part 3 until RP2D(s) have been reviewed by local regulatory agency. In the EU, TN unfit AML patients will not be enrolled in Part 3 until RP2D(s) for TN AML have been selected and a summary of the SMC recommendation for RP2D(s) has been submitted via the EMA’s Clinical Trials Information System.

ii. R/R to = 1 prior lines of systemic therapy as defined by 2017 European LeukemiaNet (ELN) response criteria (Döhner et al 2017, see Appendix 6). In France, Italy, and Spain, patients with R/R AML with FLT3 ITD or TKD mutation confirmed using a validated test, after induction chemotherapy, must have received gilteritinib, if eligible.

iii. HMA-failure AML – Patients who had received an HMA-containing regimen for AML and their AML disease did not respond, defined as received = 1 cycle of hypomethylating agent and had disease progression (Döhner et al 2017, see Appendix 6) or no = PR after 4 cycles after receiving > 75% of planned dose

b. MDS (bone marrow blast > 5%) and meets one of the following disease activity criteria:
i. TN with Revised International Prognostic Scoring System score > 3.5 (intermediate, high, or very high)

NOTE: TN MDS patients will not be enrolled in France or Germany to the sonrotoclax monotherapy cohort.

ii. R/R to = 1 prior lines of systemic therapy as defined by modified IWG 2006 criteria for relapse, or failure, or disease progression (Cheson et al 2006, see Appendix 8)

iii: HMA-failure MDS – received = 1 cycle of hypomethylating agent and had disease progression (Cheson et al 2006, see Appendix 8) or no = PR or HI after 4 cycles after receiving > 75% of planned dose

c. MDS/MPN including CMML, 2016 World Health Organization classification subtypes CMML-1 or CMML-2, or other MDS/MPN requiring treatment, with bone marrow blast > 5% and meets one of the following criteria:

i. TN

NOTE: TN MDS/MPN patients will not be enrolled in France or Germany to the sonrotoclax monotherapy cohort.

ii. R/R to = 1 prior lines of systemic therapy as defined by modified IWG 2006 criteria for relapse, or failure, or disease progression (Cheson et al 2006, see Appendix 8)

iii. HMA-failure MDS/MPN– received = 1 cycle of hypomethylating agent and had disease progression (Cheson et al 2006, see Appendix 8) or no = PR or HI after 4 cycles after receiving > 75% of planned dose

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

5. Adequate organ function defined as:

a. Creatinine clearance = 50 mL/min (or between 30 and 49 mL/min in TN unfit AML cohort) as estimated by one of the following:

i. Cockcroft-Gault equation:
(1) (140 - age) x mass (kg)/[72 x creatinine (mg/dL)]; multiply by 0.85 if female
(2) (140 - age) x mass (kg) x 1.23 if male (or 1.04 if female)/creatinine (Mikromol/L)

ii. CKD-EPI equation

iii. 24-hour urine collection

b. Adequate liver function indicated by:

i. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase = 3 x ULN

ii. Alanine aminotransferase/serum glutamic-pyruvic transaminase = 3 x ULN

iii. Total bilirubin level = 1.5 x ULN (except in TN unfit AML or patients with documented Gilbert syndrome, must be = 3 x ULN)

6. Women of childbearing potential must have a negative serum pregnancy test = 7 days before the first dose of study drug. In addition, they must use a highly effective method of birth control initiated before the first dose of study drug, during the study treatment period, and for = 90 days after the last dose of sonrotoclax and = 180 days after the last dose of azacitidine. They must refrain from donating eggs and participating in any processes involving the use of their eggs for achieving pregnancy (eg, in vitro fertilization) after receiving the first dose of study drug until = 90 days after the last dose of sonrotoclax and = 180 days after the last dose of azacitidine. See Appendix 12 for highly effective methods of birth control and the definition of childbearing potential.
Patients using hormonal contraceptives (eg, birth control pills or devices) must also use a barrier method of contraception (eg, condoms).

7. Nonsterile men must use a highly effective method of birth control for the duration of the study treatment period and for = 90 days after the last dose of study drug. During this same period, they must not donate sperm or participate in any processes involving the use of their sperm for the purpose of achieving pregnancy (eg, in vitro fertilization). See Appendix 12 for highly effective methods of birth control and the definition of sterile.

8. Life expectancy of > 12 weeks

9. Ability to comply with the requirements of the study

Each patient eligible to participate in this study must NOT meet any of the following exclusion criteria:

1. A diagnosis of acute promyelocytic leukemia

2. History of prior malignancy, with the exception of either a history of MDS or MDS/MPN that has transformed to AML, or other prior malignancy that was treated with a full curative intent and no evidence of recurrence within the past 2 years (eg, localized skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score = 6 prostate cancer)

3. Antecedent MPN including myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myelogenous leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation

4. Known central nervous system involvement by leukemia

5. WBC count > 25 x 10^9/L (treatment with hydroxyurea, up to 2 g/m^2 total dose of cytarabine, or leukapheresis are allowed for cytoreduction until initiation of study drug)

6. Autologous stem cell transplant = 3 months prior to screening or chimeric antigen T-cell therapy = 6 months prior to screening

7. Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD), or requiring immunosuppressive drugs for treatment of GVHD, or have taken calcineurin inhibitors within 4 weeks prior to consent

8. Use of the following substances prior to the first dose of study drug:

a. = 28 days prior to the first dose of study drug
- Any biologic and/or immunologic-based therapy (including, but not limited to, monoclonal antibody therapy and/or cancer vaccine therapy)

b. = 14 days prior to the first dose of study drug
- Systemic chemotherapy or radiation therapy (except for hydroxyurea or cytarabine used for cytoreduction)

c. = 7 days prior to the first dose of study drug
- Any tyrosine kinase inhibitor, isocitrate dehydrogenase (IDH1/2) inhibitor or other targeted small molecule (with 5 half-lives = 7 days) given with antineoplastic intent

9. Active fungal, bacterial, and/or viral infection requiring systemic therapy

NOTE: Oral antibiotics for minor bacterial infections are allowed.

10. Prior therapy with a Bcl-2 inhibitor

11. Major surgery = 28 days before the first dose of study treatment

12. Toxicity from prior anticancer therapy that has not recovered to = Grade 1 (except for alopecia, anemia, neutropenia, and thrombocytopenia).

13. Clinically significant cardiovascular disease including the following:
a. Myocardial infarction = 6 months before screening
b. Unstable angina = 3 months before screening
c. New York Heart Association Class III or IV congestive heart failure (see Appendix 3)
d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
e. Heart rate-corrected QT interval > 480 milliseconds based on Fridericia’s formula
f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
g. Uncontrolled hypertension at Screening, defined as systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg by = 2 consecutive measurements

14. Chronic respiratory disease that requires continuous oxygen; history of significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or cardiovascular disease; or any other medical condition that, in the opinion of the investigator, would adversely affect his/her participation in this study

15. Known history of infection with human immunodeficiency virus (HIV). Serologic status reflecting active viral hepatitis B or viral hepatitis C infection as follows:

a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb)

NOTE: Patients with presence of HBcAb, but absence of HBsAg are eligible only if hepatitis B virus (HBV) DNA is undetectable by an assay with sensitivity = 20 IU/mL. If so, patients may undergo either regularly scheduled monitoring of HBV DNA or less frequent monitoring of HBV DNA while on prophylactic antiviral medication as defined by regional standard of care (see Section 8.3.5).

b. Presence of hepatitis C virus (HCV) antibody

NOTE: Patients with presence of HCV antibody are eligible only if HCV RNA is undetectable and if they are willing to undergo monitoring for HCV reactivation (see Section 8.3.5).

16. Current pregnancy or lactation

17. Inability to swallow tablets or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedure, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction

18. Receiving treatment with any moderate or strong CYP3A4 inhibitor (= 7 days or 5 half-lives, whichever is longer) or moderate or strong CYP3A4 inducer (= 14 days or 5 half-lives, whichever is longer) before the first dose of sonrotoclax (see Appendix 4)

19. History of stroke or intracranial hemorrhage = 6 months before the first dose of study drug

20. History of hypersensitivity to an excipient or active ingredient of the sonrotoclax tablet, azacitidine, or for the Part 3 DDI cohort only, posaconazole

21. History of a severe bleeding disorder such as hemophilia A, hemophilia B, or von Willebrand disease, or history of unexplained spontaneous bleeding requiring blood transfusion or other medical or surgical intervention

22. This exclusion criterion was deleted.

23. Receiving treatment with warfarin

24. Vaccination with a live vaccine = 35 days before first dose of study drug

NOTE: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

25. Inability to comply with study procedures

26. Concurrent treatment with sirolimus, HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (eg, atorvastatin, lovastatin, and simvastatin) and/or ergot alkaloids while receiving posaconazole (Part 3 DDI cohort only)

Patients are eligible to be included in the study only if they meet all the following criteria:

1. Patients must sign the ICF and be capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

2. Patients must be = 18 years of age, inclusive, at the time of signing the informed consent.

3. Patients must have confirmed diagnosis of CLL/SLL that meets the iwCLL criteria (Hallek et al 2018, Appendix 7 ).

The prior documented CLL or SLL diagnosis that meets the iwCLL criteria (Hallek et al 2018) will be eligible.

4. Patient must have received = 1 prior therapy for CLL/SLL. For each line of therapy, patients must receive at least 2 cycles of this therapy.

For patients who received a BCL2i, only those with CLL/SLL who received BCL2i in the first-line setting with fixed duration therapy, have a remission for = 3 years, and have a time interval of = 2 years from the last dose of BCL2i to screening, are eligible. Patients should be informed about their options to choose other approved CLL/SLL therapies in this setting.

5. Indication for CLL/SLL therapy is met by one of the criteria per the iwCLL 2018 criteria, modified as follows:

^a Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Hemoglobin concentrations < 11 g/dL or platelet counts < 100 x 10^9 cells/L are generally regarded as indications for treatment.

^b Massive/progressive, or symptomatic splenomegaly.

^c Massive/progressive or symptomatic lymphadenopathy.

^d Progressive lymphocytosis with an increase of = 50% over a 2-month period, or LDT < 6 months.

NOTE: LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initial blood lymphocyte counts < 30 x 10^9 cells/L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (eg, infections and steroid administration) should be excluded.

^e Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, and spine).

^f Disease-related symptoms as defined by any of the following:

- Unintentional weight loss = 10% within the previous 6 months.

- Significant fatigue (cannot work or unable to perform usual activities).
NOTE: Patients with significant fatigue cannot have an ECOG Performance Status score of 0.

- Fevers = 100.5 Grad F or = 38.0 Grad C for = 2 weeks without evidence of infection.

- Night sweats for = 1 month without evidence of infection.

6. ECOG Performance Status score 0, 1, or 2.

7. Adequate marrow function as defined by:

^a Absolute neutrophil count = 1.0 x 10^9 cells/L with an exception for patients with bone marrow involvement, in which case the absolute neutrophil count must be = 0.75 x 10^9 cells/L (without growth factor support within the past 7 days).

^b Platelet counts = 75 x 109 cells/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet count should be = 30 x 10^9 cells/L (without growth factor support or transfusion within the past 7 days).

^c Hemoglobin > 75 g/L (may be posttransfusion).

8. Adequate liver function as indicated by AST and ALT = 2.5 x ULNs value; serum total bilirubin =1.5 x ULNs (unless documented Gilbert syndrome where total bilirubin = 3 x ULNs).

9. Adequate renal function, defined by a value = 30 mL/min, determined either by creatinine clearance directly measured with a 24-hour urine collection or via estimated GFR calculated according to the CKD-EPI equation (Appendix 15).

10. Life expectancy > 6 months.

11. Female patients of childbearing potential must be willing to use a highly effective method of birth control and refrain from egg donation for the duration of the study and for at least 7 days after the last dose of sonrotoclax, = 30 days after last dose of venetoclax, = 12 months after the last dose of rituximab, or = 18 months after last dose of obinutuzumab, whichever is later. They must also have a negative highly sensitive urine or serum pregnancy test result = 7 days before randomization as well as within 72 hours prior to first dose of the study drug. (Section 8.3.5)

Note: A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming postmenopausal) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy (Appendix 2)

12. Nonsterile male patients must be willing to use a condom and refrain from sperm donation for the duration of the study and for at least 7 days after the last dose of sonrotoclax, = 30 days after last dose of venetoclax, = 12 months after the last dose rituximab, or = 18 months after last dose of obinutuzumab, whichever is later. See Appendix 2 for details on contraceptive guidelines.

Note: A sterile male patient is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. Male patients with known "low sperm counts" (consistent with "subfertility") are not to be considered sterile for purposes of this study.

Patients are excluded from the study if they meet any of the following criteria:

1. Known active prolymphocytic leukemia or currently suspected Richter’s transformation (biopsy based on clinical suspicion may be needed to rule out transformation).

2. Patients who have active symptomatic COVID-19 infection.

3. Patients who are unable to comply with the requirements of the protocol.

4. Known central nervous system involvement by CLL/SLL.

5. Prior autologous stem cell transplant < 3 months after transplant; or prior CAR-T therapy < 3 months after cell infusion

Note: Patients who received autologous transplant or CAR-T therapy more than 3 months after transplant or cell infusion without clear complications will be eligible.

6. Prior allogeneic stem cell transplant with active GVHD, requiring immunosuppressive drugs for treatment of GVHD, or have taken calcineurin inhibitors within 4 weeks prior to consent.

7. Received any of the following agents within the defined days below prior to the first dose of the study drug, or has not recovered to at least Grade 2 or better clinically significant adverse effect(s)/toxicity(s) of the previous therapy:

- Received anticancer therapy including chemotherapy or radiation therapy within 14 days prior to the first dose of the study drug.

- Received targeted inhibitors within the 5 half-lives of the specific agent prior to the first dose of the study drug. Targeted inhibitors are defined as small-molecule inhibitors that target proteins that control how cancer cells grow, divide, and/or spread. Examples of common targeted inhibitors used to treat CLL/SLL are BTKi, BCL2i, and PI3Ki.

- Received mAb directed to cancer within 28 days prior to the first dose of the study drug.

- Received corticosteroid more than equivalent prednisone dose of 60 mg daily for antineoplastic intent within 5 days prior to the first dose of the study drug unless it is used to control BTKi withdrawal flare.

8. Patients with a history of confirmed progressive multifocal leukoencephalopathy.

9. Severe or debilitating pulmonary disease, defined as diffusing lung capacity for carbon monoxide < 60% and/or respiratory failure requiring assisted ventilation.

10. Clinically significant cardiovascular disease including the following:

- Myocardial infarction within 6 months before screening.

- Unstable angina within 3 months before screening.

- New York Heart Association class III or IV congestive heart failure (Appendix 16).

- History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes).

- QTcF > 480 msecs based on Fridericia’s formula.

NOTE: QTcF value should be calculated as the numerical average of up to 3 separate readings for eligibility.

- History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.

- Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing an average systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening.

11. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring active treatment. If this immune cytopenia is controlled, patients will be eligible.

12. History of prior or active malignancy within the past 18 months, except for conditions as listed below and as long as patients have recovered from the acute side effects incurred because of previous therapy:

- Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated cervical carcinoma in situ without evidence of disease.
- Localized prostate cancer with Gleason score = 6 or controlled prostate cancer with androgen deprivation treatment.
- Treated early-stage breast cancer with or without hormonal therapy.

13. Active fungal, bacterial, and/or viral infection requiring systemic therapy at the time of study treatment initiation.

14. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products.

15. Hypersensitivity to sonrotoclax, obinutuzumab, venetoclax, rituximab, or any of its excipients (eg, trehalose) that prohibit to use these agents per investigator’s opinion.

16. Any patient who is pregnant or breastfeeding will not be eligible for the study.

17. Vaccination with a live vaccine = 4 weeks before the first dose of the study treatment.

Note: Inactivated vaccines (eg, seasonal vaccines for influenza) are allowed. Intranasal vaccines are live vaccines and are not allowed = 4 weeks before the first dose of the study treatment (see also Section 6.9.2.2 Prohibited Medications)

18. Patients with underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study treatment, will affect the explanation of drug toxicity or AEs, or will result in insufficient or impaired compliance with study conduct.

19. Positive serologic status reflecting active hepatitis B or C infection or positive HIV serology as follows:

- Presence of HBsAg.

- Patients with presence of HBcAb, in the absence of HBsAg, with detectable HBV DNA.

NOTE: The limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL (Section 8.1.2). Patients with the presence of HBcAb but undetectable HBV DNA and if they are willing to undergo HBV DNA monitoring per protocol requirement for HBV reactivation (every cycle for patients receiving no prophylactic antiviral therapy or 12 weeks for patients receiving prophylactic antiviral therapy) are eligible.

- Patients with the presence of HCV antibody and HCV RNA detectable (NOTE: The limit of detection for HCV RNA must have a sensitivity of < 15 IU/mL; Section 8.1.2). Patients with the presence of HCVAb and undetectable HCV RNA and if willing to undergo HCV RNA monitoring per protocol requirement for HCV reactivation (every cycle) are eligible.

- Positive HIV antibody.

20. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in the study.

21. Unable to swallow capsules or tablets or diseases significantly affecting the GI function, such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

22. Receiving treatment with any moderate or strong CYP3A4 inhibitor, or moderate or strong CYP3A4 inducer (= 14 days or 5 half-lives, whichever is shorter) before the first dose of sonrotoclax/venetoclax, or requiring ongoing treatment with a moderate or strong CYP3A inhibitor or a moderate/strong CYP3A inducer at the study entry.

23. Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment.

24. Antineoplastic therapy with Chinese traditional medicine or antibody-based therapies within 4 weeks of the start of the study drug.

Patients are eligible to be included in the study only if they meet all the following criteria:

1. Provision of signed and dated written informed consent prior to any study-specific procedures, sampling, or data collection.

2. Age = 18 years (or age = 20 years for patients in Part 1e).

3. Confirmed diagnosis (per World Health Organization [WHO] guidelines, unless otherwise noted) of one of the following:

a. Patients with R/R MZL (Phase 1 Parts 1a, 1b, 1c, 1e, and 1f; and Phase 2 Cohort 4 only) or with treatment-naive MZL (ONLY for Phase 1 Part 1f at non-EU sites) and all of the following:

i. Extranodal, splenic, or nodal MZL.

ii. R/R MZL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen).

(1) For patients enrolling at US sites ONLY: patients must have been treated with a covalent BTKi and an anti-CD20 monoclonal antibody in any line of therapy to be eligible for the study.

(2) For patients enrolling at EU sites ONLY: patients must have been treated with an anti-CD20 monoclonal antibody in any line of therapy to be eligible for the study.

(3) For patients enrolling at United Kingdom (UK) sites: enrollment is limited to patients who are intolerant of or refuse standard therapy, or for whom no approved therapy with demonstrated clinical benefit is indicated or available.

(4) For Part 1f, patients must NOT have been treated with a BTKi (covalent or noncovalent) since the time of diagnosis. Patients are not required to have had prior therapy (ie, patients can be treatment naive), except at EU sites, where patients must have disease that relapsed after, or was refractory to, = 1 prior lines of therapy including anti-CD20 therapy.

(5) Patients who discontinued anti-CD20 antibody therapy due to related severe or life-threatening adverse events, such as anaphylaxis, are not required to have received 2 consecutive cycles of that therapy.

iii. Active disease requiring treatment

b. Patients with R/R FL (Phase 1 Parts 1a, 1c, and 1e; and Phase 2 Cohort 5 only) and all of the following:

i. Grade 1, 2, or 3a based on the WHO 2008 classification of tumors of hematopoietic and lymphoid tissue.

ii. R/R FL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen).
Note: prior therapy must include = 1 line of therapy containing an anti-CD20 monoclonal antibody.

(1) For patients enrolling at UK sites: enrollment is limited to patients who are intolerant of or refuse standard therapy, or for whom no approved therapy with demonstrated clinical benefit is indicated or available.

(2) Patients who previously received but discontinued anti-CD20 antibody therapy due to related severe or life-threatening adverse events, such as anaphylaxis, are not required to have received 2 consecutive cycles of that therapy.

iii. Active disease requiring treatment.

c. Patients with R/R MCL (Phase 1 Parts 1a, 1b, 1e, and 1f; and Phase 2 Cohort 2 only) or with treatment-naive MCL (ONLY for Phase 1 Part 1f at non-EU sites) and all of the following:

i. [Exclusion Criterion deleted to remove the requirement for baseline tumor tissue for central pathology confirmation of MCL diagnosis for Phase 2 Cohort 2]

ii. R/R MCL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of systemic therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen).

(1) Patients must have been treated with a covalent BTKi (eg, ibrutinib, acalabrutinib, or zanubrutinib; as monotherapy or in combination with other anticancer agents) in any line of therapy and anti-CD20 monoclonal antibody in any line of therapy.

(2) For patients enrolling at UK sites: enrollment is limited to patients who are intolerant of or refuse standard therapy, or for whom no approved therapy with demonstrated clinical benefit is indicated or available.

(3) For Phase 2 Cohort 2 only, patients must have received their last BTKi (covalent or noncovalent) for = 6 consecutive months since BTKi treatment initiation except if discontinued earlier for reasons other than disease progression.

(4) For Part 1f ONLY, patients must NOT have been treated with a BTKi (covalent or noncovalent) since the time of diagnosis. Patients are not required to have had prior therapy (ie, patients can be treatment naive), except at EU sites, where patients must have disease that relapsed after, or was refractory to, = 1 prior lines of therapy including anti-CD20 therapy.

(5) Patients who previously received but discontinued anti-CD20 antibody therapy due to related severe or life-threatening adverse events, such as anaphylaxis, are not required to have received 2 consecutive cycles of that therapy.

iii. Requiring treatment in the opinion of the investigator.

d. Patients with R/R CLL/SLL (Phase 1 Parts 1a, 1b, 1d, 1e, and 1f; and Phase 2 Cohort 1 ONLY) or with treatment-naive CLL/SLL (ONLY for Phase 1 Part 1f) and all of the following:

i. R/R CLL/SLL diagnosis that meets the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria (Hallek et al 2018).

ii. R/R CLL/SLL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen).

(1) In Part 1a, 1b, and 1e, patients enrolling at the US, EU, Japanese, and Australian sites ONLY must have been treated with a covalent BTKi (eg, ibrutinib, acalabrutinib, or zanubrutinib; as monotherapy or in combination with other anticancer agents) in any line of therapy.

(2) For enrollment at UK sites: enrollment is limited to patients who are intolerant of or refuse standard therapy, or for whom no approved therapy with demonstrated clinical benefit is indicated or available.

(3) In Part 1f ONLY, patients must not have been treated with a BTKi (covalent or noncovalent) since the time of diagnosis and are not required to have had prior therapy (ie, patients can be treatment naive).

iii. In Part 1d and Phase 2 Cohort 1 (starting with Protocol Amendment 7), all patients must have been treated with a covalent BTKi (eg, ibrutinib, acalabrutinib, or zanubrutinib; as monotherapy or in combination with other anticancer agents) and a Bcl-2 inhibitor (eg venetoclax as monotherapy or in combination with other anticancer agents) in any line of therapy.

iv. Requiring treatment as defined by = 1 of the following criteria:

(1) Requires treatment in the opinion of the investigator or meets criteria for initiation of a subsequent line of therapy per the 2018 iwCLL criteria, including substantial persistent disease burden following a prior line of therapy or the lack of resolution of the indication for a prior line of therapy.

(2) Evidence of progressive marrow failure as manifested by the development or worsening of anemia and/or thrombocytopenia.

(3) Massive (ie, = 6.0 cm below left costal margin), progressive, or symptomatic splenomegaly.

(4) Massive (ie, = 10.0 cm in longest diameter), progressive, or symptomatic lymphadenopathy.

(5) Progressive lymphocytosis with an increase of = 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. The LDT may be determined by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initial blood lymphocyte counts < 30 x 10^9 /L (30,000/MikroL) may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis or lymphadenopathy other than R/R CLL/SLL (eg, infection, steroid administration, BTKi treatment) should be excluded.

(6) Autoimmune complications, including anemia or thrombocytopenia that respond poorly to steroids or other systemic therapies.

(7) Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine).

(8) Disease-related symptoms defined as any of the following:
a. Unintentional weight loss = 10% within the previous 6 months.
b. Significant fatigue (ie, ECOG Performance Status 2 or worse; cannot work or unable to perform usual activities).
c. Fevers = 100.5 Grad F or 38 Grad C for = 2 weeks without evidence of infection.
d. Night sweats for = 1 month without evidence of infection.

e. Patients with R/R WM (Phase 1 Parts 1a, 1b, 1c, 1e, and 1f; and Phase 2 Cohort 3 only) or with treatment-naive WM (ONLY for Phase 1 Part 1f) and all of the following:

i. Clinical and definitive histological diagnosis.
ii. R/R WM is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen).
iii. = 1 line of therapy containing an anti-CD20 monoclonal antibody.

(1) For patients enrolling at US, EU, Japanese, and Chinese sites ONLY:
patients must also have been treated with a covalent BTKi in any line of therapy to be eligible for the study.

(2) For patients enrolling at UK sites: enrollment is limited to patients who are intolerant of or refuse standard therapy, or for whom no approved therapy with demonstrated clinical benefit is indicated or available.

(3) For Part 1f ONLY: patients must not have previously received a BTKi (covalent or noncovalent) since the time of diagnosis and are not required to have had prior therapy (ie, patients can be treatment naive).

(4) Patients who previously received but discontinued anti-CD20 antibody therapy due to related severe or life-threatening adverse events, such as anaphylaxis, are not required to have received 2 consecutive cycles of that therapy.

iv. Meeting = 1 criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenström Macroglobulinemia (Dimopoulos et al 2014):
(1) Recurrent fever, night sweats, weight loss, fatigue.
(2) Hyperviscosity.
(3) Lymphadenopathy that is either symptomatic or bulky (= 5 cm in maximum diameter).
(4) Symptomatic hepatomegaly and/or splenomegaly.
(5) Symptomatic organomegaly and/or organ or tissue infiltration.
(6) Peripheral neuropathy due to WM.
(7) Laboratory indications for initiation of therapy.
(a) Symptomatic cryoglobulinemia.
(b) Cold agglutinin anemia.
(c) Immune hemolytic anemia and/or thrombocytopenia or nephropathy related to WM.
(d) Amyloidosis related to WM.
(e) Hemoglobin = 10 g/dL.
(f) Platelet count < 100 x 10^9/L.

f. Patients with R/R DLBCL (Phase 1 Parts 1a and 1c and Phase 2 Cohort 6 only) and all of the following:

- Nongerminal center B-cell DLBCL not otherwise specified (non-GCB-DLBCL NOS), as defined by IHC per the Hans algorithm (Hans et al 2004). A previously locally performed gene expression profiling assay designed to identify the lymphoma cell-of-origin, such as the NanoString Lymphoma Subtyping Test (Seattle, WA, USA), may be substituted to determine non-GCB pathology.

i. R/R DLBCL is defined as relapsed after, or was refractory to, = 2 prior lines of systemic therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen).

(1) Patients must have been treated with an anthracycline and an anti-CD20 monoclonal antibody.
(2) Patients who are not candidates for or refuse intensive chemotherapy, hematopoietic stem cell transplant, and CAR-T-based regimens are eligible for this study.
(3) Patients who have previously received allogenic or autologous stem cell transplantation or CAR-T-based regimens are eligible for this study.
(4) Patients must not require concurrent CNS-directed therapy or prophylaxis with systemic or intrathecal chemotherapy or radiotherapy.
(5) Systemic chemotherapy followed by autologous or allogeneic SCT will be considered as 1 line of systemic therapy.
(6) For patients enrolling at UK sites: enrollment is limited to patients who are intolerant of or refuse standard therapy, or for whom no approved therapy with demonstrated clinical benefit is indicated or available.
(7) Patients who previously received but discontinued anti-CD20 antibody therapy due to related severe or life-threatening adverse events, such as anaphylaxis, are not required to have received 2 consecutive cycles of that therapy.

g. Patients with RT to DLBCL (Phase 1 Parts 1a, 1c, and 1f; and Phase 2 Cohort 7 ONLY) and all of the following:

i. History of R/R CLL/SLL diagnosis that meets the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria (Hallek et al 2018).

(1) Patients enrolling at US, EU, and Australian sites ONLY must have been treated with a covalent BTKi (eg, ibrutinib, acalabrutinib, or zanubrutinib; as monotherapy or in combination with other anticancer agents) in any line of therapy for prior R/R CLL/SLL diagnosis or for RT diagnosis.

(2) For patients enrolling at UK sites: enrollment is limited to patients who are intolerant of or refuse standard therapy, or for whom no approved therapy with demonstrated clinical benefit is indicated or available.

(3) For Part 1f ONLY: patients must NOT have previously received a BTKi (covalent or noncovalent) since the time of diagnosis and are not required to have had prior therapy (ie, patients can be treatment naive).

(4) Patients with history of RT now with progressive CLL/SLL may be included.

ii. Confirmed histopathological diagnosis of RT to DLBCL.

iii. R/R RT is defined as disease that relapsed after, or was refractory to, = 1 prior line of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen) administered for RT.

iv. Part 1f ONLY: Patients must NOT have previously received a BTKi (covalent or noncovalent) for RT since the time of diagnosis. Patients are not required to have had prior therapy (ie, patients can be treatment naive), except in the EU, where they must have disease that relapsed after, or was refractory to, = 1 prior line of therapy including anti-CD20 therapy.

4. For patients who have previously received a BTKi:

a. Parts 1a, 1b, 1c, 1d, and 1e only: Patients who have experienced disease progression during or after = 1 regimen containing a covalent BTKi are eligible for the dose-finding cohorts.

b. Parts 1a, 1b, 1c, 1e, and Phase 2: Patients may (but do not have to) have been treated with noncovalent BTKi(s) to be eligible.

c. Parts 1a, 1b, 1c, 1d, 1e, and Phase 2: Received treatment with a BTKi as monotherapy or in combination with other anticancer agents for = 8 consecutive weeks (= 6 consecutive months for Phase 2 Cohort 2), except if discontinued earlier for intolerance.

d. Parts 1a, 1b, 1c, 1d, 1e, and Phase 2: Discontinued the previous BTKi due to disease progression, toxicity, or intolerance OR experienced progression after completing treatment with the BTKi.

e. Phase 2, Cohorts 1, 2, and 3 only: Had disease progression on only 1 regimen containing a covalent BTKi (Note: Patients may have received treatment with = 2 different covalent BTKi if additional covalent BTKis were discontinued secondary to an event other than disease progression.)

f. Phase 2 Cohort 1 (CLL/SLL) only: Patients may have discontinued the previous BTKi (either covalent or noncovalent) or Bcl-2 inhibitor due to disease progression, toxicity, completion of treatment course, or intolerance OR experienced progression after completing treatment with the BTKi or Bcl-2 inhibitor.

5. All patients in Phase 1 Parts 1a, 1b, 1c, 1d, 1e, and 1f and Phase 2 must have measurable disease defined as follows:

a. R/R CLL/SLL: = 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular dimensions (assessed by computed tomography [CT]/magnetic resonance imaging [MRI]) OR a minimum ALC of 5.0 x 10^9/L. NOTE: The presence of measurable disease is NOT required for patients with CLL in Parts 1a, 1b, 1d, 1e, or 1f only.

b. NHL: = 1 lymph node > 1.5 cm in longest diameter OR 1 extranodal lesion > 1.0 cm in the longest diameter, measurable in 2 perpendicular dimensions (assessed by CT/MRI).
i. For patients with MZL, isolated splenomegaly is considered measurable disease for the purposes of eligibility for this study (assessed by CT/MRI).
ii. For patients with R/R MCL in Parts 1a, 1b, 1e, and 1f, isolated splenomegaly is considered measurable disease for the purposes of eligibility for this study (assessed by CT/MRI).

c. WM: serum or plasma IgM level > 0.5 g/dL.

6. ECOG Performance Status of 0 to 2 (For EU only: ECOG Performance Status of 0 to 1).

7. Adequate organ function defined as follows (based on the results during the screening period):

a. Absolute neutrophil count (ANC) = 1.0 x 10^9/L. There is an exception for patients with bone marrow involvement, in which case ANC must be = 0.75 x 10^9/L. Patients in either scenario must be free from growth factor support as evidenced by an ANC dated = 14 days following the most recent administration of peg-filgrastim (or other pegylated myeloid growth factors)
and = 4 days following the most recent administration of filgrastim or other myeloid growth factors.

b. Platelets = 50 x 10^9/L (= 50,000/mm^3). There is an exception for patients with bone marrow involvement, in which case platelet count must be = 25 x 10^9/L (= 25,000/mm^3). Patients must be free from growth factor support for = 7 days and/or transfusion for = 3 days.

c. Hemoglobin = 80 g/L (independent of growth factor support or transfusion, defined as no growth factor support for = 7 days and/or transfusion for = 3 days). Patients may have hemoglobin < 80 g/L with or without growth factor or transfusion if the reduced hemoglobin is due to bone marrow involvement.

d. Coagulation meeting all of the following:
International normalized ratio (INR) = 1.5 (patients on therapeutic anticoagulation may have an INR that is > 1.5 as long as it is within the therapeutic range for the medication that they are receiving. Note: Use of warfarin or other vitamin K antagonists is NOT permitted for patients in this study; see Exclusion Criterion 24.)

Activated partial thromboplastin time (aPTT) = 1.5 x upper limit of normal (ULN) (patients on therapeutic anticoagulation may have aPTT > 1.5 x ULN as long as it is within the therapeutic range for the medication that they are receiving).

EU Only: patients on anticoagulation must be on a stable dose for 7 days or longer prior to start of study medication for Parts 1a and 1b.

Note: Patients with factor inhibitors that prolong prothrombin time/activated partial thromboplastin time without increasing the bleeding risk or those with lupus anticoagulant or acquired von Willebrand syndrome due to WM can be enrolled. In countries other than the UK, a discussion with the medical monitor or designee is required before enrollment.

e. Glomerular filtration rate (GFR) or creatinine clearance (CrCl) = 30 mL/min as estimated using Chronic Kidney Disease Epidemiology Collaboration equation 2021 (Appendix 4).

f. Adequate pancreatic function.
i. Serum or plasma amylase = 1.5 x ULN. Note: Testing of amylase will not be required for any sites that cannot perform this test locally.
ii. Serum or plasma lipase = 1.5 x ULN.

g. Adequate liver function indicated by the following:
i. Aspartate aminotransferase (AST)/serum or plasma glutamic-oxaloacetic transaminase = 2 x ULN.
ii. Alanine aminotransferase (ALT)/serum or plasma glutamic-pyruvic transaminase = 2 x ULN.
iii. Total bilirubin level = 1.5 x ULN (unless documented Gilbert syndrome) and direct bilirubin level = 1.0 x ULN for patients with documented Gilbert syndrome.

8. Women of childbearing potential must have 2 negative pregnancy tests: a serum or plasma test within 10 to 14 days before the first dose of BGB-16673 and a serum, plasma, or urine pregnancy test within 24 hours prior to the first dose of BGB-16673. In addition, they must use a highly effective method of birth control initiated before the first dose of the study drug, for the duration of the study treatment period, and for = 30 days after the last dose of the study drug. See Appendix 2 for highly effective methods of birth control and the definition of childbearing potential.

9. Nonsterile men must use a highly effective method of birth control for the duration of the study treatment period and for = 30 days after the last dose of the study drug. During this same period, they must not donate sperm. See Appendix 2 for highly effective methods of birth control and the definition of sterile.

10. Life expectancy of > 6 months.

11. Ability to provide written informed consent and to understand and comply with the requirements of the study. Patients with psychiatric conditions or cognitive dysfunction that would preclude providing independent informed consent are NOT eligible for the study.

Each patient who is eligible to participate in this study must NOT meet any of the following exclusion criteria:

1. Prior malignancy (other than the disease under study) within the past 2 years, except in situ malignancies that have been curatively resected, localized breast cancer treated with curative intent with no evidence of active disease for more than 3 years and receiving adjuvant hormonal therapy, localized Gleason score = 6 prostate cancer undergoing observation or treatment with androgen deprivation, or any other cancer treated with curative intent, not on adjuvant treatment, and in the opinion of the investigator is unlikely to recur.

2. Requires ongoing systemic treatment for any other malignancy (except as noted in Exclusion Criterion 1).

3. Any life-threatening illness, medical condition, organ system dysfunction, need for profound anticoagulation, or bleeding disorder, which, in the investigator’s opinion, could compromise the patient’s safety or confound the interpretation of safety or efficacy data.

4. Requires ongoing systemic (defined as = 10 mg/day of prednisone or equivalent) corticosteroid treatment. Systemic corticosteroids must be discontinued = 7 days before the first day of study drug treatment. For patients in Phase 1 or Phase 2 Cohorts 6 and 7, a short course (= 7 days prior to start of study drug treatment) is allowed if needed to control lymphoma-related symptoms and it is tapered off within 5 days after initiation of study treatment. (Note: Use of inhaled corticosteroids for primary pulmonary disorders and topical or ophthalmic corticosteroids are not considered systemic treatments and DO NOT meet protocol exclusion criteria).

5. Current or history of central nervous system involvement including the brain, spinal cord, leptomeninges, and cerebrospinal fluid (as documented by imaging, cytology, or biopsy) by B-cell malignancy, regardless of whether patient had received treatment for central nervous system disease.

6. Known active plasma cell neoplasm, prolymphocytic leukemia, T-cell lymphoma (including T-cell/histiocyte-rich large B-cell lymphoma), Burkitt lymphoma, AIDS-related B-cell lymphoma, Castleman disease, posttransplant lymphoproliferative disorders, hairy cell leukemia, GCB DLBCL, EBV+ DLBCL NOS, primary DLBCL of the CNS, primary cutaneous DLBCL – leg type,
DLBCL associated with chronic inflammation, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, primary effusion lymphoma, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, high-grade B-cell lymphoma - NOS, B-cell lymphoma unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma, or history of or currently suspected transformation of an indolent lymphoma to an aggressive histology (except for patients with Richter Transformation to DLBCL who are eligible for Part 1a, 1c, 1f, or Phase 2 Cohort 7 and patients with history of follicular lymphoma transforming to non-GCB DLBCL who are eligible for Part 1a, 1c, or Phase 2 Cohort 6).

7. Prior autologous stem cell transplant unless = 3 months after transplant.

8. Prior CAR-T unless = 6 months after cell infusion.

9. Prior allogeneic stem cell transplant = 6 months before the first dose of the study drug (Note: patients who have previously received allogeneic stem cell transplant must have no signs or symptoms of graft versus host disease and must not be receiving immunosuppressive therapy.)

10. Use of the following substances prior to the first dose of the study drug:

a. = 28 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug:
i. Any biologic and/or immunologic-based anticancer therapy(ies) including experimental therapy(ies) (including but not limited to monoclonal antibody therapy such as rituximab and/or cancer vaccine therapy).

b. = 14 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug:
i. Systemic chemotherapy or radiation therapy.

c. = 7 days before the first dose of the study drug:
i. Corticosteroid given with antineoplastic intent (symptom control will not be considered as antineoplastic intent).

d. = 7 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug:
i. BTKi, tyrosine kinase inhibitor, or other targeted small molecules given with antineoplastic intent.

11. [Criterion deleted to remove restrictions around use of CYP3A inhibitors and inducers.]

12. Active fungal, bacterial, and/or viral infection requiring systemic therapy. Note: Patients with infections that are managed by oral antibiotics who are otherwise clinically stable are not excluded from study participation.

13. Coadministration of herbal or homeopathic medication administered with antineoplastic intent is not permitted while on study treatment. Patients must discontinue all herbal or homeopathic medications being administered with antineoplastic intent = 28 days prior to initiating study treatment.

14. Major surgery = 4 weeks before the first dose of study treatment.

15. Toxicity from prior anticancer therapy that has not recovered to = Grade 1 (except for alopecia, ANC, absolute lymphocyte count, hemoglobin, and platelet count; for guidance regarding ANC, absolute lymphocyte count, hemoglobin, and platelet count, see inclusion criteria above).

16. Clinically significant cardiovascular disease including the following:
a. Myocardial infarction = 6 months before screening.
b. Unstable angina = 3 months before screening.
c. History of or active clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes).
d. New York Heart Association class III or IV congestive heart failure (see Appendix 13).
e. Heart rate-corrected QT interval based on Fridericia’s formula (QTcF) > 480 milliseconds. Patients with bundle branch block can be allowed after discussion with the medical monitor.
f. History of or active Mobitz II second- or third-degree heart block without a permanent pacemaker in place.
g. Uncontrolled hypertension as indicated by = 2 consecutive blood pressure measurements, at screening, showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg. For Parts 1a and 1b, EU only: uncontrolled Grade 3 hypertension is defined as systolic blood pressure = 160 mmHg and diastolic blood pressure = 100 mmHg, or lower grade
hypertension where dose of antihypertensives, if administered, is not stable for at least 14 days.

17. Known infection with human immunodeficiency virus (HIV) or serologic status reflecting active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as follows:

a. Presence of viral hepatitis B surface antigen (HBsAg) or viral hepatitis B core antibody (HBcAb).

Note: Patients with the presence of HBcAb, but the absence of HBsAg, are eligible if HBV DNA is undetectable (the limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL), and patients must be willing to undergo monitoring for HBV reactivation (see Section 8.1.5). Patients who are positive for hepatitis B surface antibody (HBsAb) secondary to a history of vaccination against HBV are eligible.

b. Presence of HCV antibody.

Note: Patients with the presence of HCV antibody are eligible if HCV RNA is undetectable (the limit of detection for HCV RNA testing must have a sensitivity of < 15 IU/mL), and patients must be willing to undergo monthly monitoring for HCV reactivation (see Section 8.1.5).

c. [Criterion deleted].

18. Pregnant or lactating women.

19. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel (except in Part 1f), bariatric surgery procedure, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

20. Inability to comply with study procedures.

21. History of stroke or intracranial hemorrhage = 6 months before the first dose of the study drug.

22. Concurrent treatment for the disease under study outside this clinical study.

23. Requires treatment with warfarin or other vitamin K antagonists.

24. Ongoing drug-induced liver injury, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.

25. History of a severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease (see Inclusion Criterion 7d regarding patients with acquired von Willebrand syndrome due to WM), or history of spontaneous bleeding requiring blood transfusion or other medical intervention.

26. NOTE: Original Exclusion Criterion 27 has been removed.

27. Vaccination with a live vaccine = 35 days before the first dose of the study drug
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

28. Prior treatment with BGB-16673 or any other compound where the mechanism of action involves increased degradation of BTK.

29. Known hypersensitivity to any component or excipient of BGB-16673.

30. Concurrent participation in another therapeutic clinical trial (for any indication).

Patients are eligible to be included in the study only if they meet all the following criteria:

1. Patients (or legal representative[s] where permitted; see Section 10.3.1 for details) must sign the ICF and be capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

2. Patients must be = 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of signing the informed consent.

3. Patients have confirmed diagnosis (per WHO guidelines, unless otherwise noted) of a R/R B-cell malignancy including the following:

NOTE: Relapse is defined by the reappearance of any disease-related symptoms (including clinical, biological, or radiological), progression of the disease during treatment, or the absence of response achieved with the immediate last treatment. Refractory disease is defined by disease relapse during an interval of = 6 months between the last dose of the immediate prior treatment and the first dose of the current study treatment.

a. CLL/SLL that meets the iwCLL criteria. [8]
i. R/R CLL/SLL is defined as disease that relapsed after, or was refractory to, = 1 prior line of therapy [= 2 prior lines of therapy in the EU] (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen).
Note that Substudy 1 includes a safety expansion cohort (Part 1b) for patients with TN CLL/SLL (details provided in the corresponding substudy protocol).

b. DLBCL meeting all the following criteria:
i. Non-GCB-DLBCL-NOS, as defined by IHC per the Hans algorithm. [13] A previously locally performed gene-expression profiling assay designed to identify the lymphoma cell-of-origin may be substituted to determine non-GCB pathology.
ii. Relapsed after, or was refractory to, = 2 prior lines of systemic therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)
iii. Patients must have been treated with an anthracycline-based regimen and an anti-CD20 monoclonal antibody-based regimen
iv. Patients who are not candidates for or refuse intensive chemotherapy, hematopoietic stem cell transplant, and chimeric antigen receptor T cell (CAR-T) based regimens are eligible for this study
v. Patients must not require concurrent central nervous system-directed therapy or prophylaxis with systemic or intrathecal chemotherapy or radiotherapy
vi. Systemic chemotherapy followed by autologous or allogeneic stem cell transplantation will be considered as 1 line of systemic therapy

c. FL: Grade 1, 2, or 3a based on the WHO 2008 classification of tumors of hematopoietic and lymphoid tissue
i. R/R FL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen). NOTE: Prior therapies must include = 1 line of therapy containing an alkylating agent and an anti-CD20 monoclonal antibody.
Patients with R/R FL should have an indication for treatment per their treating physician.

d. WM: must meet the clinical and definitive histological diagnosis

i. R/R WM is defined as disease that relapsed after, or was refractory to, = 1 prior lines of therapy [= 2 prior lines of therapy in the EU] (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen). NOTE: = 1 line of therapy containing an anti-CD20 monoclonal antibody (prior CD20 antibody therapy is not required for patients Substudy 1 Part 1b)

ii. Meeting = 1 criterion for treatment according to consensus panel criteria from the Eleventh International Workshop on Waldenstrom Macroglobulinemia [9]
a. Recurrent fever, night sweats, weight loss, fatigue
b. Hyperviscosity
c. Lymphadenopathy that is either symptomatic or bulky (= 5 cm in maximum diameter)
d. Symptomatic hepatomegaly and/or organ or tissue infiltration
e. Peripheral neuropathy due to WM
f. Laboratory indications for initiation of therapy:
- Symptomatic cryoglobulinemia
- Cold agglutinin anemia
- Immune-mediated hemolytic anemia and/or thrombocytopenia or nephropathy related to WM
- Amyloidosis related to WM
- Hemoglobin = 10 g/dL
- Platelet count < 100 x 10^9/L

e. MCL: Blastoid or nonblastoid-variant
i. R/R MCL is defined as disease that relapsed after, or was refractory to, = 1 prior lines of systemic therapy [= 2 prior lines of therapy in the EU] (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)
ii. Requiring treatment in the opinion of the investigator

f. MZL: must meet all the following criteria
i. Extranodal, splenic, or nodal MZL
ii. R/R MZL is defined as disease that relapsed after, or was refractory to, = 1 prior lines of therapy [= 2 prior lines of therapy in the EU] (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)
iii. Active disease requiring treatment

g. RT: must meet the following criteria:
i. History of R/R CLL/SLL diagnosis meeting the iwCLL criteria [8]
ii. Confirmed histopathological diagnosis of RT with large cell histology.
Non-LBCL histologies are not eligible.
iii. R/R RT is defined as disease that relapsed after, or was refractory to, = 1 prior line of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen) administered for RT

4. Patients must have measurable disease defined as follows:

a. For patients with CLL: = 1 abnormal parameter from Group A (including = 1 lymph node measuring = 1.5 cm in the longest diameter, OR splenomegaly, OR abnormal circulating lymphocyte count, excluding constitutional symptoms only) according to iwCLL guidelines.

b. For patients with NHL (including SLL): = 1 lymph node measuring > 1.5 cm in the longest diameter OR 1 extranodal lesion measuring > 1.0 cm in the longest diameter, measurable in 2 perpendicular dimensions (assessed by CT/MRI). Isolated splenomegaly (assessed by CT/IRM) is also considered measurable disease for the purpose of eligibility for the study (patients with MZL or MCL).

c. For patients with WM: Serum or plasma IgM level > 0.5 g/dL.

6. Patient has a life expectancy of > 3 months.

7. Patients must have a stable ECOG Performance Status of 0 to 2 [ECOG Performance Status of 0 to 1 in the EU].

8. Patients must have adequate organ function as indicated by the following laboratory values during screening:

a. Patients must not have required blood transfusion or growth factor support = 14 days before sample collection at screening for the following:
i. ANC = 1.0 x 10^9/L, except for patients with bone marrow involvement by lymphoma in which case ANC must be = 0.75 x 10^9/L
ii. Platelets = 75 x 10^9/L, except for patients with bone marrow involvement by lymphoma in which case platelets must be = 50 x 10^9/L
iii. Hemoglobin = 80 g/L

b. Serum total bilirubin = 1.5 x ULN (total bilirubin must be = 3 x ULN with conjugated bilirubin = 1.5 x ULN for patients with Gilbert syndrome)

c. Adequate liver function as indicated by AST and ALT = 3.0 x ULN

d. Amylase = 1.5 x ULN, and lipase = 1.5 x ULN

e. Adequate blood clotting function as defined by an international normalized ratio of = 1.5 x ULN and activated partial thromboplastin time of = 1.5 x ULN

Patients are excluded from the study if they meet any of the following criteria:

1. Patients with TN B-cell malignancies, except for patients in Substudy 1 Cohorts 5 and 6.

2. Patients who are unable to comply with the requirements of the protocol unless the written approval of the medical monitor has been obtained before informed consent.

3. Patients with active leptomeningeal disease or uncontrolled, untreated brain metastasis.

4. Patients with any malignancy = 2 years before first dose of study treatment except for the specific cancer under investigation in this study or any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score = 6 prostate cancer).

5. Autologous stem cell transplant = 3 months prior to screening or chimeric antigen T-cell therapy = 3 months prior to screening.

6. For Substudies 1 and 2, patients with a prior allogeneic stem cell transplant with active GVHD, or requiring immunosuppressive drugs for treatment of GVHD, or who have taken calcineurin inhibitors within 4 weeks prior to consent.

For Substudies 3 and 4, all patients with a prior allogeneic stem cell transplant.

7. Patients with active HBV by presence of HBcAb and HBsAg. Patients with presence of HBcAb, but absence of HBsAg, are eligible if HBV DNA is undetectable (Note: The limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL), and if they are willing to undergo monitoring for HBV reactivation.

8. Patients with active hepatitis C. Note: Patients with a negative HCV antibody test at screening, or a positive HCV antibody test and undetectable HCV RNA at screening (Note: The limit of detection for HCV RNA must have a sensitivity of < 15 IU/mL), and who are willing to undergo monitoring for HCV reactivation, are eligible. For patients who have recently received anti-HCV treatment, sustained virologic response by undetectable HCV RNA for at least 12 weeks must be achieved prior to enrollment.

9. Patients with HIV infection by local testing at screening. Patients who tests positive for HIV infection are eligible provided they meet all the following criteria:
a. Are stable on antiretroviral therapy for = 4 weeks before the first dose of study
treatment.
b. Agree to adhere to antiretroviral therapy per WHO guidelines.
c. Have no documented multidrug resistance that would prevent effective antiretroviral therapy.
d. Have viral load of < 400 copies per mL at screening.
e. Have CD4+ T-cell count = 350 cells/µL at screening.
f. Have no history of an AIDS-defining opportunistic infection = 12 months before the first dose of study treatment unless eligibility is agreed to by the medical monitor after consultation.
g. If prophylactic antimicrobial drugs are indicated, patients may still be eligible after discussion with the medical monitor.

10. Patients who have symptomatic COVID-19 infection.

11. Active fungal, bacterial, and/or viral infection requiring systemic therapy.

12. Patients with any major surgical procedure = 28 days before first dose of study treatment.
Patients must have recovered adequately from the procedure and/or complications from the procedure before first dose of study treatment.

13. Chronic respiratory disease that requires continuous oxygen; history of significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or cardiovascular disease; or any other medical condition that, in the opinion of the investigator, would adversely affect his/her participation in this study.

14. Patients with clinically significant cardiovascular disease, such as the following:
a. Myocardial infarction within 3 months before the first dose of study treatment
b. NYHA Classification III or IV congestive heart failure (Appendix 7)
c. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
d. QTcF > 480 milliseconds based on Fridericia’s formula. Patients with prolonged QTcF due to bundle branch block can be allowed after consultation with the cardiologists.
e. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
f. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure = 160 mmHg and diastolic blood pressure = 100 mmHg at screening

16. Patients with toxicities because of prior anticancer therapy that have not recovered to = Grade 1 or stabilized, except for adverse events not considered a likely safety risk (eg, alopecia, neuropathy, and specific laboratory abnormalities such as anemia, neutropenia, and thrombocytopenia).

17. Use of the following substances prior to the first dose of study drug:
a. = 28 days prior to the first dose of study drug: Any biologic and/or immunologic based therapy (including, but not limited to, monoclonal antibody therapy and/or cancer vaccine therapy)
b. Systemic chemotherapy or radiation therapy (except for steroids to control highly proliferative disease) administered = 14 days prior to the first dose of study drug.
c. Any tyrosine kinase inhibitor or other targeted small molecule given with antineoplastic intent administered = 7 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
d. Corticosteroid given = 7 days or 5 half-lives, whichever is longer, with antineoplastic intent (NOTE: Symptom control will not be considered as antineoplastic intent).

19. Patients who were administered a live vaccine = 35 days before first dose of study drug/treatment. NOTE: Vaccines for COVID-19 are allowed except for any live vaccine that may become available. Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

20. Any Chinese patent medicine with anticancer activity approved by the China NMPA (regardless of the type of cancer) used = 14 days before the first dose of study treatment.

21. Patients with underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study treatment, will affect the explanation of drug toxicity or adverse events, or will result in insufficient or impaired compliance with study conduct.

22. History of intracranial hemorrhage = 6 months before the first dose of study drug.

23. Patients receiving a vitamin K antagonist.

24. History of a severe bleeding disorder such as hemophilia A, hemophilia B, or von Willebrand disease, or history of unexplained spontaneous bleeding requiring blood transfusion or other medical or surgical intervention.

25. Patients who are unable to swallow capsules or with disease/procedure significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or gastrointestinal perforation or fistulae. Note: Gastroesophageal reflux disease under treatment with proton-pump inhibitors is allowed (assuming no drug interaction potential). Refer to Section 6.9.2.

26. Female patients who are pregnant or are breastfeeding.

27. Patients with concurrent participation in another therapeutic clinical study. Note: Concurrent participation in observational or noninterventional studies is allowed. In addition, patients who have completed active treatment in a clinical study and are in the follow-up period can be enrolled in this study.

28. Prior treatment with BTK degraders, including BGB-16673.

29. Prior IFI, except if patient agrees to receive secondary antifungal prophylaxis during the entire treatment period

3.3.1.1 PART 1 - INCLUSION CRITERIA

1. Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or metastatic or relapsed/refractory solid tumor unless specified in the specific indications in Part 2.

2. Measurable disease as defined in Appendix 10.5

3. One or more accessible lesion (Table 3.3.2.1), within either:
Intra-tumoral arms (Arms A, C or D), which require at least one accessible lesion, although two are preferred. The lesion(s) must either be easily accessible, or if not easily accessible, the patient must be willing to undergo repeat procedures (e.g., imaging guided procedures) for both biopsies and injections of BI 1831169.

- If only one accessible lesion is available, it must have a minimum lesion diameter of =10mm for injection of BI 1831169 and be amenable to biopsy.
- If two accessible lesions are available, one must have a minimum lesion diameter of =10mm for injection of BI 1831169 and be amenable to biopsy, and the other must be amenable to biopsy.

Intravenous only arms (Arms B, E, F or G), also require at least one accessible lesion which is amenable to biopsy. The lesion must either be easily accessible, or, if not easily accessible, patient must be willing to undergo repeat procedures (e.g., imaging guided procedures) for biopsies. However, patients with PDAC (Arm E) without at least one accessible lesion could be enrolled after agreement with the Sponsor. Collection of all mandatory biopsies is required unless they pose significant safety risks or are clinically unfeasible.

4. Has failed conventional treatment or for whom no therapy of proven efficacy exists, who is not eligible for established treatment options or for whom the available treatment options
are not suitable. Patient must have exhausted available treatment options known to prolong survival for their disease or have refused established treatment options for the malignant
disease. This criterion does not apply to the specific indications in Part 2.

5. Medically fit and willing to undergo all mandatory trial procedures.

6. Eastern Cooperative Oncology Group (ECOG) score of 0 or1(Appendix 10.5).

7. Adequate organ function or bone marrow reserve as demonstrated at screening by the following laboratory values:

a) Absolute neutrophil count = 1.5 x 10^9/L (= 1.5 x 10^3/µL, = 1500/mm^3), Platelet count = 100 x 10^9/L (= 100 x 10^3/µL, = 100 x 10^3/mm^3), without using hematopoietic growth factors within 4 weeks of start of trial

b) Hemoglobin = 90 g/L (= 9.0 g/dL, = 5.6 mmol/L)

c) Creatinine = 1.5 times the upper limit of normal (ULN)

d) Aspartate transaminase (AST) and alanine transaminase (ALT) = 3 x ULN if no demonstrable liver metastases, or otherwise = 5 x ULN if transaminase elevation is attributable to liver metastases

e) Total bilirubin = 1.5 x ULN, except for patients with Gilbert's Syndrome: total bilirubin = 3.0 x ULN or direct bilirubin = 1.5 x ULN

f) PTT / aPTT <1.5 x ULN

8. All toxicities related to previous anti-cancer therapies (including irAEs) have resolved to = grade 1 CTCAE/ASTCT prior to the start of trial treatment (except for alopecia, xerostomia and immunotherapy related endocrinopathies which may be included if clinically stable on hormone supplements or antidiabetic drugs as per Investigator judgement). Any toxicity exceptions not listed here that should not impact the patient’s participation per the investigator’s judgement should be discussed and agreed with the Sponsor.

9. Patients = 18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signature of the ICF.

10. Signed and dated written informed consent in accordance with ICH-GCP and local legislation, obtained before performing any protocol related procedures that are not part of normal standard of practice care. Note: If a patient declines to participate in the voluntary biobanking component of the trial, he/she will not be excluded from other aspects of the trial.

11. Life expectancy of at least = 3 months after the start of the treatment according to the Investigator’s judgement.

12. Male or female patients. Women of childbearing potential (WOCBP) ^1 and men able to father a child must be willing and able to use highly effective methods of birth control per ICH M3 (R2) (that result in a low failure rate of less than 1% per year when used consistently and correctly) during trial participation and for at least 6 months after the last administration of trial medication. A list of contraception methods meeting these criteria and information on definition of non-childbearing potential is provided in Section 4.2.2.3.

^1 A woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilization.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


3.3.1.3 PART 2 – INCLUSION CRITERIA

See 3.3.1.1 Part 1 Inclusion Criteria plus the below indication specific inclusion criteria:

3.3.1.3.1 Arm D Melanoma: 2L

13. Diagnosis of unresectable/metastatic cutaneous melanoma, independent of BRAF status.

14. Patients with advanced unresectable/metastatic disease, must have received only one prior anti-PD1 mAb containing regimen (monotherapy or combination) in the advanced unresectable or metastatic setting, for a minimum duration of 6 weeks with radiological documentation of disease progression within 3 months after the last anti-PD1 dose.

15. Patients that have received prior anti-PD1 therapy in the neo-adjuvant/adjuvant settings are eligible if progression occurred at least 6 months after the last anti-PD1 dose.

3.3.1.3.2 Arm E PDAC: 2L

16. Diagnosis of pancreatic ductal adenocarcinoma

17. Metastatic disease with progression after only one prior chemotherapy-based regimen with no other prior systemic therapies.

18. Patients who received prior chemotherapy for local/locoregional disease and present with distant metastases = 6 months after treatment are allowed.

19. Verification within 72 hours prior to first treatment:

- Adequate organ or bone marrow reserve functions as defined in 3.3.1.1
- Albumin = 3.0 g/dL
- ECOG score of 0 or 1

3.3.1.3.3 Arm F CRC: Refractory and other solid tumors

20. Progression during or following the last administration of approved standard therapies in the respective countries, if eligible and not contraindicated per investigator.

3.3.1.3.4 Arm G HNSCC: 1L

21. Diagnosis of R/M Head and Neck squamous cell carcinoma

22. Combined positive score (CPS) of 1-19.

23. Primary tumor locations are oropharynx, oral cavity hypopharynx, and larynx.

24. Patients who received systemic therapy administered as part of a multimodal treatment for locally advanced disease are allowed if progression occurred at least 6 months after the last dose.

3.3.1.2 PART 1 - EXCLUSION CRITERIA

1. Major surgery (major according to the Investigator’s assessment) performed within 4 weeks prior to start of study treatment.

2. Radiotherapy within 4 weeks prior to the start of study treatment, except in case of a brief course of palliative radiotherapy (e.g., for analgesic purpose or for lytic lesions at risk of fracture) which can then be completed within two weeks prior to start of study treatment.
Note: No radiation must have been given to any lesions planned to be injected and/or biopsied within 6 months of start of treatment.

3. Active hepatitis B or C infection e.g., Hepatitis B surface antigen (HBsAg) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative), which in the opinion of the Investigator may interfere with participation in the trial.

4. Patients with history of human immunodeficiency virus (HIV) infection who meet one or more of the following criteria:

- CD4+ count < 350 cells/µL.
- Viral load > 400 copies/µL (local lab assessment).
- Not receiving antiretroviral therapy.
- Receiving established antiretroviral therapy for less than four weeks prior to the start of study treatment.
- History of AIDS-defining opportunistic infections within 12 months prior to start of study treatment.

Patients with a history of HIV who do not meet any of the above criteria are eligible to participate but the patient must be under the care of an HIV/Infectious Diseases specialist, or an HIV/Infectious Diseases specialist must be consulted prior to inclusion.

5. Any severe or serious, acute or chronic medical or psychiatric condition or laboratory abnormality as per Investigator’s judgement that may increase the risk associated with study participation or study drug administration, including ongoing or active infection requiring systemic antibiotics.

6. Presence of brain tumors, brain metastases and / or carcinomatous meningitis (as per cranial imaging MRI or CT, performed at most 6 weeks prior to first treatment).

7. Active infection requiring systemic therapy (antibacterial, antiviral, antiparasitic or antifungal therapy) at the start of treatment in the trial.

8. History of allergy or hypersensitivity to study agent components.

9. History of primary immunodeficiency, history of allogeneic organ transplant, history of interstitial lung disease.

10. Women who are pregnant, nursing, or who plan to become pregnant or nurse during the trial or within 6 months after the last dose of study treatment.

11. Presence of other active invasive cancers other than the one treated in this trial within 5 years prior to screening, except for appropriately treated basal-cell carcinoma of the skin, in situ carcinoma of the uterine cervix, or other local tumors considered cured by local treatment.

12. The patient has a confirmed active infection/positive test with SARS-CoV-2 (as confirmed by PCR test or antigen test, see Section 5.2.5.3) within 8 weeks prior to start of treatment.

13. Previous treatment with VSV-based agents (including BI 1831169).

14. Live vaccination within 28 days of first treatment.

15. Prior treatment with a systemic anti-cancer therapy or investigational drug within 28 days or 5 half-lives (whichever is shorter) of the first administration of trial medication.

16. Prior, within 21 days of first dose or less than 5 half-lives (whichever is shorter) or concomitant use of interferon, immunosuppressive agents, or immunotherapy regimens during treatment phase.

17. Concomitant medication or condition considered a high risk for complications from injection or biopsy as per Investigator’s judgement.

18. Concomitant use of anticoagulant or antiplatelet therapy in patients for whom an interruption or a switch to heparin for deep/visceral injections/biopsies would be considered high risk for a thromboembolic event per investigator assessment,(see Section 4.2.2.1) Prior (within 30 days of first dose) or concomitant use of Tamoxifen.

19. Patients who must or wish to continue the intake of restricted medications (see Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.

20. Patients requiring chronic use of steroids regardless of the daily dosing or other immunosuppressive medication. Patients with a condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone equivalent) or other immunosuppressive medications require a 14-day washout period prior to the first dose of study drug. Topical, ocular, intra-articular, intranasal, inhaled steroids are permitted in the absence of active immune disease.

21. Patients not expected to comply with the protocol requirements, or not expected to complete the trial as scheduled (e.g., chronic alcohol or drug abuse or any condition) that in the Investigator’s opinion makes the patient unreliable for trial participation.

22. Patients currently enrolled in another device or drug trials, less than 28 days since ending other device or drug trials or receiving other investigational treatments.


3.3.1.4 PART 2 EXCLUSION CRITERIA

See 3.3.1.2 Part 1 Exclusion Criteria plus the below Part 2 and indication specific exclusion criteria

3.3.1.4.1 Additional Exclusion Criteria for Part 2

23. Any of the following cardiac criteria:

- Patients with an ejection fraction (EF) < 55% or the lower limit of normal of the institutional standard (if the lower limit of normal of institutional standard is higher than 55%) will be excluded. A historic measurement of EF no older than 6 months prior to first administration of trial drug can be accepted if there is no clinical evidence that the EF value has worsened since this measurement in the opinion of the Investigator or of the treating physician or both.

- Mean resting corrected QT interval (QTcF) > 470 msec.

- Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block.

- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval.

24. History of severe hypersensitivity reactions to any other monoclonal antibody.

25. History of pneumonitis (non-infectious) within the last 5 years.

26. Patients who were permanently discontinued from previous anti-PD-1 or anti-PD-L1 therapy because of an immune-related adverse event (irAE).

27. Patients who experienced the following G3/4 irAEs on previous anti-PD-1 or anti-PD-L1 based therapy: myocarditis, encephalitis, meningitis, colitis, hepatitis and pneumonitis

28. Patients with an active known or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.

3.3.1.4.2 Arm D Melanoma: 2L

29. Non cutaneous melanomas: uveal, ocular, nasopharyngeal, genitourinary, and anorectal.

30. Prior non-immunotherapy treatment or BRAF/MEK inhibitors therapy

3.3.1.4.3 Arm E PDAC: 2L

31. Ascites requiring =1 paracentesis every 2 weeks and/or the use of diuretics.

32. Prior history of receiving immune checkpoint inhibitors.

3.3.1.4.4 Arm F CRC: Refractory and other solid tumors

33. Confirmed microsatellite instability (MSI) and mismatch repair deficient (dMMR).

34. Prior history of receiving immune checkpoint inhibitors.

3.3.1.4.5 Arm G HNSCC: 1L

35. Disease is suitable for local therapy administered with curative intent.

36. Prior systemic therapy administered in the recurrent or metastatic setting.

37. Prior immune checkpoint inhibitor therapy.

38. Patients with primary tumor site of the nasopharynx, independent of the histology.

Participants are only eligible for enrollment in this trial if all of the following criteria apply at screening:

1 Have given informed consent by signing and dating an ICF before initiation of any trial-specific procedures.

2 Are willing and able to comply with scheduled visits, treatment schedule, the planned trial assessments, lifestyle restrictions, and other requirements of the trial. This includes that they are able to understand and follow trial-related instructions.

3 Agree not to enroll in another trial of an IMP, starting at the time of giving informed consent and continuously during participation in this trial.

4 Are = 18 years of age.

5 Have an ECOG PS of 0 to 1 (see Section 15.2).

6 Have measurable disease per RECIST 1.1, except for ovarian cancer where participants will be evaluated according to Gynecologic Cancer InterGroup criteria.

7 Have an archival FFPE tumor tissue sample available or are willing to be biopsied to obtain a fresh tumor tissue sample. If an archival tumor tissue sample is provided, it should be the latest available sample and should not be > 2 years old. The FFPE sample will be used to retrospectively assess the CA19-9 tumor expression status, conduct molecular studies, and/or conduct genetic studies.

8 Have a life expectancy of = 3 months in the opinion of the investigator.

9 Have adequate coagulation function defined as:
- Activated partial thromboplastin time and international normalized ratio =1.5 x ULN, except for participants receiving anticoagulant therapy, who must have international normalized ratio within therapeutic range as deemed appropriate by the investigator.

10 Have adequate hematologic function defined as shown:
- Hemoglobin = 9.0 g/dL (without receiving a blood transfusion or erythropoietin treatment within 14 days prior to sampling),
- Absolute neutrophil count = 1.5 x 10^9/L (without granulocyte colony-stimulating factor, or granulocyte-macrophage colony-stimulating factor within 14 days prior to sampling), and
- Platelet count = 100 x 10^9/L if no demonstrable hepatic metastases or = 75 x 10^9/L in the presence of hepatic metastases (without receiving platelet transfusion, thrombopoietin, or IL-11 within 14 days prior to sampling).

11 Have adequate organ function defined as:
- Total bilirubin = 1.5 x ULN (or = 3.0 x ULN for participants with liver metastasis),
- AST and ALT = 2.5 x ULN (or = 3 x ULN for participants with liver metastasis). Note, ULN is based on local laboratory ranges,
- Serum albumin = 2.5 g/dL, and
- Glomerular filtration rate = 60 mL/min/1.73 m^2 according to the abbreviated modification of diet in renal disease equation: Glomerular filtration rate = 175 x (serum creatinin^-1.154) x (age^-0.203) where the serum creatinine level is expressed in mg/dL; multiply it by 0.742 if the participant is female; multiply it by 1.212, if the participant is African-American (Levey et al. 2007).

12 Are POCBP who have a negative serum ßhCG pregnancy test.
Participants who are post-menopausal (defined as 12 months with no menses without an alternative medical cause) or permanently sterilized (i.e., have had a hysterectomy, bilateral salpingectomy, and bilateral oophorectomy, as verified by medical records) will not be considered POCBP and therefore are not required to undergo pregnancy testing.

13 Are POCBP who agree to practice a highly effective form of contraception starting at the time of giving informed consent and continuously until 195 days (ungefahr 6.5 months) after receiving the last dose of IMP.
For guidance on highly effective forms of contraception, see Section 13.3.2.

Note: The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a participant with an early undetected pregnancy.

14 Are POCBP who agree to require their potentially fertile male partners to use condoms starting at the time of giving informed consent and continuously until 195 days (ungefähr 6.5 months) after receiving the last dose of IMP.

15 Are potentially able to father children (i.e., are not surgically [e.g., have had a bilateral orchidectomy vasectomy] or congenitally sterile) that are sexually active with a partner of childbearing potential, who agree to use condoms during the trial, and to ask their sexual partners to practice a highly effective form of contraception during the trial, starting at the time of giving informed consent and continuously until 105 days (ungefähr 3.5 months) after receiving the last dose of IMP.

For guidance on highly effective forms of contraception, see Section 13.3.2.

16 Are POCBP who are willing to refrain from donation of germs cells (ova, oocytes) for the purposes of assisted reproduction during the trial, starting at the time of giving informed consent and continuously until 195 days (ungefähr 6.5 months) after receiving the last dose of IMP.

17 Are potentially able to father children and are willing to refrain from donation of germs cells (sperm) for the purposes of assisted reproduction during the trial, starting at the time of giving informed consent and continuously until 105 days (ungefähr 3.5 months) after receiving the last dose of IMP.

Part-specific criteria

Parts A, B, and C

18 Have a histologically confirmed advanced/metastatic tumor type that is known to express CA19-9: PDAC, carcinoma of the bile ducts, invasive urothelial carcinoma of the bladder and urinary tract, colorectal adenocarcinoma, adenocarcinoma of the esophagogastric junction, gastric adenocarcinoma, endometrial carcinoma, and epithelial ovarian cancer (including adenocarcinoma of the fallopian tube and peritoneal epithelial cancer [except mesothelioma]). These tumor types are known to express CA19-9 at a frequency of =55% (Note, the 55% expression frequency refers only to the population expression level and not the individual expression level as referenced by Loy et al.1993).

19 Have no available standard of care therapy likely to confer clinical benefit in the opinion of the investigator. Participants must have received all available standard therapies, including targeted therapies based on mutation status (per guidelines from the FDA, American Society of Clinical Oncology, European Society for Medical Oncology, or local guidelines used at the site), and failed at least first-line standard of care therapy prior to enrollment.

Part D

20 Have a histologically confirmed diagnosis of PDAC.

21 Must have been offered all available standard therapies including targeted therapies based on mutation status. Established second-line therapies available must not be withheld.

22 Have radiographic disease progression and no available standard of care therapy likely to confer clinical benefit in the opinion of the investigator.

Participants are not eligible for enrollment in this trial if any of the following criteria apply at screening:

1 Have a medical, psychological, or social condition which, in the opinion of the investigator, could compromise their wellbeing if they participate in the trial, or that could prevent, limit, or confound the protocol-specified assessments or procedures, or that could impact adherence to protocol-described requirements.

2 Are pregnant or breastfeeding or are planning pregnancy during the trial or within 6.5 months after receiving the last dose of IMP. Are planning to father children during the trial or within 3.5 months after receiving the last dose of IMP.

3 Are enrolled in another investigational trial or are subject to exclusion periods from another investigational trial.

4 Have a history or allergies, hypersensitivities, or intolerance to the trial treatments including excipients thereof (e.g., an intolerance to prior treatment with a topoisomerase I inhibitor or an ADC that consists of a topoisomerase I inhibitor, including but not limited to topotecan, irinotecan, and deruxtecan).

5 Have received prior treatment with a CA19-9 targeting therapy.

6 Have had major surgery (not including diagnostic surgery) within the 4 weeks prior to the first dose of trial treatment or are planned to undergo major surgery during the course of the trial.

7 Have had prior allogeneic hematopoietic stem cell transplantation or solid-organ transplantation.

8 Have had an inadequate washout period for prior anticancer treatment prior to the first dose of IMP, defined as follows:
- Endocrine therapy within < 3 weeks of the start of trial treatment.
- Monoclonal antibodies or other biological therapy within < 3 weeks of the start of trial treatment.
- Herbal medicine with anti-tumor indications within < 3 weeks of the start of trial treatment.
- Chemotherapy, or small molecular-targeted agents within 3 weeks or 5 half-lives (whichever is longer) of the start of trial treatment.
- Strong and moderate CYP2D6 or CYP3A4 inhibitors within 3 weeks or 5 half-lives (whichever is longer) of the start of trial treatment.
- Immunotherapy/monoclonal antibodies within 3 weeks of the start of trial treatment; nitrosoureas, ADCs, or radioactive isotopes within 6 weeks of the start of trial treatment.
- Radiotherapy in the last 6 weeks prior to the first dose of IMP, except:
- Whole brain radiation therapy which must be discontinued 3 weeks prior to the first IMP dose or stereotactic brain radiation therapy which must be discontinued 1 week prior to the first IMP dose.
- Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation which must be discontinued 4 weeks prior to the first IMP dose or palliative radiation therapy which must be discontinued 2 weeks prior to the first IMP dose.

Previously irradiated tumor lesions cannot be considered as target lesions or non-target lesions in this trial.

Note: Washout periods for specific prior treatments are provided in this protocol to ensure participants are not exposed to undue risks, as prior treatments may have an influence on either the safety and overlapping toxicities and/or for the efficacy assessment of the IMP in this trial. Participants must have recovered from clinically significant adverse events resulting from previous anticancer therapy at screening (see Exclusion Criterion 22). Based on prior experience of the adverse event profile of relevant IMPs to BNT329, in addition to washout periods, trial criteria require relevant clinical and laboratory parameters (e.g., Inclusion Criteria 9, 10, and 11) to ensure the safety and welfare of participants.

9 Have received systemic steroids (> 10 mg/day of prednisone or its equivalent) or other immunosuppressive therapy within 2 weeks prior to the first dose of IMP. The following are exceptions to this criterion:
- Inhaled sprays, topical steroids, or local steroid injections (e.g., intra-articular injection).
- Systemic steroids at physiological doses as replacement therapy (e.g., physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency).
- Steroids as pre-medication for hypersensitivity reactions (e.g., CT scan pre-medication).

10 Have received any live vaccine within 4 weeks prior to the first dose of IMP or intend to receive a live vaccine during the trial.

11 Have a history of leptomeningeal carcinomatosis.

12 Have brain metastases or spinal cord compression unless asymptomatic or treated and stable off steroids and anticonvulsants for at least 2 weeks prior to the first dose of IMP.

13 Have a history of (noninfectious) ILD/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

14 Have clinically significant concomitant pulmonary disease, including but not limited to:
- Pulmonary embolism within 3 months of the start of trial treatment.
- Any autoimmune, connective tissue, or inflammatory disorder (e.g., rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis) where there is documented or suspicion of pulmonary involvement at the time of screening.
- Prior complete pneumonectomy.

15 Have a diagnosis of Gilbert’s syndrome.

16 Have benign diseases/co-morbidities with a high risk of CA19-9 elevation, such as participants with a history of chronic or acute liver impairment (e.g., hepatitis or cholestasis), acute pancreatitis, and chronic CA19-9 elevation due to inflammatory disease (e.g., primary biliary cirrhosis, sclerosing cholangitis, or secondary chronic cholangitis) except for participants with PDAC and carcinoma of the bile ducts.

17 Have uncontrolled third-space fluid (e.g., pleural effusions, ascites, pericardial effusions) that requires repeated drainage. (Patients with controlled third-space fluid with only one therapeutic drainage are eligible).

18 Have active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal conditions that may cause bleeding or perforation in the opinion of the treating investigator.

19 Have an active infection that requires systemic therapy within 1 week prior to the first dose of IMP. Participants receiving prophylactic anti-infective therapy (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) may be eligible after discussion with the sponsor.

20 Have a known HIV, HBV, or HCV infection. Participants with HIV, HBV, or HCV infection may be enrolled after evaluation of eligibility based on FDA’s guidance Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus Infections.

21 Have any other primary malignancy within 2 years prior to the first dose of IMP, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other curatively treated solid tumors.

22 Have unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia and pigmentation) not yet resolved to NCI CTCAE Grade =1, baseline, or the level specified in the inclusion/exclusion criteria. Participants with chronic Grade 2 toxicities who are asymptomatic or adequately managed with stable medication may be eligible after discussion with the sponsor.

23 Have a history of relevant CNS pathology or current relevant CNS pathology (e.g., seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson's disease, epilepsy requiring pharmacologic treatment).

24 Are receiving immunosuppressive agents (e.g., azathioprine, cyclosporine A).

25 Have abnormal ECGs that are clinically significant, such as QTcF prolongation = 470 ms.

26 Have, in the opinion of the treating investigator any concurrent condition(s) that could pose an undue medical hazard or interfere with the interpretation of the trial results; these conditions include, but are not limited to:
- Ongoing or active infection requiring antibiotic/antiviral/antifungal therapy.
- Concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV).
- Concurrent unstable angina.
- Concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation).
- Acute coronary syndrome within the previous 6 months.
- Arterial thromboembolic event within the previous 6 months.
- Significant pulmonary disease (shortness of breath at rest or on mild exertion) for example due to concurrent severe obstructive pulmonary disease.

27 Are vulnerable individuals, i.e., are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. This includes all sponsor, trial site, or third party (e.g., CRO, vendor) personnel directly involved in the conduct of the trial and their family members or dependents, as well as all trial site personnel otherwise supervised by the investigator.

1. Subjects must be >= 18 years of age.

2. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of <= 2.
3. Subjects must voluntarily sign and date an informed consent form.

4. Subjects must have had documented multiple myeloma requiring treatment as defined by the criteria below:

a. Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy proven plasmacytoma at some point in their disease his tory requiring treatment according diagnostic criteria (IMWG up dated criteria 2014, Rajkumar et al. 2014) with measurable disease at screening (serum M-protein > 500 mg/dL or urine M protein 200 mg/24h, in case of oligosecretory MM serum free light chain > 10mg/dL and abnormal kappa/lambda free light chain ratio)

5. Cytogenetics/FISH confirming t(11;14); in case of prior testing, provision of original findings report is necessary

6. Prior treatment requirements:

a. Subjects must have received at least 1 prior treatment line (induc tion, high-dose, consolidation and maintenance is considered as one treatment line). All patients have to have received at least one proteasome inhibitor and at least one immunomodulatory agent and at least one anti-CD38 monoclonal antibody.
b. Subjects must have documented evidence of progressive disease on or after the last treatment line.
c. Subjects with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met:
- ASCT was >100 days prior to initiating study treatment, and
- No active bacterial, viral, or fungal infection(s) present.

7. Subjects must have adequate organ function, defined as follows:

a. Hemoglobin >= 8.0. g/dL (without transfusion of red blood cells for the past 14 days)
b. Absolute neutrophil count >= 1.5 x10^9/L (without growth factor support for the past 14 days)
c. Platelet count more or equal 75 x10^9/L (without growth factor or platelet stimulating agents for the past 14 days)
d. Adequate hepatic function per local laboratory reference range as follows:
i. Aspartate aminotransferase (AST) <= 2,5 x upper limit of normal (ULN);
ii. Alanine aminotransferase (ALT) <=2.5 x ULN
iii. Total bilirubin <= 1.5 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome. Isolated bilirubin >=1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%.

e. Subject must have adequate renal function as demonstrated by eGFR >=30 mL/min/ 1.73 m^2 as calculated by Modified Diet in Renal Disease (MDRD) formula
f. Spot urine (albumin/creatinine ratios (spot urine) <500 mg/g (56 mg/mmol) OR Urine Dipstick Negative/trace (if >=1+ only eligible if confirmed <500 mg/g (56 mg/mmol) by albumin/creatinine ratio (spot urine from first void)
g. Corrected serum calcium <= 14 mg/dL (<=3,5 mmol/L); or free ionized calcium < 6,5 mg/dL ( 1,6 mmol/L)

8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

- Is not a woman of childbearing potential (WOCBP)

OR

- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency (as described in Appendix 14.1.4) before and during the intervention period and for at least 5 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.

A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 24 hours before the first dose of study intervention and agree to use a highly effective method of contraception before and during the study and for 5 months after the last dose of IMP. Additional requirements for pregnancy testing during and after study intervention are provided in Section Pregnancy Testing and the SoA.

Non-childbearing potential must be clearly documented and be confirmed previously and is defined as follows (by other than medical reasons):

- >=45 years of age and has not had menses for >1 year
- Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation.
- Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation (> 6 weeks post-surgery). Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records ot the actual procedure.

9. Male participants are eligible to participate if they agree to the following during the intervention period and for 6 months after the last dose of study treatment to allow for clearance of any altered sperm:
- Refrain from donating sperm
PLUS either:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
OR
- Must agree to use contraception/barrier as detailed below:
Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective con traceptive method with a failure rate of <1% per year as when having sexual intercourse with a woman of childbearing potential (including
pregnant females).

10.All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.

11.All subjects must agree not to share study medication.

12.All prior treatment-related toxicities (defined by National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0)
must be <= Grade 1 at the time of enrolment except for alopecia.

Patients are excluded from the study if any of the following criteria are met at screening or on Day 1:

1. Subject has received prior Venetoclax and/or anti BCMA treatment.

2. Participant has used an investigational drug or approved systemic anti-myeloma therapy within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug. The only exception is emergency use of a short course of corticosteroids (equivalent of Dexamethasone 40 mg/day for a maximum of 4 days) up to 7 days before treatment.

3. Participant has had plasmapheresis or radiation therapy within 7 days prior to first dose of study treatment.

4. Participant has current corneal epithelial disease except mild changes in corneal epithelium.

5. Participant has current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria.

6. Participant has a presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil inclusion criteria.

7. Participant has had major surgery <= 4 weeks prior to initiating study treatment. Kyphoplasty is not considered a major surgery.

8. Participant must not use contact lenses while participating in this study. Band age contacts may be prescribed by an eye care professional if needed.

9. Participant has any evidence of active mucosal or internal bleeding or other gastrointestinal disease that may significantly alter the absorption of oral drugs.

10.Participant has evidence of cardiovascular risk including any of the following:

a. Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block.
b. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within three (3) months prior to screening.
c. Class III or IV heart failure as defined by the New York Heart Association functional classification system [NYHA, 1994] (see Appendix II)
d. Uncontrolled hypertension
e. Left ventricular Ejection Fraction <= 50%

11.Participant has known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to IMPs or drugs chemically related to IMPs, or any of the components of the study treatment

12.Participant has an invasive malignancy other than disease under study, within 5 years before trial inclusion, except

- Adequately treated in situ carcinoma of the cervix uteri or the breast;
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
- Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment; or
- Previous malignancy with no current evidence of disease, and which was confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.

13.Participant is pregnant or lactating

14.Participants who have had prior allogeneic stem cell transplant.

15.Participants with symptomatic amyloidosis, active POEMS syndrome (polyneu ropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes) or active plasma cell leukaemia at the time of screening.

16.Participants with any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures.

17. Subject is known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B (defined by a positive test for hepatitis B surface antigen (HBsAg) or antibodies to hepatitis B surface and core antigen (anti HBs and anti HBc respectively), or hepatitis C (anti-HCV antibody positive or HCV RNA quantitation positive).

18.Current immune or inflammatory conditions requiring immunosuppressive treatment (e.g. systemic lupus erythematosus, rheumatoid arthritis).

19.Subject must not have received any live vaccines within 8 weeks prior to first dose of study treatment.

20.Subject must not use or anticipate the use of prohibited medications or foods during study participation.

21.Subject does not have a history of or show any signs of known meningeal/central nervous system involvement by myeloma.

22.Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal) requiring treatment.
b. Any concurrent medical or psychiatric condition or disease (e. g. uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for the participating in this study.

23.Subject is known or suspected of not being able to comply with the study proto col (eg. because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e. g., compromise the wellbeing) or that could prevent, limit or confound the protocol-specified assess ments.

24.Treatment with any of the following within 7 days prior to the first dose of study drug:

a. moderate or strong cytochrome P450 3A (CYP3A) inhibitors (see Appen dix VII for examples)
b. moderate or strong CYP3A inducers (see Appendix VII for examples)

25.Administration or consumption of any of the following within 3 days prior to the first dose of study drug:

a. grapefruit or grapefruit products
b. Seville oranges (including marmalade containing Seville oranges)
c. star fruit

26.Participation in any other clinical trial (with the exclusion of observational studies)

Patient Inclusion Criteria

Patients suffering from hematological malignancies and eligible for haploidentical allogeneic stem cell transplantation. Patients will be included prior start of conditioning for HCT.
Inclusion criteria for IMP infusions will be rechecked on day 30+/-2 after HCT prior to IMP administration.

Patient population:
- Patients suffering from hematological malignancies and eligible for haploidentical allogeneic stem cell transplantation. Patients will be included prior start of conditioning for
HCT. Inclusion criteria for IMP infusions will be rechecked on day 30 after HCT prior to IMP administration.

Inclusion criteria indications:

- Adult and pediatric patients with hematological malignancies in complete remission (CR), partial remission (PR) or with stable disease
- Acute myeloid leukemia (AML):
- Patients with high-risk AML in CR1
- Patients with relapsed or primary therapy-refractory AML
- Acute lymphoid leukemia (ALL):
- Patients with high-risk ALL in CR1
- Patients with relapsed or primary refractory ALL
- Hodgkin’s disease: Patients with relapsed or primary refractory Hodgkin’s disease
- Non-Hodgkin’s lymphoma: Patients with relapsed or primary refractory Non-Hodgkin’s lymphoma
- Myelodysplastic Syndrome (MDS)/ Myeloproliferative Syndrome (MPS):
- Patients with refractory MDS/MPS
- Multiple myeloma (MM): Patients with relapsed or refractory multiple myeloma

Additional patient inclusion criteria:

- Decision for haplo-identical HHCT with TCR /ß and CD19 depleted stem cell grafts has been made according to hospital routine prior to inclusion of the patient into this study. Patient scheduled for haploidentical transplantation according to hospital routine with an TCRalpha/beta depleted haploidentical stem cell graft
- No signs of acute GVHD on day 30 (day of infusion of DLI/IMP) after haploidentical HHCT
- Patients aged >=1 year to <=65 years
For safety reasons, dose escalation part within this study should only be performed for adults and older children (>6 years). The second part of the study, with already evaluated
safe dose level, also younger children (>=1 year) can be included.
- Karnofsky (patients >16 years)/Lansky (patients <=16 years) index >60%
- Patient in good clinical condition without concomitant diseases significantly increasing the risk of transplantation, see exclusion criteria
- Pediatric patients without uncontrollable, progressive infections at the time of transplantation
- Informed consent given (patient or legal representative).

Exclusion criteria for patients:

- Age >65 years or <1 year
- Patients with progressive disease prior HCT
- <3 months after preceding hematopoietic cell transplantation (HCT)
- Treatment with T-cell or IL-2 targeted medication (e.g. alemtuzumab, basiliximab) within 60 days prior to study product infusion
- Continuous treatment with prednisolone (or alternative glucocorticosteroid e.g. dexamethasone, short term use =3 days for other indication as GVHD allowed) within two weeks prior study product infusion (DLI)Known allergy/hypersensitivity to any component of the study product
- Treatment with another investigational drug within one month before inclusion
- History of neurological impairment (active seizures, severe peripheral neuropathy, signs of leukencephalopathy, active CNS infection)
- Note: For patients with HLH or Malignant Osteopetrosis or other patients with heavy pretreatment with irradiation or intrathecal chemotherapy pre-transplant CNS MRI and neurological consultation are mandatory.
- Fungal infections with radiological and clinical progression
- Liver function abnormalities with bilirubin >2 mg/dL and elevation of transaminases higher than 400 U/L
- Chronic active viral hepatitis
- Ejection fraction <40% or Shortening fraction <20% on echocardiography. Patients with > grade II hypertension by CommonToxicity Criteria (CTC)
- Creatinine clearance below threshold defined for stem cell transplantation according to local clinical standard
- Respiratory failure necessitating supplemental oxygen
- HIV infection
- Female patients who are pregnant or breast feeding
- or adults of reproductive potential not willing to use an effective method of birth control during study treatment and for at least 12 months thereafter
Note: Women of childbearing potential must have a negative serum pregnancy test at study entry.
- Subject (male or female) is not willing to use highly effective birth control methods according to the Clinical Trial Faciliation Group (CTFG) recommendations
(https://www.hma.eu/fileadmin/dateien/Human_Medicines/01- About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) during the treatment and for 6 months after last transplantation (male or female). Such methods include combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner^1, sexual abstinence^2

^1 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success.
^2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

- Concurrent severe or uncontrolled medical disease (e.g. uncontrolled diabetes, congestive heart failure, myocardial infarction within 6 months prior to the study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which by assessment of the treating physician could compromise participation in the study
- Patients with a history of psychiatric illness or a condition which could interfere with their ability to understand the requirements of the study (this includes alcoholism/drug addiction)
- Patients unwilling or unable to comply with the protocol or unable to give informed consent

Donor Selection

Donor selection is done as part of standard of care in haploidentical transplantation. All apheresis centers will use a Health Questionnaire based on the current version of the
“Richtlinie zur Gewinnung von Blut und Blutbestandteilen und zur Anwendung von Blutprodukten .

1. Haploidentical family member previously identified as eligible donor by donor/recipient cross-matching including HLA-typing.
Note: In case of positive cross-match results for donor-reactive anti HLA antibodies an alternative donor with negative cross-match results should be preferred, if available. If no alternative donor with negative cross-match results is available, removal of anti HLA antibodies is highly recommended to prevent graft rejection.

2. Donor age >=16 years
Note: Positive evaluation for allogeneic hematopoietic cell donation has to have been performed at the collection center according to local standard practice. Also informed consent for mobilization and collection of peripheral blood stem cells according to local institutional guidelines has to have been given in this context independently of the present clinical study. Stem cell mobilization and collection procedures are not part of this study and will be performed at the collection center according to local standard procedures.

3. Study specific informed consent given.
.

Patients eligible for inclusion in this study must meet all of the following criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Male or female patients must be = 18 years of age.

3. Eastern Cooperative Oncology Group (ECOG) performance status of = 2. (Inclusion criterion 3 has been replaced with 3a and is no longer applicable with protocol amendment v03).
3a. Eastern Cooperative Oncology Group (ECOG) performance status of = 1.

4. Patients with one of the following indications:

- Histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive and HER2-negative breast cancer based on the most recently analyzed tissue sample; all tested by a local laboratory using an assay that meets applicable local regulations and all data must be available in the patient’s medical record. HER2-negative breast cancer is defined as a negative in situ hybridization (ISH) test or an IHC status of 0 or 1+, or an IHC status of 2+ in conjunction with a negative in situ hybridization test [such as fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), silver-enhanced in situ hybridization (SISH) or dual in situ hybridization (DISH)].

- Histologically and/or cytologically confirmed diagnosis of cancer with a CCNE1 amplification (only solid tumor data is allowed). CCNE1 amplifications must have been previously identified through local molecular assays that meet applicable local regulations and data must be available in the patient’s medical record.

Phase I:

- BC: Patients with HR+/HER2- breast cancer must have had disease progression on or following, or have been intolerant to, at least one line of hormone-based therapy in combination with a CDK4/6 inhibitor (CDK4/6i) and at least one additional line of systemic therapy (including cytotoxic chemotherapy, targeted therapies, and/or antibody-drug conjugate therapies) for metastatic disease and not be a candidate for any available standard therapy, in the investigator's judgement.

- CCNE1 amplified solid tumors: Patients must have received, but are not benefitting from standard therapies, are intolerant or ineligible to receive such therapy, or have no standard therapy option. For dose expansion only: no more than 3 prior lines of therapy for advanced or metastatic disease are allowed.

- OC: Patients must have received platinum-based chemotherapy and be considered to have platinum-resistant or refractory disease. If appropriate, they should have received prior treatment with anti-VEGF therapy or PARP inhibitor in accordance with local standard of care, unless the patient was ineligible to receive such therapies. In addition, patients must have received at least one line of chemotherapy in the platinum-resistant setting and not be a candidate for any available standard therapy, in the investigator's judgement.

- GEA: Patients must have received one line of therapy with a fluoropyrimidine and platinum-based regimen, and, if appropriate, prior treatment with HER2 targeted therapy or anti-PD-(L)1 therapy in accordance with local standard of care, unless the patient was ineligible to receive such therapy or not be a candidate for any available standard therapy, in the investigator's judgement.

Phase II:

- BC: Patients with HR+/HER2- breast cancer who have received an aromatase inhibitor or tamoxifen in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) for unresectable or metastatic disease and demonstrated evidence of disease progression. They must not have received more than two lines of endocrine therapy in the unresectable/metastatic setting. Patients whose disease progressed while on an adjuvant CDK4/6 inhibitor are permitted without a CDK4/6 inhibitor in the metastatic setting; such patients are permitted only one additional line of endocrine therapy in the unresectable/metastatic setting.

5. Measurable disease as determined by RECIST version 1.1 (refer to Appendix 8).
Tumor lesions previously irradiated or subjected to other locoregional therapy will only be considered measurable if there is documented disease progression at the treated site after completion of therapy.

- BC only: If no measurable disease is present, then at least one predominantly lytic bone lesion must be present that can be accurately assessed at baseline and is suitable for repeated assessment (patients with no measurable disease and only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).

6. Patients must be suitable and willing to undergo study required biopsies if safe and medically feasible according to the treating institution’s own guidelines and requirements.
Patient must be willing to undergo a new tumor biopsy at screening (and additionally during treatment for Phase I additional escalation cohorts). If a newly obtained biopsy cannot be safely performed at screening, a recent archival sample may be substituted from patients that have not received systemic therapy since the collection of the biopsy.
Exceptions to the mandatory baseline tumor sample requirement may be allowed following documented discussion with Novartis.

Patients meeting any of the following criteria are not eligible for inclusion in this study.

1. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
- Previous treatment with a CDK2 inhibitor at any time.
- = 2 weeks for fluoropyrimidine therapy
- = 4 weeks for extended-field radiotherapy or = 2 weeks for limited field radiation for palliation. For the combination treatment, patients in whom = 25% of the bone marrow has been previously irradiated are also excluded.
- = 4 weeks or = 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
- = 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C.
- For the combination treatment: = 5 half-lives wash out period after treatment with tamoxifen or toremifene.

2. Having out of range laboratory values defined as:
- Creatinine clearance (calculated using CKD-EPI 2021 formula, or measured) < 50 mL/min
- Total bilirubin > 1 x ULN, (except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN) and direct bilirubin > 1.5 x ULN
- Alanine aminotransferase (ALT) > 2.5 x ULN, except for patients with liver metastasis, who are excluded for ALT = 5 x ULN.
- Aspartate aminotransferase (AST) > 2.5 x ULN except for patients with liver metastasis, who are excluded for AST = 5 x ULN.
- Absolute neutrophil count (ANC) < 1.5 x 10^9/L
- Platelet count < 100 x 109/L
- Hemoglobin < 9 g/dL
- QTcF = 450 msec (as a mean value of triplicates) on screening ECGs, or inability to determine the QTcF interval
- Clinically significant electrolyte abnormalities, including any grade of hypocalcemia, hypokalemia, or hypomagnesemia, that are not corrected before the first dose of the study medication

3. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
- History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
- Documented cardiomyopathy
- Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
- Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, complete left bundle branch block, high-grade atrioventricular (AV) block, Mobitz type II and third-degree AV block)
- Uncontrolled arterial hypertension with systolic blood pressure (SBP) > 160 mmHg.

4. Presence of Grade = 2 toxicity due to prior cancer therapy according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) that has not resolved, with the exception of Grade 2 neuropathy, any grade alopecia, amenorrhea, skin rash that is adequately treated or endocrinopathies that are adequately treated with replacement therapy.

5. Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery) or increasing doses of corticosteroids within 2 weeks prior to study entry. Patients with treated symptomatic brain metastases must be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of = 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.

6. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy.

7. For the combination treatment:
- Patients with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine-based therapy per the investigator’s judgment.
- Patients who could not tolerate the prescribed dose of ribociclib during a previous course of treatment, requiring dose reduction or permanent discontinuation due to adverse events.

8. For patients with breast cancer: Patient is concurrently using hormone replacement therapy.

9. Any serious uncontrolled infection (acute or chronic), such as but not limited to those caused by bacteria, viruses, or fungi, confirmed by clinical evidence, imaging, and/or relevant positive laboratory tests (e.g., blood cultures, Polymerase Chain Reaction (PCR) for DNA/RNA, etc.). Patients with active Hepatitis B (HBV) or Hepatitis C (HCV) infection whose disease is controlled (defined as positive anti-HBc and negative hepatitis B virus surface antigen (HBsAg) for HBV and undetectable viral load by real-time PCR for HCV) under antiviral therapy should not be excluded. Testing for HBV or HCV status is not necessary unless clinically indicated or if the patient has a history of HBV or HCV infection.

10. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., gastrointestinal perforation, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome). Patients who have undergone gastrectomy are eligible.

11. Unable or unwilling to swallow oral drugs as per dosing schedule.

12. Patients who have undergone major surgery = 4 weeks prior to first dose of study treatment or who have not recovered from the surgical procedure (mediastinoscopy, insertion of a central venous access device and insertion of a feeding tube are not considered major surgery).

13. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.

14. Use of hematopoietic growth factors or transfusion support = 2 weeks prior to start of study treatment. If growth factors were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.

15. History of hypersensitivity to any of the study treatments or its excipients (for the combination treatment arm: including to peanut and soy) or to drugs of similar chemical classes.

16. Patients taking prohibited therapies as listed in Section 6.6.2 that cannot be stopped within 7 days or 5 half-lives (whichever is longer) prior to study treatment and for the duration of the study treatment.

- Medications with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication
- Strong or moderate inhibitors or inducers of CYP3A4/5
- Substrates of CYP3A4/5 with a narrow therapeutic index
- Proton pump inhibitors (PPIs)
- Herbal products
- Other investigational and antineoplastic therapies

17. Women of childbearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they are using highly effective methods of contraception (failure rate < 1% per year) while taking study treatment and for 7 days plus six (6) months after the last dose of ECI830 if receiving ECI830 alone or in combination with ribociclib, or for 1 year after the last dose of fulvestrant or per approved local label requirements (e.g. fulvestrant USPI, SmPC) if receiving any combination treatment with fulvestrant. WOCBP must not donate eggs for 7 days + 6 months or 1 year after the last dose of study treatment as defined above.

Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate [should be generally age = 40 years], history of vasomotor symptoms [e.g., hot flush]) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she not considered to be of childbearing potential.

Highly effective contraception methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Note that periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception.
- Bilateral oophorectomy with or without hysterectomy, total hysterectomy or bilateral salpingectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment are they considered to be not of childbearing potential.
- Bilateral tubal occlusion, bilateral tubal ligation (at least six weeks before taking study treatment)
- Sterilization (vasectomy) of male partner(s) of the female patient at least 6 months prior to screening provided partner(s) has(have) received medical confirmation of surgical success.
- For breast cancer patients: Placement of non-hormonal intrauterine device (IUD).
- For non-breast cancer patients: Placement of hormonal or non-hormonal IUD, or IUS, or hormonal vaginal ring.

Note: Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or any other forms of hormonal contraception (which result in systemic exposure) is not allowed in this study.
If local regulations are more stringent than the contraception methods listed above, local regulations apply and will be described in the informed consent.

18. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 days + three (3) months after stopping study treatment. A condom is required for all sexually active male patients to prevent them from fathering a child AND/OR to prevent delivery of study treatment via seminal fluid to their partner.
In addition, male patients must not donate sperm for the time period specified above.
Male patients must inform female partner(s) of the potential risks of ECI830 and any combination study treatment and the requirement to use a method of highly effective contraception.

19. Pregnant or nursing (breast feeding) women.

Inclusion Criteria - Core

Participants must meet the eligibility criteria of both the core protocol and the module-specific criteria, as applicable. Module-specific inclusion criteria for Module 1 are presented in Section 10.5.1 and Module 2 are presented in Section 11.5.1.

Type of Participant

1. Adequate organ function per Table 5 below:

Criteria for Adequate Organ Function at Screening - Table 5

Parameter: Value

HEPATIC
- Total bilirubin: = 1.5 x ULN in the absence of Gilbert’s syndrome
= 2 x ULN if liver involvement by disease
= 3 x ULN if the participant has Gilbert’s syndrome
- AST and ALT: = 3 x ULN
= 5 x ULN if liver involvement by disease

RENAL
- CrCL (Cockcroft-Gault equation): = 50 mL/min

CARDIAC
- LVEF as measured by ECHO, MUGA, or cardiac MRI: = 50%
- Mean resting QT interval (QTcF) obtained from 3 electrocardiograms (ECGs), in the absence of a cardiac pacemaker: = 450 msec

PANCREATIC
- Lipase: = 1.5 x ULN
- Amylase: = 1.5 x ULN and no active pancreatitis

Sex and Contraceptive/Barrier Requirements

2. Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a) Male participants:

- Male participants must agree to use a condom plus an additional contraceptive method (see Appendix J 2) and to refrain from sperm donation during and after the conduct of
the study post-screening through 90 days following the last dose of study treatment.

b) Female participants (see Appendix J 1 for definitions of child-bearing potential):

- Female participants of child-bearing potential must agree to use one highly effective form of contraception and to refrain from egg donations or freezing for future reproductive use during and after the conduct of the study post-screening through 6 months after the last dose of study treatment. WOCBPs opting for systemic hormonal contraception are advised to utilise an additional barrier method of contraception during this time period. Cessation of contraception after this point should be discussed with the treating physician.

- A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly (see Appendix J 2).
Pregnancy test:

- All WOCBP must have a negative serum pregnancy test result at the visit when the first dose of AZD3632 will be administered. WOCBP are also required to have negative pregnancy test results during treatment (per module-specific SoA) through the end of relevant exposure (as described above).

Informed Consent

3. Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

4. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative (see Appendix D 2). Note: inclusion in the Genomics Initiative Research is optional, and participants will not be excluded from the study if they choose not to participate in this optional part of the study and consequently are not required to sign the Optional Genomics Initiative Consent Form.



Inclusion Criteria

Refer to Section 5.1 of the core protocol for inclusion criteria applicable to all modules.
Additional inclusion criteria applicable to Module 1 only are described in this section.
Participants are eligible to be included in the study only if all the inclusion criteria in the core protocol (Section 5.1) and the Module 1 specific inclusion criteria below apply.

Age

1. Participant must be at least 18 years of age at the time of signing the informed consent. Note: In the UK, participants must be at least 16 years of age at the time of signing consent.

Type of Participant and Disease Characteristics

2. Advanced haematologic malignancy as specified below:

a. Dose Escalation: Diagnosis of acute leukaemia according to the World Health Organization (WHO) 2022 or diagnosis of a myelodysplastic neoplasia (MDS) according to the WHO 2022 and harbouring one of the following genetic alterations (or equivalent gene nomenclature for each) per local testing associated with upregulation of HOX:

i. NPM1 mutation
ii. KMT2Ar - 11q23 rearrangements
iii. KMT2A-PTD with normal karyotype
iv. NPM1::MLF1 - t(3;5)(q25;q34)
v. NUP98r - 11p15 rearrangements
vi. SET::NUP214 - t(9;9)(q34;q34)
vii. RUNX1::EVI1 - t(3;21)(q26;q22)
viii. MYST3::CREBBP - t(8;16)(p11;p13)
ix. CDX2::ETV6 - t(12;13)(p13;q12)
x. CALM::AF10 - t(10;11)(p13;q14-21)
xi. MN1::ETV6 - t(12;22)(p13;q12)
xii. UBTF-TD with Normal karyotype

b. Backfill: Participants must have a diagnosis of AML or ALL/MPAL according to the WHO 2022 harbouring a KMT2Ar or NPM1m per local testing.

4. Participants must have measurable disease that is relapsed/refractory to conventional therapies known to be effective for their disease and not have any available approved therapies.

a. Relapsed and primary refractory acute leukaemia is defined by 2022 European Leukemia Net criteria (Döhner et al, 2022) after standard of care therapy including but not limited to 2 cycles of intensive chemotherapy, HMA monotherapy, or HMA combinations such as HMA/venetoclax.

b. Relapsed and primary refractory MDS is defined by = 5% blasts in the bone marrow and/or persistence of peripheral blasts after treatment with at least 2 cycles of HMA. Participants ineligible for the treatment with an HMA and without any other SoC options are allowed to enrol.

c. White blood cell count below 25,000/µL. Participants may receive cytoreduction per protocol-specified criteria (Section 6.9.1).

d. Performance status: ECOG = 2 (Appendix H)

e. Life expectancy: = 8 weeks

Additional Inclusion Criteria for Nested Food Effect participants

To participate in the nested food effect study (Section 10.4.4), participants must:
- Be at least 18 years of age.
- For the fed assessment portion, be willing to fast overnight (for at least 10 hours) prior to consuming a high-fat meal as defined in Section 10.4.4.1.

Exclusion Criteria - Core

Participants must meet the eligibility criteria of both the core protocol and the module-specific criteria, as applicable. Module-specific exclusion criteria for Module 1 are presented in Section 10.5.2 and Module 2 are presented in Section 11.5.2.

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

1. Participants with Burkitt lymphoma/leukaemia based on WHO 2022 (Alaggio et al, 2022 ) or Acute Promyelocytic Leukaemia based on WHO 2022 criteria (Khoury et al, 2022).

2. Isolated extramedullary disease.

3. Active testicular or active CNS (> CNS1 or radiographic) involvement by leukaemia.

4. Participants with any of the following are required to have a diagnostic CSF analysis performed during the screening period to ensure CNS1 status:
a) Participants with symptoms or signs of CNS involvement.
b) Participants with a history of CNS involvement.
c) Participants with history of extramedullary disease.
d) WBC = 50,000/µL at most recent presentation.

5. Acute or active chronic GvHD Grade > 0 within 4 weeks of enrolment except Grade = 2 GvHD of the skin.

6. Unresolved treatment-related toxicities Grade = 2 from prior therapy (except alopecia, stable Grade = 2 neuropathy, vitiligo, and endocrine disorders that are controlled with replacement hormone therapy).

7. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial or other treatment).

a) Participants who test positive for anti-HBc IgG will need to have a negative HBV PCR result before enrolment and the HBV viral load by PCR must be monitored repeatedly while on study per institutional guidance. Those who are HBV surface antigen positive and those with detectable HBV using PCR will be excluded.

b) Participants who are HCV antibody positive will need to have a negative PCR result before enrolment and sustained undetectable viral load for > 12 weeks prior to enrolment. HCV viral load must be monitored while on study per institutional guidance.

c) Participants with positive CMV IgM and/or positive PCR (as defined by local clinical laboratory standard) will be excluded.

d) HIV-infected participants on an effective anti-retroviral therapy with sustained undetectable viral load for > 6 months prior to enrolment are eligible for this study after confirmation from the Sponsor. HIV viral load must be monitored while on study per institutional guidance.

e) Participants with active tuberculosis infection (based on clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice).

8. Clinically significant cardiovascular disorder as judged by the investigator or defined as:

f) History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade = 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia within 6 months prior to start of study treatment. Participants with atrial fibrillation controlled by an allowed concomitant medication are permitted. Note: Participants with atrial fibrillation or flutter and ventricular rate of < 100 bpm may be eligible as judged by the investigator.

g) Complete bundle branch block or intraventricular conduct dysfunction with QRS > 120 ms or high-degree AV block (II-III) or sinus node dysfunction with significant sinus pause, untreated with pacemaker.

h) Uncontrolled hypertension.

i) Symptomatic hypotension as judged by the investigator or systolic BP < 90 mmHg.

j) Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months of enrolment.

k) History of brain perfusion problems (eg, carotid stenosis) or stroke (haemorrhagic or thrombotic), or transient ischemic attack in the last 6 months prior to enrolment.

l) Symptomatic heart failure (as defined by New York Heart Association >II) or history of hospitalisation for heart failure within 6 months of enrolment.

m) Prior or current cardiomyopathy that is not adequately controlled.

n) Severe valvular heart disease.

o) Any factors that increase risk of QTc prolongation or risk of arrhythmic events such as symptomatic heart failure, congenital long QT syndrome (LQTS), family history of LQTS, or unexplained sudden death under 40 years of age in first-degree relatives.

9. Abnormal levels of potassium or magnesium prior to first dose of AZD3632 (supplementation is permitted).

10. History of a prior non-haematological malignancy, except for adequately treated basal cell or squamous cell skin, carcinoma in situ, or other cancer from which the participant has been disease free with no evidence of recurrence for = 2 years.

11. Any severe and uncontrolled medical condition requiring treatment including but not limited to bleeding disorders, unstable respiratory, uncontrolled psychiatric illness, substance abuse, or social situations which in the investigator’s judgement substantially increase risk of incurring AEs or limit compliance with study requirements.

12. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, previous significant bowel resection, or other condition or procedure (eg, gastric bypass, gastroparesis) that would preclude adequate absorption of AZD3632 or inability to swallow the formulated product (tablets or capsules).

Prior/Concomitant Therapy

13. Receipt of live attenuated vaccine within 30 days before the first dose of study treatment(s).

14. Major surgery within 28 days of first dose of study treatment.

15. Any concomitant medications known to be associated with Torsades de Pointes or QT/QTcF prolongation (must be discontinued at least 5 half-lives prior to the first dose of AZD3632). Note: Drugs with low risk of QT/QTc prolongation used as standard supportive therapies are permitted with caution (eg, diphenhydramine, famotidine, ondansetron, Bactrim).

Prior/Concurrent Clinical Study Experience

16. Participation in another clinical study with a study intervention administered in the last 14 days or 5 half-lives whichever is shorter (for investigational biologic or cell therapies, refer to individual module exclusion criteria)Participants with a known hypersensitivity to AZD3632 or any of the excipients of the product.

Other Exclusions

18. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Judgement by the investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements, and should not
participate in the study.

20. Previous enrolment in the present study.

21. For WOCBP: Currently pregnant (confirmed by a positive pregnancy test) or breast-feeding, or intending to become pregnant during the study period.



Exclusion Criteria

Refer to Section 5.2 of the core protocol for exclusion criteria applicable to all modules.
Additional exclusion criteria applicable to Module 1 only are described in this section.
Participants are excluded from the study if any of the exclusion criteria in the core protocol (Section 5.2) or the Module 1 specific exclusion criteria below apply.

Prior/Concomitant Therapy

1. Prior exposure to other menin inhibitors:
a. Participants in dose escalation may be menin-inhibitor naive or menin-inhibitor exposed.
b. Participants in backfill may ONLY be menin-inhibitor naive (eg, participants with prior menin inhibitor exposure will be excluded from backfill).

2. Prior DLI < 4 weeks, cell therapy (eg, CAR-T, NK) or autologous HSCT < 8 weeks, or prior allogeneic HSCT < 12 weeks of the first scheduled dose. Participants must have completed systemic immunosuppressive therapy for the treatment of acute or active chronic GvHD within 4 weeks prior to AZD3632 treatment. The following are permitted:
a. Topical steroids for = Grade 2 GvHD of the skin may continue indefinitely.
b. Stable (= 10 mg of prednisone or equivalent per day) or tapering systemic steroids for GvHD up to 4 weeks prior to the first dose of study treatment.

3. Receipt of any anticancer agent (non-investigational or investigational):

a. For non-biologic agents, therapy within 14 days or 5 half-lives (whichever is shorter) of the first scheduled dose.
b. For biologic agents, therapy within 30 days or 5 half-lives (whichever is shorter) of the first scheduled dose.
c. Prior treatment with other menin inhibitors (backfill participants ONLY)
d. The following are permitted
i. Cytoreduction with short-term steroids or hydroxyurea (Section 6.9.1)
ii. Intrathecal therapy per institutional guidance (Section 6.9.3). Dose escalation participants may ONLY receive intrathecal therapy after the DLT period.

4. Receipt of non-CNS radiation therapy within 2 weeks and of CNS radiation within 8 weeks of the first scheduled dose.

5. Any concomitant medications (including St John’s wort) known to be strong or moderate inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) (must be discontinued at least 14 days or 5 half-lives, whichever is longer prior, prior to the first dose of AZD3632).

Additional Exclusion Criteria for Nested Food Effect participants

Participants must not participate in the nested food study (Section 10.4.4), if the following exclusion criteria are fulfilled:
- Diagnosis of diabetes mellitus (Type I or Type II)
- Any other conditions which in the investigator’s judgement increase the risk of incurring AEs or limit compliance with the food effect evaluation

Participants are eligible to be included in the study only if all of the following criteria apply.
The below are the core inclusion criteria for all modules of the study; all participants must also meet the criteria described in the relevant module in addition to those described below.
Where module-specific criteria are more stringent than core study criteria, the module-specific criteria take precedence.

Age

1 Participant must be 18 or the legal age of consent in the jurisdiction in which the study is taking place, or older, at the time of signing the informed consent.

Type of Participant and Disease Characteristics

2 Eastern Cooperative Oncology Group performance status of = 2 (Note: in EU countries this inclusion is Eastern Cooperative Oncology Group performance status of < 2).

3 Able to provide a tumor biopsy sample collected before treatment with AZD5492 (except for participants with CLL, for whom a bone marrow sample should be provided).
Note: Receipt of tumor samples does not have to occur prior to study enrolment.

4 Adequate organ and bone marrow function as detailed in Table 5.

Criteria for Adequate Organ and Bone Marrow Function at Screening

Parameter: Value

HEMATOLOGICALl ^a
- Hemoglobin: = 8 g/dL (4.96 mmol/L)
- Absolute neutrophil count: = 1 x 10^9/L (1000 per mm^3) ^b
If BM involvement, = 0.75 x 10^9/L
- Platelet count = 50 x 10^9/L (50000 per mm^3)
- Absolute lymphocyte count = 25 x 10^9/L (25000 per mm^3)

HEPATIC
- TBL: = 1.5 x ULN in the absence of Gilbert’s syndrome (or = 3.0 x ULN in presence of Gilbert’s syndrome)
- AST and ALT: = 3 x ULN (or = 5 x ULN if elevated values are primarily due to the significant liver involvement of the disease)

RENAL
- CrCl by Cockcroft and Gault method: CrCl = 50 mL/minute
OR
- Serum creatinine: Serum creatinine < 1.5 x ULN

COAGULATION
- INR: < 1.5 x ULN

PANCREATIC
- Lipase: = 1.5 x ULN
- Amylase: = 1.5 x ULN and no active pancreatitis

CARDIAC
- LVEF as measured by echocardiography, MUGA, or MRI: > 45%

a Hematological criteria cannot be met with ongoing or recent blood transfusions (within 7 days prior to the date of the screening laboratory assessment)
b Short acting myeloid growth factors (eg, G-CSF) are permitted up to 72 hours prior to the date of the screening laboratory assessment. Long-acting myeloid growth factors (eg, Peg-G-CSF) are permitted up to 21 days prior to the date of the screening laboratory assessment.

Sex and Contraceptive/Barrier Requirements

5 Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Refer to Appendix L for definitions of women of childbearing potential and highly effective methods of contraception.

(a) Male participants:
(i) Condom use is required throughout the study and for 75 days (ie, 5 half lives and 2 weeks to clear exposed sperm) following last dose.
(ii) Male participants must not donate or bank sperm during the same time period.
(b) Female sexual partners of male study participants:
(i) One form of highly effective contraception (see Appendix L) for the sexual partners of male trial participants throughout the study and for 75 days (ie, 5 half-lives and 2 weeks) following last dose.

(c) Female participants of childbearing potential:
(i) All women of childbearing potential must have a negative serum pregnancy test result at the Screening Visit (Note: In Japan, even if the pregnancy test result is negative, a participant could be excluded where it is judged that there is a possibility of pregnancy based on the investigator’s interview, etc.).
(ii) All women of childbearing potential who are sexually active with a non-sterilized male partner must use a highly effective form of contraception (see Appendix L) throughout the study and for 60 days (ie, 5 half-lives) following last dose. Male partners of female participants of childbearing potential shall use a condom during the same period. Cessation of contraception after this point should be discussed with a responsible physician.
(iii) Female condom and male condom should not be used together.
It should be noted that interaction between hormonal contraception and AZD5492 has not been studied. Therefore, it is unknown whether AZD5492 may reduce the efficacy of the
contraceptive method.

Informed Consent

6 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

7 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the
Genomic Initiative (see Appendix D 2).

Participants are excluded from the study if any of the below criteria apply. The below are the core exclusion criteria for all modules of the study; all participants must also meet the criteria described in the relevant module in addition to those described below. Where module-specific criteria are more stringent than core study criteria, the module-specific criteria take precedence.

Medical Conditions
1 Active CNS involvement by lymphoma, leptomeningeal disease or spinal cord compression. Participants with a prior history of CNS localization of lymphoma who received treatment are eligible provided that there is no evidence of CNS involvement at study entry as documented by CSF cytology and/or brain MRI.

2 CNS pathology including, but not limited to:

History of CNS disease which was symptomatic or required treatment in the past year such as CNS vasculitis, severe brain injury, dementia, Parkinson’s disease,
neurodegenerative diseases, cerebellar disease, severe uncontrolled mental illness, psychosis, CNS involvement of autoimmune diseases.
Paresis, aphasia, or stroke within 3 months prior to consent.
History of seizure disorder/epilepsy.
History of progressive multifocal leukoencephalopathy (PML).

3 History of Grade >= 3 CRS or Grade >=3 ICANS (see Appendix I).

4 Participants with previous history of hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

5 Participants with positive anti-HCV Ab will be excluded unless HCV PCR is undetectable at screening. Participants treated with antivirals require sustained negativity for 12 to 24 weeks following end of antiviral treatment.

6 Serologic status reflecting active hepatitis B: participants who are HBsAg positive or anti-HBc IgG Ab positive will be excluded if HBV PCR is positive. If HBV PCR is negative, they can enroll if repeat (or serial) HBV PCR is negative prior to commencing study treatment (refer to relevant SoA).

7 Active HIV infection. HIV-infected participants on effective anti-retroviral therapy with sustained undetectable viral load for longer than 6 months prior to enrollment are eligible
for this study after confirmation from the sponsor.

8 Participant has any medical or psychiatric condition which, in the opinion of the investigator or Medical Monitor, places the participant at an unacceptably high risk for toxicities, could interfere with successful or safe delivery of therapy, or could interfere with evaluation of the investigational product or interpretation of participant safety or study results. Examples include major psychiatric illness and drug or alcohol abuse.

9 History of QT prolongation associated with other medications, that required discontinuation of that medication.

10 Congenital long QT syndrome.

11 History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia) which is symptomatic or requires treatment, symptomatic or uncontrolled atrial fibrillation, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication are permitted.

12 Major cardiac abnormalities, including but not limited to the following: uncontrolled angina (or unstable life-threatening arrhythmias), history of myocardial infarction
<= 12 weeks before screening, Class >= 3 New York Heart Association congestive heart failure, severe cardiac insufficiency, or persistent QTc prolongation (>= 480 msec, QTcF).

13 Unresolved non-hematological AEs Grade = 2 (NCI CTCAE v5.0) due to prior anticancer therapy except for:

Alopecia
Fatigue
Grade 2 peripheral neuropathy
Endocrine disorders that are controlled with replacement hormone therapy
Stable vitiligo

14 Other invasive malignancy within 2 years prior to screening with the exception of:

(a) Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and considered to be at low risk of recurrence by the treating physician.
(b) Adequately treated lentigo malignant melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer.

15 Any severe and uncontrolled medical condition (eg, uncontrolled hypertension, bleeding diathesis, hepatic failure, clinically significant liver disease including cirrhosis or hepatitis, unstable respiratory or cardiac conditions, active infection [bacterial, viral, fungal or other infection], any major infection that required hospitalization or treatment with IV or oral antimicrobials within 14 days of Day 1, evidence of clinically active ILD or active pneumonitis, or history of pneumonitis/ILD) requiring treatment which in the investigator's opinion makes it undesirable or poses a safety risk for the participant to participate in the study. Note that chronic active EBV infection (known or suspected) must be excluded and that a past COVID-19 infection may be a risk factor, but if resolved and the participant is vaccinated, it may be allowable to enroll the participant.
Additionally, an active COVID-19 infection detected using either molecular or antigen tests in accordance with local testing guidelines will be excluded. Please note: Fully recovered participants (defined as no ongoing COVID-19 symptoms, except loss of sense of smell/taste) who present persistence of positive PCR test with a negative antigen test and the presence of IgG antibodies, may be included in the study.

16 Active or prior documented autoimmune or inflammatory disorders including, but not limited to, inflammatory bowel disease (eg, colitis or Crohn’s disease), myasthenia gravis,
myositis, autoimmune hepatitis, diverticulitis, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves’ disease,
rheumatoid arthritis, hypophysitis, uveitis, vascular thrombosis associated with antiphospholipid syndrome, Sjogren syndrome, Guillain-Barre syndrome, vasculitis, glomerulonephritis, etc. The following are exceptions to this criterion:

(a) Vitiligo or alopecia
(b) Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
(c) Controlled Type 1 diabetes mellitus on insulin.
(d) Any chronic skin condition that does not require systemic therapy.
(e) Participants without active disease in the last 5 years may be included but only after consultation with the Study Physician.
(f) Celiac disease, controlled by diet alone.

Prior/Concomitant Therapy

17 Treatment with any of the following:

(a) Received adoptive cellular therapy such as autologous or donor NK cell or T lymphocyte infusions [eg, CAR-T cells]), or T-cell engager therapy, within 90 days prior to the first dose of study treatment.
(b) Received any anti-CD20 monoclonal antibody within 28 days prior to the first dose of study treatment.
(c) Received any investigational drug within 21 days (or 5 half-lives, whichever is shorter) prior to the first dose of study treatment.
(d) Received any other chemotherapy, immunotherapy, immunosuppressant medication (other than low dose of corticosteroids, ie, <= 20 mg prednisone or equivalent) or anticancer agents within 21 days or 5 half-lives (whichever is shorter, except for steroids, which should be 21 days) prior to the first dose of study treatment.
(e) Received radiation therapy with curative intent within 14 days prior to the first dose of study treatment (localized palliative radiotherapy is permitted).
(f) Received prior allogeneic HSCT, unless the transplant occurred > 180 days prior to the first scheduled dose and the participant has no active graft-versus-host disease requiring treatment and has been stable off immunosuppression for at least 2 months.
(g) Received prior autologous HSCT unless the transplant occurred > 90 days prior to the first scheduled dose and transplant-related toxicities are resolved to at least a Grade 1.
(h) Received major surgery within 28 days prior to the first dose of study treatment.

18 Receipt of live, attenuated vaccine within 28 days before the first dose of study treatment(s).

Prior/Concurrent Clinical Study Experience

19 Participants with a known hypersensitivity to AZD5492 or any of the excipients of the product.

Other Exclusions

20 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

21 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

22 Previous dosing with AZD5492 in the present study.

23 Currently pregnant (confirmed with positive pregnancy test) or breast feeding or intention of becoming pregnant (female) or having child (male) during the study or within 75 days
(male)/60 days (female) after the last dose of AZD5492.

General Inclusion Criteria

Individuals must meet the following criteria for study entry:

- Signed Informed Consent Form

- Age = 18 years at time of signing Informed Consent Form

- Ability to comply with the study protocol

- Agreement to adhere to the contraception requirements described in Section 5.4

- Measurable, or non-measurable but evaluable, disease per RECIST v1.1
Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.

- ECOG Performance Status of 0 or 1

- Life expectancy = 12 weeks

- Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:

- ANC = 1.2 x 10^9/L (1200/MikroL) without granulocyte colony-stimulating factor support

- Platelet count = 100 x 10^9/L (100,000/MikroL) without transfusion

- Hemoglobin = 90 g/L (9 g/dL)

- AST, ALT, and ALP = 2.5 x ULN, with the following exceptions:
Individuals with documented liver metastases: AST and ALT = 5 x ULN
Individuals with documented liver or bone metastases: ALP = 5 x ULN

- Total bilirubin = 1.5 x ULN with the following exception:
Individuals with known Gilbert disease: total bilirubin = 3 x ULN – Estimated creatinine clearance = 60 mL/min, calculated using the Cockcroft-Gault equation

- Albumin = 25 g/L (2.5 g/dL)

- For individuals not receiving therapeutic anticoagulation: INR and aPTT = 1.5 x ULN
For individuals receiving therapeutic anticoagulation: stable anticoagulant regimen – Calcium, magnesium, and potassium levels = Grade 1

- Negative HIV test at screening

- Negative hepatitis B surface antigen (HBsAg) test at screening

- Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following:

- Negative hepatitis B core antibody (HBcAb)

- Positive HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL

The HBV DNA test will be performed only for individuals who have a negative HBsAg test, a negative HBsAb test, and a positive HBcAb test.

- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening The HCV RNA test will be performed only for individuals who have a positive HCV antibody test.

- Confirmed presence of the KRAS G12D mutation as documented through central laboratory testing of a representative tumor tissue sample or a prior local laboratory testing of a blood or tumor tissue sample

Local testing of blood or tumor tissue for KRAS G12D must be performed using an FDA-approved PCR or NGS assay or locally validated PCR or NGS assay performed at a CLIA-certified or equivalently certified laboratory. Refer to Section 8.6 for additional information on collection and analysis of screening samples.

- Consent to provide fresh (preferred) or archival tumor tissue specimen

It is preferred that the specimen be from the most recently available tumor tissue, and whenever possible, from a metastatic site of disease. See the laboratory manual for instructions.

- Participants must not have a known concomitant second oncogenic driver in the RTK/MAPK pathway with approved targeted therapies (e.g., sensitizing EGFR mutations, ALK rearrangement, ROS1 rearrangement, ERBB2 amplification, NTRK fusions, RET fusions, MET Exon 14 skipping mutations, BRAF V600E mutation, KRAS G12C mutation) by PCR-based or NGS assay performed at a local CLIA-certified or equivalently certified laboratory.


Participants with CRC

- Histologically documented, locally advanced, recurrent, or metastatic incurable adenocarcinoma of the colon or rectum

Participants with appendiceal tumors are excluded.
Disease progression during or after treatment with at least one prior systemic therapy. Prior systemic therapy must include an oxaliplatin-based (e.g., FOLFOX +/- bevacizumab) and irinotecan-based (e.g., FOLFIRI +/- bevacizumab) chemotherapy regimen, either given in combination (e.g., FOLFOXIRI +/- bevacizumab) or as individual lines of therapy, unless the participant has a medical contraindication to one of the required therapies.


Participants with PDAC

- Histologically documented, locally advanced, recurrent, or metastatic incurable PDAC

Disease progression during or after treatment with at least one prior systemic therapy (e.g., gemcitabine with nab-paclitaxel, FOLFIRINOX), unless the participant has a medical contraindication to one of the required therapies.


Participants with NSCLC

- Histologically documented, locally advanced, recurrent, or metastatic incurable NSCLC

Disease progression during or after treatment with at least one prior systemic therapy. Prior systemic treatment must include a platinum-based doublet chemotherapy regimen and a PD-L1/PD-1 inhibitor, either given in combination as one line of therapy or as individual lines of therapy, unless the participant has a medical contraindication to one of the required therapies.

Participants with Other Solid Tumors

- Histologic documentation of locally advanced, recurrent, or metastatic incurable malignancy except CRC, PDAC, and NSCLC

Participants who have received all available standard therapies; or for whom standard therapy has proven to be ineffective or intolerable; or for whom a clinical trial of an investigational agent is a recognized standard of care may be enrolled.

Backfill Biopsy Participants

- Accessible lesion(s) that permit a total of at least two biopsies (pre-treatment and on-treatment) without unacceptable risk of a significant procedural complication

If multiple lesions are available, it is preferable to obtain the on-treatment biopsy from the same lesion (or organ) as the pre-treatment biopsy, if feasible, to avoid introduction of heterogeneity related to site of metastasis.

General Exclusion Criteria

Individuals who meet any of the following criteria will be excluded from study entry:

- Known hypersensitivity or medical contraindication to any component of GDC-7035 formulation

- Inability or unwillingness to swallow pills

- Inability to comply with study and follow-up procedures

- Malabsorption syndrome or other condition that would interfere with enteral absorption

- Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control)

Participants with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
- Measurable or evaluable disease outside the CNS
- No history of intracranial hemorrhage or spinal cord hemorrhage
- No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for = 2 weeks prior to enrollment and no ongoing symptoms attributed to CNS metastases
- No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to Cycle 1 Day 1
- No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study

Note: Participants with new asymptomatic CNS metastases detected at screening are eligible for the study after receiving radiotherapy and/or surgery. Following treatment, these participants may be eligible without the need to repeat the additional brain scan, if all other criteria are met.

- Pregnant or breastfeeding, or intention of becoming pregnant during study treatment and for 2 months after the final dose of GDC-7035 and 2 months after the final dose of panitumumab (see Section 5.4)

Participants of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

- Participants with chronic diarrhea, short bowel syndrome or significant upper GI surgery including gastric resection, a history of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or any active bowel inflammation (including diverticulitis)

- Treatment with chemotherapy, immunotherapy, biologic therapy, or an investigational agent as anti-cancer therapy within 3 weeks or five half-lives prior to initiation of study treatment, whichever is shorter, or endocrine therapy within 2 weeks prior to initiation of study treatment, except for the following:

Hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate, endometrial, hormone receptor-positive breast cancer) is allowed.

Kinase inhibitors, approved by regulatory authorities, may be used up to 2 weeks prior to initiation of study treatment, provided any drug-related toxicity has completely resolved and upon consultation with the Medical Monitor.

- Radiation therapy (other than palliative radiation to bony metastases and radiation to CNS metastases as described above) as cancer therapy within 4 weeks prior to initiation of study treatment

- Palliative radiation to bony metastases within 2 weeks prior to initiation of study treatment

- Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better except for alopecia, vitiligo, endocrinopathy managed with replacement therapy, or Grade =
2 peripheral neuropathy

- Treatment with a strong or moderate CYP3A inhibitor or strong or moderate CYP3A inducer within 14 days or 5 drug elimination half-lives, whichever is longer, prior to initiation of study treatment

- Treatment with a strong P-glycoprotein or breast cancer resistance protein (BCRP) inhibitor or inducer within 14 days or 5 drug elimination half-lives, whichever is longer, prior to initiation of study treatment

- Expected need for ongoing treatment with a strong or moderate CYP3A inhibitor, strong or moderate CYP3A inducer, or strong P-glycoprotein or BCRP inhibitor or inducer

- Poor peripheral venous access without central access

- Major surgical procedure within 28 days prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study

Participants with biliary obstruction for whom a biliary drain or stent has been placed are eligible, provided that the drain or stent has been in place for at least 10 days prior to initiation of study treatment, and the liver function has stabilized.

- Prophylactic routine immunizations or vaccinations within 2 weeks prior to initiation of study treatment or planned vaccine treatment during the DLT assessment window

- Infection requiring systemic (i.e., oral, IV, or intramuscular) antibiotics within 7 days prior to initiation of study treatment or any evidence of current infection (e.g., bacterial, viral, fungal)

In the setting of a pandemic or epidemic, screening for active infections should be considered according to local or institutional guidelines or guidelines of applicable professional societies.

- Any medical condition or abnormal clinical laboratory finding that, in the investigator's judgment, would preclude the individual's safe participation in and completion of the study or could affect the interpretation of the results

- Any prior treatment with RAS targeted small molecule inhibitors (e.g., KRAS G12C inhibitors, KRAS G12D inhibitors, pan KRAS inhibitors, and pan RAS inhibitors)

Prior treatment with inhibitors targeting other components of the MAPK pathway (e.g., MEK or BRAF inhibitors) is permitted.

- History of other malignancy within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death and/or treated with expected curative outcome (such as appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer)

- Known clinically significant liver disease, including active viral, alcoholic, or other forms of hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse, or evidence of active or clinically significant biliary disease

- History of or active clinically significant cardiovascular dysfunction, including the following:

- History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment
- History of myocardial infarction within 6 months prior to initiation of study treatment
- New York Heart Association Class III or IV cardiac disease or congestive heart failure requiring medication (see Section 12.9)
- Uncontrolled arrhythmias, history of or active ventricular arrhythmia requiring medication
- Coronary heart disease that is symptomatic or unstable angina
- Congenital long QT syndrome or family history of sudden unexplained death or long QT syndrome

- QT interval corrected through use of Fridericia's formula (QTcF) > 450 ms

- Medications that are well known to prolong the QT interval within 14 days or 5 drug elimination half-lives, whichever is longer, prior to initiation of study treatment or anticipated need during study treatment with GDC-7035 and for 30 days after the final dose of GDC-7035

- Any other diseases, metabolic dysfunction, physical examination finding, and/or clinical laboratory finding giving reasonable suspicion of a disease or condition that, in the opinion of the investigator, contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk from treatment complications


Participants with CRC

- Known hypersensitivity to any of the components of panitumumab

- History of interstitial pneumonitis, or pulmonary fibrosis

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Males or females aged 18 years or older (=18 years).

2. Tumor diagnosis and past anti-tumor treatment history:

Phase 1a: participants with pathologically confirmed advanced solid tumor (key local diagnostic molecular and/or immunophenotyping testing results/ tumor cell phenotype results for confirmed diagnosis should be provided) who have failed or are intolerant to standard of care.

Phase 1b: participants with pathologically confirmed advanced solid tumor (key local diagnostic molecular and/or immunophenotyping testing results/tumor cell phenotype results for confirmed diagnosis should be provided). Participants will be enrolled in 1 of 2 cohorts according to tumor diagnosis:

- Cohort 1 PROC:

a. Histologically documented, advanced (metastatic and/or unresectable) high -grade serous/endometrioid ovarian, primary peritoneal, or fallopian tube cancer.
b. Must have received or are intolerant to 1 but no more than 4 lines of prior systemic therapy.
c. Platinum-resistant disease, defined as progression or relapse within 6 months after the completion of platinum-based therapy.
d. Must have had prior bevacizumab, unless there is a documented contraindication or intolerance.
e. Participants with known FR-alpha expressing tumors must have received mirvetuximab soravtansine if the regimen is locally available, unless there is a documented contraindication or intolerance.
f. Participants with known BRCA mutated tumors should have received a PARP inhibitor if the regimen is locally available, unless there is a documented contraindication or intolerance.

- Cohort 2 EC:

a. Histologically documented, advanced (metastatic and/or unresectable) or recurrent EC.
b. Must have received or are intolerant to 1 but no more than 4 lines of prior systemic therapy.
c. Must have had prior platinum and PD(L)-1 inhibitor (in same regimen or in separate regimens) if the regimen is locally available, unless there is a documented contraindication or intolerance.
d. All epithelial histologies are permitted including carcinosarcoma.

NOTE: Prior lines of therapy are defined as follows:

- Adjuvant +/- neoadjuvant is considered one line of therapy.
- Maintenance therapy (e.g., bevacizumab, PARPi) will be considered as part of the preceding line of therapy (i.e., not counted independently).
- Therapy changed to another agent in the same class due to toxicity, in the absence of progression, will be considered as part of the same line of therapy (i.e., not counted independently).
- Unplanned addition or switching to a new drug in a different class is considered a separate line of therapy.
- Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.

NOTE: A regimen is considered locally available when it has regulatory approval in the relevant tumor type in the participating country, is reimbursed or otherwise routinely accessible through national healthcare or private insurance in countries without national healthcare, and, where applicable, an approved diagnostic test is available. In dose expansion study, if participants who are intolerant to standard of care are eligible for enrollment, ensure that the reason for this determination (i.e., why participant was considered intolerant to standard therapy) is well documented in the case report form for each participant.

3. Participants have at least 1 TL as assessed per the RECIST 1.1. A TL is defined as a measurable lesion that has not undergone locoregional treatment such as irradiation, or a lesion that has worsened following locoregional treatment. Note: It is preferable not to have a pathological lymph node as a singular TL.

4. Requirements for tumor tissue samples: tumor tissue from a newly obtained biopsy or archival tumor tissue is required for retrospective detection of B7-H4 expression by IHC in central laboratory and other biomarker analysis. Tissue from a newly obtained biopsy is preferred. If a newly obtained biopsy is not feasible, archival tumor tissue obtained from the most recent sample prior to the first dose of study drug is acceptable.

5. The ECOG PS score of 0 to 2 and no deterioration within 2 weeks before the first dose.

6. Have a life expectancy of at least 12 weeks.

7. Is willing to use adequate contraception. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

a. Male participants:
Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 5 months after the last dose of study intervention:

- Refrain from donating sperm.

PLUS either:

- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.

OR

- Must agree to use contraception/barrier as detailed below:
- Agree to use a male condom with female partner use of an additional highly effective contraceptive method with a failure rate of < 1% per year as described in Section 10.4 when having sexual intercourse with a WOCBP who is not currently pregnant.

b. Female participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

- Is a WONCBP as defined in Section 10.4.

OR

- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency, as described in Section 10.4, 28 days prior to and during the study intervention period and for at least 8 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.
The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.

8. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention (see Section 8.3.6).

- If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

- Additional requirements for pregnancy testing during and after the study intervention are located in Section 8.3.6.

- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

9. Participants must be voluntarily enrolled in this clinical trial, be able to understand the study procedures and to sign written informed consent.

Participants cannot be enrolled in this study if they meet any of the following exclusion criteria:

1. Have received any B7-H4 targeted therapy.

2. Have received any cytotoxic chemotherapy drugs, anti-tumor traditional Chinese medicines or other anti-tumor drugs (including endocrine therapy, molecular targeted therapy, immunotherapy, biotherapy and investigational drug) within 28 days prior to the first dose of study drug; or need to continue these drugs during the study.

3. Have received locoregional radiation therapy within 2 weeks prior to the first dose of study drug; more than 30% of bone marrow irradiation (see Section 10.10 for details) or wide-field radiation therapy within 4 weeks prior to the first dose of study treatment.

4. Presence of pleural/abdominal effusion/ascites requiring clinical intervention (participants who do not need drainage or are stable for more than 2 weeks after effusion drainage are eligible); presence of pericardial effusion (minor pericardial effusion stable for 2 weeks or longer is allowed). If anti-tumor drugs are used locally during drainage (such as thoracic perfusion), at least 5 half-lives or 21 days (whichever is shorter) should also be elapsed before the first dose of study treatment.

5. Major surgery (such as craniotomy, thoracotomy or laparotomy, et al.) within 28 days prior to the first dose of study treatment.

6. Evidence of brain metastasis (unless meeting all of the following criteria:
asymptomatic; medically stable for at least 4 weeks prior to initial dosing; no steroid treatment required for at least 2 weeks prior to initial dosing; and no imaging evidence of severe edema located around the tumor lesion); untreated progression due to brain metastasis during or after the last treatment prior to screening; evidence of meningeal or brainstem metastasis; evidence of spinal cord compression (detected by radiographic examination, symptomatic or not).

7. Use of inhibitors or inducers of P-gp, or inhibitors of BCRP or OATP1B1/1B3 are prohibited throughout the study and until 30 days after discontinuation of the investigational product. P-gp, BCRP, or OATP1B1/1B3 inhibitors should be discontinued for at least 7 days before the start of the study drug. P-gp inducers should be discontinued for at least 14 days before the start of the study drug (see Section 6.9.3.2).

8. Has ongoing adverse reaction(s) from prior therapy that has (have) not recovered to = Grade 1 or to the baseline status preceding prior therapy, excluding e.g., alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy, or that the investigator, with the agreement of the sponsor, considers to be not clinically relevant for the tolerability of study intervention in the current clinical study.

9. Have a known history of prior malignancy except for:
a. Malignancies that have been cured, inactive for = 5 years before enrollment and at very low risk of relapse;
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of relapse;
c. Adequately treated carcinoma in situ (e.g., cervix carcinoma in situ) without evidence of relapse;
d. Definitively treated non-metastatic prostate cancer.

10. Has inadequate bone marrow reserve or hepatic/renal functions with any of the following laboratory abnormalities (blood product transfusions or colony-stimulating factors within 14 days prior to screening is not permitted):
a. Neutrophil count < 1.5 x 109^/L;
b. Platelet count < 100 x 10^9/L;
c. Hemoglobin < 90 g/L;
d. Bilirubin > 1.5 x ULN; NOTE: Participants with Gilbert’s syndrome can be included with a total bilirubin value > 1.5 x ULN, provided direct bilirubin is = 1.5 x ULN and participant otherwise meets entry criteria.
e. Has an ALT value > 2.5 x ULN and/or for participants documented liver metastases/tumor infiltration has an ALT value > 5 x ULN;
f. eGFR < 30 mL/min calculated by CKD-EPI 2021 formula and indexed to body surface area [Section 10.12]);
g. INR >1.5 and APTT > 1.5 x ULN;
h. Serum albumin < 28 g/L.

11. Any following cardiological examination abnormality:
a. Has QTcF > 450 msec or QTcF > 480 msec for participants with bundle branch block;
b. Evidence of current clinically significant arrhythmias or ECG abnormalities (e.g., complete left bundle branch block, third-degree AV block, second-degree AV block, PR interval > 250 msec);
c. Risk factors of prolonged QTc or arrhythmia events, such as heart failure, refractory hypokalemia, or unexplained sudden death of any direct relative under 40 years old;
d. LVEF < 50%.

12. Have severe, uncontrolled or active cardiovascular disorders, including but not limited to:
a. MI within 6 months prior to first dose of study treatment;
b. Unstable angina within 6 months prior to the first dose of study treatment;
c. CHF within 6 months prior to the first dose of study treatment;
d. Cerebrovascular accident or transient ischemic attack within 6 months prior to the first dose of study treatment;
e. History of clinically significant (as determined by the investigator) atrial arrhythmia;
f. History of clinically significant (as determined by the investigator) ventricular arrhythmia, or occurrence of any clinically significant ventricular arrhythmia during screening.

13. Serious or poorly controlled hypertension, including: history of hypertensive crisis, hypertensive encephalopathy; adjustment of antihypertensive medications due to
poor blood pressure control within 2 weeks prior to the first dose of study treatment.

14. Clinically significant bleeding symptoms or significant bleeding tendency within 1 month prior to the first dose of study treatment.

15. Serious arteriovenous thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, etc.) within 3 months prior to the first dose of study treatment (except for implantable venous port, catheter-related thrombosis, or superficial vein thrombosis, which are not considered "serious" thromboembolism).

16. Serious infections within 4 weeks prior to the first dose, including but not limited to infectious complications, bacteremia, severe pneumonia treated with intravenous antibiotics for = 2 weeks; Participants who are receiving or have received prophylactic antibiotics (e.g., prophylaxis against urinary infections) are allowed.

17. Have documented presence of HBsAg, HBcAb or HBsAb (except for presence of
HBsAb attributable to previous vaccination) at Screening or within 3 months prior to
first dose of study intervention.

18. Has a positive HCV antibody test result at Screening or within 3 months prior to first dose of study intervention. NOTE: Participants with a positive HCV antibody test result due to prior resolved disease can be enrolled, only if a confirmatory negative HCV RNA test is obtained and the participant otherwise meets entry criteria.

19. Has a positive HCV RNA test result at Screening or within 3 months prior to first dose of study intervention. NOTE: The HCV RNA test is optional and participants with negative HCV antibody test are not required to undergo HCV RNA testing as well.

20. Have active infectious diseases, such as tuberculosis (evidence of active tuberculosis infection within 1 year), syphilis (positive for treponema pallidum-specific antibodies and nonspecific antibodies), or HIV infection (anti-HIV antibody positive), etc. Screening tests for these diseases are not mandatory in screening.

21. Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.

NOTE: Stable noncirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if the participant otherwise meets entry criteria.

22. Has current active pneumonitis/ILD or any history of ILD, any history of pneumonitis requiring steroids or immunomodulatory treatment within 90 days of planned randomization/enrollment or any history of drug-induced pneumonitis/ILD.

23. History of severe neurological or psychiatric disorders, including epilepsy, dementia or major depression that interfere with the assessment.

24. Pregnant or breastfeeding women or women who intend to become pregnant during the study.

25. Allergy or hypersensitivity to any component of Mo-Rez (antibody-drug conjugate, antibody, toxin HS-9265) or its excipients, history of severe allergies (e.g., anaphylactic shock), or severe infusion-related reactions, or idiosyncrasy to recombinant humanized or mouse proteins.

26. Participants unlikely to comply with study procedures, restrictions and requirements as determined by the investigator.

27. Participants with any condition that jeopardizes the safety of the participant or interferes with the assessment of the study, as judged by the investigator.

28. Receipt of live vaccine within 30 days of the start of study intervention. Seasonal flu vaccines that do not contain live virus and COVID-19 vaccines are permitted.

29. Additional exclusion criteria specific to Cohort 1 and Cohort 2 are as below:

Cohort 1: PROC

a. Primary platinum refractory disease (as per GCIG criteria [Vergote, 2022], i.e., those who have progressed on or within 12 weeks of last dose of first line of platinum therapy) are not permitted.

b. Non-epithelial carcinoma, clear-cell, mucinous, germ-cell, low-grade serous, or lowgrade endometrioid carcinoma not permitted.

c. Have received prior therapy with topoisomerase I inhibitors or topoisomerase I inhibitor ADCs.

Cohort 2: EC

a. Mesenchymal tumors of the uterus (uterine sarcomas) not permitted.

b. Have received prior therapy with topoisomerase I inhibitors or topoisomerase I inhibitor ADCs.

All patients must be registered before start of treatment and must meet all of the following eligibility criteria.

- Documented relapsed or refractory CLL or SLL (SLL in phase II part only) following at least one systemic 1st-line treatment

- Requiring treatment according to IWCLL criteria (appendix A);

- Age at least 18 years;

- ECOG/WHO performance status 0-2;

- Adequate BM function defined as:
- Hemoglobin > 5.6 mmol/l or Hb > 9 g/dL, unless low Hb is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy;
- Absolute neutrophil count (ANC) >1.0 x 10^9/L (1,000/µL), unless low ANC is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy;
- Platelet count > 30 x 10^9/L (30,000/µL), unless low platelets is directly attributable to CLL/SLL infiltration in the BM;

- Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) = 50ml/min (Cockcroft-Gault appendix F);

- Adequate liver function as indicated:
- Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) = 3.0 x upper limit of normal (ULN);
- Bilirubin = .5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or controlled autoimmune hemolytic anemia);

- Prothrombin time (PT)/International normal ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (aPTT) < 1.5 x ULN; unless receiving anticoagulation;

- Negative serological testing for hepatitis B virus (HBV) (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C
antibody). Patients who are positive for anti-HBc or hepatitis C antibody may be included if they have a negative PCR within 6 weeks before enrollment. Those who are PCR positive
will be excluded;
Please note: For patients positive for anti-HBc or antibodies for hepatitis C at screening but negative with retesting, HBV-DNA or HCV-DNA PCR, respectively, has to be repeated every
month until 12 months after last dose of study treatment;

- Patient is able and willing to adhere to the study visit schedule and other protocol requirements;

- Patient is capable of giving informed consent;

- Written informed consent.

- Patient received treatment with anti-cancer agent as follows:
a. Standard agents within 2 weeks or 5 half-lives, whichever is shorter, prior to the planned first dose of epcoritamab (excluding anti-CD20 mAbs and BTKi, which can be administered until first full dose of epcoritamab); OR b. Patient received treatment with an investigational drug, within 4 weeks or 5 half-lives, whichever is shorter, prior to the planned first dose of Venetoclax;

- Prior treatment with a CD3 x CD20 bispecific antibody or CAR T-cell therapy

- Patient received prior venetoclax treatment within 24 months of registration OR patient had progressed during previous venetoclax treatment

- Transformation of CLL (Richter’s transformation);

- Prior allogeneic stem cell transplantation and/or solid organ transplantation;

- Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML);

- Malignancies other than CLL/SLL currently requiring systemic therapy or not treated in curative intention or showing signs of progression after curative treatment;

- Known allergy to xanthine oxidase inhibitors and/or rasburicase;

- History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components);

- Active bleeding or uncontrolled severe bleeding diathesis (e.g., hemophilia or severe von Willebrand disease);

- a. Ongoing active bacterial, viral, fungal, mycobacterial, parasitic or other infection requiring systemic treatment (excluding prophylactic treatment) at the time of enrollment or within the previous 2 weeks prior to the planned first dose of trial drug, including COVID-19 infection. Note that a past COVID-19 infection may be a risk factor, but if resolved and the subject is vaccinated, it may be allowable to enroll the subject.

b. Has suspected active or inadequately treated latent tuberculosis;

- Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.);

- Patient known to be HIV-positive;

- Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer (see appendix I);

- CTCAE grade III-IV cardiovascular disease including but not limited to:
- Unstable or uncontrolled disease/condition related to or affecting cardiac function, eg, unstable angina, congestive heart failure grade III or IV as classified by the New York Heart Association (see appendix A), uncontrolled clinically significant cardiac arrhythmia (CTCAE grade II or higher), or clinically significant electrocardiogram (ECG) abnormalities.
- Myocardial infarction within 6 months prior to registration.
- Patient age = 75 and or more active grade = cardiovascular conditions.
- Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 480 msec. NOTE: this criterion does not apply to patients with a left bundle branch block.
- Stroke or intracranial hemorrhage within 6 months prior to registration.

- Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D);

- Severe neurological or psychiatric disease (CTCAE grade III-IV, see appendix D);

- Neuropathy > CTCAE grade II

- Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication;

- Vaccination with live vaccines within 28 days prior to registration;

- Major surgery within 28 days prior to registration;

- Pregnant women and nursing mothers;

- Fertile men or women of childbearing potential (WOCBP) unless: ( ) surgically sterile or = years after the onset of menopause; (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device or sexual abstinence during study treatment and for 4 months after last dose of epcoritamab and 30 days after last dose of venetoclax;

- Previous participation in the HO139 CLL or HO140 CLL trial and eligible for and willing to participate in the HO159 CLL trial;

- Current participation in other clinical trial and using study medication;

- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Inclusion Criteria; HLA (S1), and Tumor Tissue Collection (S2) and Treatment Eligibility Assessment (VA)

No Inclusion criterion S1 S2 VA

1 Patients must have voluntarily signed a written ICF, be able to understand and comply with clinical trial procedures. S1 - ICF1, VA - ICF2

2 Patients = 18 years old S1 - X

3 Patients must have pathologically confirmed and documented advanced or metastatic malignancies corresponding to the planned cohort indication. S1 - X

Cohort: Treatment - Indication

Phase Ia: IMA402 monotherapy and IMA402 + pembrolizumab - Cutaneous melanoma, uveal melanoma, endometrial carcinoma (excluding uterine carcinosarcoma), epithelial ovarian, fallopian tube or primary peritoneal cancer (EOFPC)

A1/A2: IMA402 monotherapy RDE1 and RDE2 - Cutaneous melanoma, uveal melanoma, endometrial carcinoma (excluding uterine carcinosarcoma), epithelial ovarian, fallopian tube or primary peritoneal cancer (EOFPC)

restricted to serous, and endometrioid subtypes, with the exception of primary platinum
refractory disease, synovial sarcoma, or sqNSCLC

B: IMA402 + decitabine - Cutaneous melanoma, uveal melanoma, endometrial carcinoma (excluding uterine carcinosarcoma), epithelial ovarian, fallopian tube or primary peritoneal cancer (EOFPC)

C: IMA402 + IMA401 - sqNSCLC

D: IMA402 + bevacizumab - EOFPC restricted to serous, and endometrioid subtypes, with the exception of primary platinum-refractory disease

E: IMA402 + paclitaxel +/- bevacizumab - EOFPC restricted to high-grade serous, and endometrioid subtypes, with the exception of primary platinum-refractory disease
Note: In case of mixed EOFPC histology, > 50% of the primary tumor must be confirmed to be high-grade serous or endometrioid subtype.

F IMA402 + PLD +/- bevacizumab - EOFPC restricted to high-grade serous, and endometrioid subtypes, with the exception of primary platinum-refractory disease
Note: In case of mixed EOFPC histology, > 50% of the primary tumor must be confirmed to be high-grade serous or endometrioid subtype.

G: IMA402 + Opdualag - Cutaneous melanoma with the requirement that patients must have experienced disease progression during or after treatment with a checkpoint inhibitor

Phase IIa: IMA402 + Opdualag - Cutaneous melanoma with the requirement that patients must have experienced disease progression during or after treatment with a checkpoint inhibitor

Phase IIa: IMA402 + pembrolizumab - Cutaneous melanoma with the requirement that patients must have experienced disease progression during or after treatment with a checkpoint inhibitor

Phase IIa: IMA402 monotherapy - Cutaneous melanoma with the requirement that patients must have experienced disease progression during or after treatment with a checkpoint inhibitor or are ineligible for checkpoint inhibitor treatment

4 Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Exception: Measurable disease according to RECIST 1.1 is not required for patients dosed with up to 0.5 mg IMA402. VA - X^2

5 HLA genotype: HLA-A*02:01 positive (repeat assessment allowed; refer to Section 8.2.1).

For cohort C (IMA401) only: In addition, HLA-A*02:05 negative (repeat assessment allowed).

Note: In case the patient is known to be HLA-A*02:01 positive as tested routinely, or in another Immatics-sponsored clinical trial, or an Immatics-supported IIT, or as a trial-specific procedure by a local hospital laboratory or central laboratory with appropriate accreditation (e.g., CLIA, CAP, EFI, ASHI, ISO15189) using a PCR-based or sequencing-based method, S1, S2 and/or VA visits may be conducted on the same day, and treatment can be started (except for cohort C, where in order to start therapy patients also need to be known to be HLA-A*02:05 negative) . In any case, for these patients, HLA genotyping will be reconfirmed at Immatics’ designated ASHI and/or EFI-certified laboratory. S1 - X^4, VA - X

6 ECOG Performance Status of 0 to 1. S1 - X, S2 - X, VA - X^1

7 Hematology parameters need to be within defined range (repeat assessments allowed). S2 - X^5, VA - X^1

Parameter: Threshold - Cohort

Absolute neutrophil count (ANC) without G-CSF support:
= 1.0 x 10^9/L - Phase Ia, cohort A1/2 (monotherapy), B (decitabine), D (bevacizumab), F (PLD +/- bevacizumab), Phase IIa pembrolizumab and monotherapy
= 1.5 x 10^9/L - Cohort C (IMA401), E (paclitaxel +/- bevacizumab), G (Opdualag ) and Phase IIa Opdualag

Platelets:
= 75,000/MikroL - Phase Ia, cohort A1/2 (monotherapy), Phase IIa pembrolizumab and monotherapy
= 100,000/MikroL - Cohort B (decitabine), C (IMA401), D (bevacizumab), E (paclitaxel +/- bevacizumab), F (PLD +/- bevacizumab), G (Opdualag ) and Phase IIa Opdualag

Hemoglobin (transfusion permitted):
= 8 g/dL - Phase Ia, cohort A1/2 (monotherapy), G (Opdualag), Phase IIa Opdualag, pembrolizumab and monotherapy
= 9 g/dL - Cohort B (decitabine), C (IMA401), D (bevacizumab), E (paclitaxel +/- bevacizumab), F (PLD +/ bevacizumab)

Absolute lymphocyte count (ALC): = 0.5 x 10^9/L - All cohorts

8 Adequate hepatic function, as defined by a total bilirubin level = 1.5 x upper limit of normal unless the patient is a hepatocellular carcinoma patient or has known Gilbert’s syndrome (total bilirubin level of = 2.5 x ULN), and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) = 2.5 x ULN or = 5 x ULN for patients with liver metastases (repeat assessment allowed). For epithelial ovarian, fallopian tube or primary peritoneal cancer only: Albumin = 3.0 g/dL (repeat assessment allowed). VA - X^1

9 For monotherapy cohorts only: Adequate renal function defined by creatinine clearance = 30 mL/min (as estimated by Cockcroft Gault or other medically acceptable formulars such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration) (repeat assessment allowed).

For combination cohorts only: Adequate renal function defined by creatinine clearance = 45 mL/min (as estimated by Cockcroft Gault or other medically acceptable formulars such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration) (repeat assessment allowed).

In addition for cohort D and patients treated in cohort E and F in combination with bevacizumab: Baseline urine dipstick = 1+ or urine protein/creatinine ratio (UPCR) < 1.0. If dipstick = 2+, eligibility requires 24-hour urine protein < 1 g/24 h (or UPCR < 1.0). Repeat assessment allowed. VA - X^1

10 Acceptable coagulation status defined by an international normalized ratio (INR) of prothrombin time (PT) of blood coagulation = 2.0 x ULN and partial thromboplastin time (PTT) or activated PTT (aPTT) = 2.0 x ULN (repeat assessment allowed).

In addition for cohort D and patients treated in cohorts E and F in combination with bevacizumab: Systemic anticoagulation or chronic aspirin therapy (> 325 mg/day) are not allowed. Patients may receive low dose anti-coagulation therapy for peripheral port patency. S2 - X^3.5, VA - X^1

11 Phase Ia and cohorts A-D: Patients must have recurrent and/or refractory solid tumors and must have received or not be eligible for all available indicated standard-of-care treatments. VA - X

12 The patient must have recovered from any side effects of prior therapy to Grade 1 or lower (except for nonclinically significant toxicities; e.g., alopecia, vitiligo) prior to treatment start. As determined by the investigator, the patient may still be eligible if not fully recovered from Grade = 2 toxicities, in case these toxicities are not anticipated to further improve and such toxicities are not anticipated to worsen with the planned trial treatment, including any combination partner. VA - X

13 Male patients must agree to use highly effective contraception or be abstinent while on treatment and for 6 months after the last trial treatment. VA - X

14 Female patients of childbearing potential must use highly effective contraception or be abstinent, while on treatment and until 6 months after the last trial treatment. For female patients treated with PLD in cohort F, a longer post-treatment contraception period of 8 months is required, in accordance with the PLD SmPC. VA - X

15 Pembrolizumab combination therapy only: Patient must have an indication approved for the treatment with Pembrolizumab as outlined in the (Keytruda) PI/SmPC or EOFPC. VA - X

^1 Assessment to be performed 7 days prior to start of IMA402 treatment
^2 Imaging to be performed as close as possible to baseline, but within 3 weeks prior to start of treatment
^3 Only to be taken in case a biopsy is performed at S2.
^4 Eligibility verification of HLA status at VA at the latest.
^5 Eligibility verification for laboratory values at VA.

Exclusion Criteria; HLA (S1), and Tumor Sample Collection (S2) and Treatment Eligibility Assessment (VA)

No Exclusion criterion S1 S2 VA

1 Other active malignancies that require treatment or that might interfere with the trial endpoints (ongoing adjuvant anti-hormonal treatment is allowed). S1 - X, VA - X

2 The patient is pregnant (confirmed by serum or urine pregnancy test) or is breastfeeding. S1 - X^1, S2 - X, VA - X

3 History of hypersensitivity to components of IMA402 or rescue medications, if no alternative treatment option is available. S1 - X, VA - X

4 Patients with prior allogeneic stem cell transplantation or organ transplantation. S1 - X, VA - X

5 Patients with autoimmune diseases needing disease-directed treatment such as clinically relevant inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), rheumatoid arthritis, multiple sclerosis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, vasculitis, hepatitis, nephritis, dermatitis. S1 - X, VA - X

6 The patient is known to have any of the following clinically relevant cardiac conditions including, but not limited to: uncontrolled hypertension despite optimal therapy, uncontrolled angina, clinically relevant ventricular arrhythmias, congestive heart disease (New York Heart Association Class II or above), baseline left ventricular ejection fraction = 50%, prior or current clinically relevant cardiomyopathy, uncontrolled atrial fibrillation, reoccurrence of pericardial effusion within previous 4 weeks, unstable ischemic heart disease (myocardial
infarction within the last 6 months or angina requiring use of nitrates), known clinically relevant stenosis upon coronary angiography/CT, or with QTcF interval prolongation >480 msec (corrected for heart rate using Fridericia’s formula [QTcF]) or congenital long QT syndrome.

In addition for cohort D and patients treated in cohorts E and F in combination with bevacizumab: Patients with peripheral vascular disease, cerebrovascular accident or transient ischemic attack and patients with systolic blood pressure >150 mmHg or diastolic blood pressure > 100 mmHg.
In addition for cohort G and Phase IIa Opdualag combination cohort only: The patient has troponin levels > 2x ULN and/or a history of myocarditis. S1 - X^1, VA - X

7 Clinically significant pulmonary dysfunction, that, in the investigator’s judgement, would compromise the patient’s ability to tolerate protocol therapy or significantly increase the risk for complications. This includes, but is not limited to, patients with any persisting radiological evidence of prior immunotherapy related pneumonitis who will be excluded from the trial. VA - X

8 The patient has concurrent severe and/or uncontrolled medical disease that could compromise participation in the trial (e.g., uncontrolled diabetes, severe malnutrition). S2 - X, VA - X

9 History of, or current, immunodeficiency disease or prior treatment relevantly compromising immune function, at the discretion of the investigator. S2 - X, VA - X

10 Any other condition that would, in the investigator’s or sponsor’s judgement, contraindicate the patient’s participation in the clinical trial because of safety concerns (e.g., potential intolerance to IMA402) or compliance with clinical trial procedures (e.g., psychiatric disorders or substance dependence, neurological impairment). S1 - X, VA - X

11 Positive for HIV or with active hepatitis B or C infection. S1 - X^1, VA - X

12 The patient has received prior to start of trial treatment live/attenuated vaccines within 1 month, systemic corticosteroids (= 10 mg/day prednisone or equivalent), major surgery, other vaccines, therapeutic radiotherapy, cytotoxic agents, small molecule treatments or treatments with investigational agents within 2 weeks, monoclonal antibodies within 3 weeks or 5 half-lives, or cell therapies within 3 months. No wash-out period is required for hormonal therapy.
In addition for cohort D and patients treated in cohorts E and F in combination with bevacizumab: The patient has not yet recovered from prior minor surgery (insertion of a vascular access device is acceptable), has any serious non-healed wound or bone fracture or has planned major surgical procedure during the treatment phase. The window for major surgery prior to study treatment start is extended to 4 weeks.
In addition for EOFPC patients only: Drainage of ascitic fluid 2 or more times in the 4 weeks prior to the study treatment start, uncontrolled pleural effusion, or permanent drain in place for ascites or pleural effusion.

Note: Use of inhaled or topical steroids is permitted. VA - X

13 Concurrent treatment in another clinical trial or a device study that could interfere with the trial treatment after signature of ICF2. VA - X

14 Patients with active CNS metastases or history of bleeding into brain metastases or with known brain metastases who are receiving therapeutic (treatment-dose) anticoagulation (prophylactic-dose anticoagulation remains acceptable).

Note: Patients with a history of newly detected CNS metastases are eligible if none of the above applies and CNS metastases indicated for treatment were treated and showed no sign of progress, imaging studies performed =4 weeks following treatment indicate stable disease of brain metastasis, the patient is asymptomatic, and steroid therapy has been discontinued for = 2 weeks. VA - X

15 No prior experimental systemic treatment line is allowed.
All cohorts except E and F: Patients who have received more than 4 prior systemic treatment lines for treatment of advanced and/or metastatic disease. Systemic adjuvant and neo-adjuvant treatment lines with curative intent are not considered. Any number of prior systemic treatment lines in the platinum-sensitive setting is allowed.
Cohorts E and F (paclitaxel or PLD +/- bevacizumab) only: Patients who have received more than 2 prior systemic lines of anti-cancer therapy after developing platinum resistance. Systemic adjuvant and neo-adjuvant treatment lines with curative intent are not considered. Any number of prior systemic treatment lines in the platinum-sensitive setting is allowed. VA - X

16 All patients except cutaneous melanoma patients: LDH > 2.0-fold ULN.
Only applicable for cutaneous melanoma patients: LDH > 1.5-fold ULN. VA - X

17 Known presence of leptomeningeal metastases. S1 - X, VA - X

18 Any active infection or ongoing reactivation of infection (e.g., HSV, EBV, CMV) within the last 3 weeks, sepsis within the last 4 weeks. VA - X

19 Rapid clinical deterioration (e.g., worsening of performance status, worsening of clinical symptoms likely associated with rapid disease progression) within 3 weeks. VA - X

20 Patients with clinical or radiological tumor progression on TCR-based therapy, except for Tebentafusp in uveal melanoma. S1 - X, VA - X

21 For all combination cohorts only: Patients with hypersensitivity to or contraindications according to current PI/SmPC for the respective combination drug.
In addition for cohorts Phase Ia pembrolizumab, Phase IIa pembrolizumab and Opdualag and D-G (CPI or bevacizumab combinations) only:
Patients with a history of toxicity leading to permanent discontinuation of the same combination partner. VA - X

22 For cohort D and patients treated in cohort E and F in combination with bevacizumab: Patients with any of the following are excluded
- History of clinically significant bleeding, thrombotic or hemorrhagic disorders or active coagulopathy (regardless of lab values)
- Current bowel obstruction/sub-occlusion; or history of GI perforation, abdominal fistula, or intra-abdominal abscess within 6 months; or rectosigmoid/bowel involvement
- Clinically significant hemoptysis (= 2.5 mL/teaspoon) within 3 months or centrally cavitating lesions at high bleeding risk
- Need for repeated therapeutic drainage > 1x/week without a functioning indwelling cathete. VA - X

^1 Based on medical history

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Ability to comprehend and willingness to sign a written ICF for the study.

2. Aged 18 years or older at the time of signing the ICF.

3. ECOG performance status score of the following:
- 0 or 1.
- 0, 1, or 2 for the dose-expansion parts (Parts 1b and 1c). In the EU, enrollment of participants with ECOG performance status score of 2 will commence only after review of aggregated data (see Section 2.2.2.3) by the regulatory agency.

4. Life expectancy is greater than 6 months.

5. Willingness to undergo a pretreatment and regular on-study BM biopsies and aspirates (as appropriate to disease).

6. Willingness to avoid pregnancy or fathering children based on the criteria below:

a. Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 90 days (a spermatogenesis cycle) after the last dose of study treatment and must refrain from donating sperm during this period. Permitted methods in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.

b. Female participants who are WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy from screening through the last safety follow-up visit and must refrain from donating oocytes during this period.
Highly effective contraception methods (failure rate of < 1% per year) must be used (see Appendix A). They should be communicated to the participants and their understanding confirmed.

c. Female participants not considered to be of childbearing potential as defined in Appendix A are eligible.

7. Existing documentation from the participant history record of CALR exon-9 mutation (preferably obtained by next-generation targeted sequencing or PCR); if not available, assay for CALR-exon 9 mutation must be performed by a local laboratory qualified per national country regulations using an assay approved for IVD use by regulations and per its manufacturer's defined intended use, or alternatively for sites in the EU, an in-house IVD assay fulfilling the criteria set forth in IVDR Article 5(5) as outlined in EU Regulation 2017/746 and MDCG 2023.

For participants with MF:

8. Histologically confirmed diagnosis of PMF or post-ET MF according to the 2022 WHO criteria (see Appendix B).

9. Myeloblast count < 10% in the BM (or in the peripheral blood if BM is not evaluable)

10. Evidence of evaluable residual burden of disease:
- Radiologic confirmation of splenomegaly (spleen volume = 450 mL per MRI or CT).
or
- Palpable spleen of > 5 cm below the left subcostal margin on physical examination at the screening visit.

11. As applicable:

a. TGA-MF: Participants with MF who have been previously treated with JAK inhibitors for = 12 weeks and are resistant, refractory, intolerant to, or lost response to JAK inhibitor treatment or have intermediate- or high-risk DIPSS MF and are ineligible for JAK inhibitor treatment.

b. TGB-MF SubOpt R:
- Intermediate- or high-risk DIPSS MF (according to IWG-MRT criteria, Passamonti et al 2010).
- Must have been on a therapeutic regimen of ruxolitinib (ie, dose and dose regimen of ruxolitinib between 5 and 25 mg BID to treat MF) for at least 12 weeks and at least 8 consecutive weeks on a stable dose immediately preceding the first dose of study treatment (see Section 6.1).
- Unlikely to benefit from further ruxolitinib monotherapy in the opinion of the investigator, and meet the criteria for evidence of evaluable residual burden of disease as defined in Inclusion Criterion 10.

c. TGA-MF TxN and TGB-MF TxN:
- Intermediate- or high-risk DIPSS MF (according to IWG-MRT criteria, Passamonti et al 2010).
- Must be JAK inhibitor–naive (TxN)

For participants with ET:

12. Confirmed diagnosis of ET according to the 2022 WHO criteria (see Appendix B).

13. High risk, defined as follows:
- Age = 60 years at the time of signing the ICF.
or
- History of thrombosis (arterial or venous)
or
- History of major bleeding (related to the underlying ET disease)
or
- Bleeding risk, defined as platelet count > 1.5 x 10^12/L (current or known history and ongoing cytoreductive therapy) or platelet count > 1 x 10^12/L (current or known history and ongoing cytoreductive therapy) with documented von Willebrand disease

14. Documented resistance/intolerance to at least 1 line of prior cytoreductive therapy as determined by the investigator (including but not limited to hydroxyurea, interferon, thalidomide, busulfan, lenalidomide, or anagrelide; Barosi et al 2007).

15. Platelet count > 450 x 10^9/L.

Participants are excluded from the study if any of the following criteria apply:

1. Presence of any hematologic malignancy other than ET, PMF, or post-ET MF.

2. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. If the screening QTcF interval is > 450 milliseconds for male participants or > 470 milliseconds for female participants, the ECG should be repeated twice and the mean QTcF of the 3 ECGs should be = 450 milliseconds for male participants or = 470 milliseconds for female participants; if the QTcF is > 450 milliseconds for male participants or > 470 milliseconds for female participants, the participant is excluded. For participants with an intraventricular conduction delay (QRS interval > 120 milliseconds), the JTc interval may be used in place of the QTcF with sponsor approval. The JTc must be = 340 milliseconds if JTc is used in place of the QTcF. Participants with left bundle
branch block are excluded. Participants with QTcF prolongation due to a pacemaker may be enrolled after discussion with the sponsor's medical monitor.

3. Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment.

4. Participants with laboratory values at screening as defined in Table 9.

Table 9: Exclusionary Laboratory Values

Laboratory Parameter: Exclusion Criterion

Hematology

a Platelets: TGA-ET: < 450 x 10^9/L
TGA-MF: < 50 x 10^9/L
TGB-MF SubOpt R, TGA-MF TxN, and TGB-MF TxN: < 75 x 10^9/L without the assistance of growth factors, thrombopoietic factors, or platelet transfusions.
b ANC: < 1.0 x 10^9/L

Hepatic

c ALT: = 2.5 x ULN

d AST: = 2.5 x ULN

e Total/direct bilirubin: = 2.0 ULN, unless conjugated (direct) bilirubin = 1.5 ULN.
If there is no institutional ULN, then direct bilirubin must be < 40% of total bilirubin.

Note: In no case can the total bilirubin exceed 3 x ULN (except participants with Gilbert syndrome may have total bilirubin > 3.0 mg/dL).

Renal

f Creatinine clearance/eGFR: < 30 mL/min according to Cockcroft-Gault formula
< 30 mL/min/1.73 m^2 according to CDK-EPI 2021

5. Unwillingness to be transfused with blood components including RBC packs and platelet transfusions.

6. Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned.

7. Active invasive malignancy over the previous 2 years.

Note: Participants with the following may be eligible to participate at the investigator's discretion:

- Early-stage basal cell or squamous cell skin cancer
- Completely resected intraepithelial carcinoma of the cervix
- Completely resected papillary thyroid and follicular thyroid cancers

Participants with malignancies with indolent behavior, such as prostate cancer treated with radiation or surgery, may be enrolled as long as they have a reasonable expectation to have been cured with the treatment modality received.

8. History of clinically significant or uncontrolled cardiac disease, including recent (within the last 12 months) unstable angina or acute myocardial infarction, or New York Heart Association Class III or IV congestive heart failure, or clinically significant arrhythmias not controlled by medication. Participants with a pacemaker and well-controlled rhythm for at least 1 month before the first dose of study treatment will be allowed.

9. Any major surgery within 28 days before the first dose of study treatment.

10. Active or chronic HBV, defined as follows: positive HBsAg result (laboratory test required at screening) and/or positive total anti-HBc result (laboratory test required at screening).

Note: Participants with a resolved prior HBV infection (based on positive HBV serologic markers such as positive total anti-HBc with or without positive anti-HBs) and undetectable HBV DNA may enroll with monitoring for reactivation as per site standard practice. Participants with no history of HBV infection or who have been vaccinated against HBV and have had a positive anti-HBs as the only evidence of prior exposure may participate in the study.

11. Active HCV, defined as follows: positive anti-HCV result (laboratory test required at screening) and quantitative HCV RNA test result greater than the lower limits of detection of the assay (laboratory test only required if anti-HCV–positive, can be done as part of screening if available locally).

Note: Anti-HCV–positive participants who received and completed treatment for HCV that was intended to eradicate the virus may participate if HCV RNA levels are undetectable at least 12 weeks after the last dose of therapy. Anti-HCV–positive participants with no available confirmatory negative HCV RNA test results will be excluded.

12. Any condition or circumstance that would, in the investigator's judgment, interfere with full participation in the study (eg, unable, unlikely, or unwilling to comply with the dose schedule and study evaluations, active alcohol or drug addiction), including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.

13. Women who are pregnant (including women who may possibly be pregnant based on medical interview by investigators in Japan) or breastfeeding. Women must also refrain from breastfeeding during the course of study and for 60 days after the last dose of study treatment. For Japan, women who are breastfeeding and wish to enroll must discontinue breastfeeding at least 30 days before receiving study treatment.

14. Presence of chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment. Participants with acute infection requiring antibiotic, antifungal, or antiviral treatment use should delay screening/enrollment until the course of antibiotic antifungal, or antiviral therapy has been completed and the infection is not active anymore.

Note: If a participant has a positive screening test result for SARS-CoV-2 infection, they should be excluded until test normalization and clinical recovery.

15. Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody, or hypomethylating agent used to treat the participant's disease (see Section 6.8), with the exception of ruxolitinib for TGBs only, within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.

16. Any prior radiation therapy within 28 days before the first dose of study treatment.
Palliative radiation therapy to single sites or small fields is allowed with at least a 1-week washout period before the first dose of study treatment.

17. Known hypersensitivity, severe reaction, or any known contraindications to the use of any of the active substances or excipients in INCA033989 drug product or ruxolitinib as appropriate to the relevant treatment group.

18. Has any unresolved toxicity = Grade 2 from previous therapy except for stable chronic toxicities (Grade 2) not expected to resolve, such as stable Grade 2 peripheral neuropathy.

19. Undergoing treatment with another investigational medication or has been treated with an investigational medication within 28 days or 5 half-lives of this medication (whichever is longer) before the first dose of study treatment.

20. For TGBs only: Undergoing treatment with a potent/strong inhibitor or inducer of CYP 3A4/5 (see Appendix G) within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment, or expected to receive such treatment during the study.

21. Current use of prohibited medication described in Section 6.8.3.

22. Participants undergoing treatment with G-CSF, GM-CSF, or TPO-R agonists at any time within 4 weeks before the first dose of study treatment.

23. The following participants are excluded in France: vulnerable populations according to article L.1121-6 of the French Public Health Code and adults under legal protection, or who are unable to express their consent per article L.1121-8 of the French Public Health Code, not affiliated to a social security per article L.1121-8-1 of the French Public Health Code.

24. Known history of HIV (1/2 antibodies).

Patients are eligible to be included in the study only if all of the following criteria apply:
1. Age =18 years at the time of signing informed consent.

2. Karnofsky Performance Status of 70 or higher with no clinically significant deterioration over the previous 2 weeks.

3. Life expectancy minimum of = 12 weeks.

4. Patients diagnosed with histologically or cytologically confirmed advanced solid tumors.

a. Phase 1a darlifarnib (KO-2806) monotherapy (US only): dose escalation and pharmacodynamic (Pd) cohorts

Patients with histologically or cytologically confirmed advanced solid tumors with the following:

- HRAS-mutant and/or amplified tumors (any solid tumor type)
- HRAS overexpression (only for HNSCC tumors)
- KRAS and/or NRAS and/or HRAS-mutant and/or amplified for the following:
- NSCLC
- CRC
- KRAS-mutant and/or amplified PDAC

Patients must have progressed on or be refractory to SOC therapies, be unsuitable for standard therapy, or for which no standard therapy exists.

b. Phase 1a cabozantinib combination dose escalation and Pd cohorts in RCC (Pd cohorts, US only)

- ccRCC: Patients must have received at least 1 prior systemic therapy with IO-based treatment (Note: treatment with prior cabozantinib and/or other TKIs is permitted) for locally advanced or metastatic RCC with predominantly clear cell subtype

- Other non-ccRCC: Patients can be treatment-naive or have received any prior systemic treatment for locally advanced or metastatic RCC.

c. Phase 1a adagrasib combination dose escalation and Pd cohorts in NSCLC, PDAC, and CRC (Pd cohorts, US only)

Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC, PDAC or CRC who have received at least 1 prior systemic therapy for advanced or metastatic disease (Note: any prior type and number KRAS G12C inhibitor is permitted, including prior adagrasib, sotorasib, and experimental [non-approved] KRAS G12C inhibitors). Patients, as assessed by the treating physician, should have received all available approved SOC treatments for advanced or metastatic NSCLC, PDAC or CRC, unless deemed inappropriate or unsuitable (eg. due to toxicity or comorbidities). Specific treatments should include:

- NSCLC: Patients must have received at least 1 prior line of systemic treatment including platinum-based chemotherapy and/or an immune checkpoint inhibitor (given concurrently or sequentially in two different lines of treatment). Patients may have or not received adagrasib or sotorasib.

- PDAC: Patients must have received at least 1 prior line of systemic treatment including platinum-based or gemcitabine chemotherapy and olaparib (as potential 1st line maintenance treatment). Additionally, patients may have had an immune checkpoint inhibitor (if microsatellite instability-high, deficient DNA mismatch repair, or tumor mutational burden-high [> 10 mutations per megabase]).

- CRC: Patients must have received at least 1 prior line of systemic treatment including oxaliplatin and irinotecan-based chemotherapy with or without antiangiogenic or anti-EGFR targeted therapy (given concurrently or sequentially in two different lines of treatment -in patients suitable for intensive chemotherapy). Patients may have or not received adagrasib or sotorasib in combination with cetuximab or panitumumab.

d. Phase 1b cabozantinib combination and cabozantinib monotherapy dose expansion in ccRCC

Patients must be cabozantinib-naive and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies including neoadjuvant, adjuvant, and subsequent therapies. Patients must have had treatment failure on their immediate prior therapy.

e. Phase 1b adagrasib combination dose expansion in NSCLC

Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC who have received at least 1 prior systemic therapy for advanced or metastatic NSCLC (Note: exact patient population for expansion may be restricted to KRAS G12C naive patients or limit it one or more prior KRAS G12C treatment depending on emerging safety and efficacy data from dose-escalation). Patients, as assessed by the treating physician, should have received all available approved SOC treatments for advanced or metastatic NSCLC, unless deemed inappropriate or unsuitable (eg. due to toxicity or comorbidities). Specific treatments should include:

- NSCLC: Patients must have received at least 1 prior line of systemic treatment including platinum-based chemotherapy and/or an immune checkpoint inhibitor (given concurrently or sequentially in two different lines of treatment). Patients may have or not received adagrasib or sotorasib.

5. Adequate organ function, as evidenced by the following laboratory results:

- Hematologic (criteria listed cannot be met with recent blood transfusions or require ongoing growth factor support within 2 weeks of starting study treatment):

i. Absolute neutrophil count > 1500 cells/mm^3.
ii. Platelet count > 100,000 cells/mm^3.
iii. Hemoglobin > 9.0 g/dL within 2 weeks prior to first dose. Note: patients with a Hb > 8.0 g/dL may be transfused within 2 weeks of first dose and included if Hb is > 9.0 g/dL.
Only applicable for patients who are NOT chronically anemic (Hb less than 8.0 g/dL) and transfusion-dependent prior to study entry)

- Hepatic:

i. Total bilirubin (TBL) = 1.5 x upper limit of normal (ULN), except in patients with previously documented Gilbert’s syndrome or in patients with liver metastases, in which case the TBL should be = 3 x ULN.
ii. AST (via serum glutamic oxaloacetic transaminase) and ALT (serum glutamic pyruvic transaminase) = 2.5 x ULN; < 5 x ULN in patients with liver metastases
iii. ALP = 2.5 x ULN; ALP < 5 x ULN for patients with hepatic and/or bone metastases

- Renal:

i. For darlifarnib (KO-2806) monotherapy and adagrasib combination, calculated creatinine clearance = 60 mL/min using the Cockcroft-Gault equation. For cabozantinib combination and cabozantinib monotherapy, calculated creatinine clearance = 40 mL/min using the Cockcroft-Gault equation.

6. Patients must have at least 1 measurable lesion according to RECIST v1.1, which must be confirmed by local radiology prior to patient entry:

a. A previously irradiated lesion can be considered a target lesion (TL) if the lesion is well defined, measurable per RECIST v1.1, and has clearly progressed.

b. Patients without available archival tissue must have a non-target lesion (NTL) that can be biopsied at acceptable risk (if biopsy is required for enrollment) as judged by the Investigator or, if no other lesion is suitable for biopsy, then a RECIST v1.1 TL used for biopsy must be = 2 cm in longest diameter.

7. The results of imaging done up to 6 months prior to screening (eg, = 1 additional time point before baseline assessment) are to be made available to the Sponsor for evaluation of the kinetics of tumor progression if allowed by country.

8. All patients must consent to providing archival tumor specimens for correlative biomarker studies if tumor tissue is available. If an archival specimen is not available, patients may consent to a fresh biopsy.

9. For patients enrolled in the Pd cohorts, paired fresh tumor biopsies at screening and at Days 18 to 21 are mandatory.

10. Capable, according to the Investigator, of complying with the study’s requirements and restrictions including sunlight restrictions: prolonged exposure to sunlight should be avoided during treatment. In addition, patients should take other measures to avoid ultraviolet exposure, such as wearing sunscreen and sunglasses, wearing protective
clothing, and avoiding tanning beds.

11. Able and willing to provide written informed consent prior to any study-related procedure (other than those provided in the course of normal care).

12. Both female patients of childbearing potential and male patients with female partners of childbearing potential must agree to use a highly effective method of contraception along
with a barrier method (eg, condom) from the time of screening and must agree to use such precautions for 180 days after last dose of IMP (see Appendix 2).

Patients are excluded from the study if any of the following criteria apply:

1. Any use of anticancer therapy (SOC or investigational therapy) within 14 days or 5 half-lives (whichever is shorter) of Cycle 1 Day 1 (darlifarnib [KO-2806] monotherapy and cabozantinib combination and monotherapy arms) or start of adagrasib lead-in (adagrasib combination arm). Note: this criterion does not apply to patients rolling over from cabozantinib monotherapy to cabozantinib+darlifarnib (KO-2806) combination therapy.

2. Received prior treatment with an FTI or HRAS inhibitor.

3. Phase 1a dose escalation and Phase 1b dose expansion (combination):

Cabozantinib combination:

- Clinically significant hematuria or any other hemorrhagic sign/symptom
- Other clinically significant disorders such as:
- Serious non-healing wound/ulcer/bone fracture needing surgical intervention or gaping wound.
- Moderate to severe hepatic impairment (Child-Pugh B or C) (Appendix 10)
- Requirement for hemodialysis or peritoneal dialysis
- History of solid organ transplantation

Adagrasib combination:

- Ongoing need for a medication with any of the following characteristics that cannot be switched to alternative treatment prior to study entry: known risk of QT prolongation or Torsades de Pointes; substrate of cytochrome p450 (CYP)3A with narrow therapeutic index; strong inducer of CYP3A4; and potent inhibitor of BCRP (Appendix 3).

4. Major surgery (as defined by the Investigator) within 28 days prior to first dose or still recovering from prior surgery. Note: Local procedures (eg, placement of a systemic port, core needle biopsy, and prostate biopsy) are allowed if completed at least 24 hours prior to the administration of the first dose of study treatment.

5. Known severe hypersensitivity to the product or similar chemical structure and class to the drug evaluated in the study or one of the active or inactive excipients.

6. Concurrent enrollment in another therapeutic clinical study. Enrollment in observational studies will be allowed.

7. Any toxicity (excluding alopecia) from prior therapy that has not been completely resolved to baseline at the time of consent. Patients with NCI CTCAE v5.0 Grade 1 or 2 toxicities that are deemed stable or irreversible can be enrolled on a case-by-case basis with prior consultation and agreement with the Medical Monitor (eg, Grade 1 peripheral neuropathy from prior oxaliplatin, Grade 1 skin toxicity from prior cetuximab).

8. Any spinal cord compression, leptomeningeal disease, or clinically active CNS metastases. Clinically active CNS metastases are defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Note: Patients with active/symptomatic CNS metastases must have previously completed local therapy.

a. Patients with previously treated CNS metastases are allowed if asymptomatic or neurologically stable (either without the use of steroids or on a steroid dose of = 10 mg/day of prednisone or its equivalent) and have recovered from the acute toxic effects of prior therapy.

b. Patients with CNS metastases treated by radiation must be:
i. = days since stereotactic radiosurgery or gamma knife prior to enrollment.
ii. =14 days since whole-brain radiation therapy prior to enrollment.

9. Any concurrent chemotherapy, immunotherapy, biologic, hormonal or radiation therapy and surgery, for the primary disease under study. Concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and hormone replacement therapy for postmenopausal symptoms) is allowed.

a. Patients are allowed after they have completed a minimum 7-day washout period for radiation to non-CNS locations prior to the start of study treatment.

10. Active autoimmune or inflammatory disorders within the past 5 years prior to the start of treatment. Patients whose condition is well controlled, does not require prohibited systemic immunosuppressive therapy (see Section 5.5.2), and is not expected to interfere with study treatment or endpoint assessment per Investigator opinion are allowed. Note:
The following are some exceptions to this criterion:

a. Vitiligo or alopecia.
b. Hypothyroidism (eg, following Hashimoto syndrome) stable and on hormone replacement.
c. Any chronic skin condition, including psoriasis, that does not require systemic therapy.
d. Celiac disease controlled by diet alone.

11. Any active infection including but not limited to:

a. Hepatitis B virus (HBV): known positive hepatitis B surface antigen (HBsAg) result.
Note: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.

b. Hepatitis C virus (HCV): Note: Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

c. HIV: Known or active HIV infection (HIV testing not required unless required by local regulations). Note the following exceptions:

i. Patients are eligible if CD4 count is > 350 cells/mm^3 and they are on an antiretroviral regimen with evidence of at least 2 undetectable viral loads within the past 6 months on this same regimen; the most recent undetectable viral load must be within the past 12 weeks.

ii. For patients who received chemotherapy in the past 6 months, a CD4 count of < 350 cells/mm^3 during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy.

iii. Patients must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months.

12. Uncontrolled intercurrent illness, including but not limited to the following: ongoing or active infection, interstitial lung disease, cavitating pulmonary lesion(s) or known endobronchial disease manifestation, lesions invading major pulmonary blood vessels, uncontrolled diabetes, serious chronic GI conditions associated with diarrhea, GI conditions associated with a risk of perforation or fistula formation, and psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent.

13. Other invasive malignancy within 2 years. Note: Noninvasive malignancies (eg, cervical carcinoma in situ, in situ prostate cancer, nonmelanomatous carcinoma of the skin, or cured ductal carcinoma in situ of the breast) are permitted after discussion with the Medical Monitor.

14. Refractory nausea and vomiting, chronic GI diseases, inability to swallow the formulated product, malabsorption syndrome and/or previous significant bowel resection that would preclude adequate absorption of study treatments.

15. Cardiac and vascular criteria:

a. Mean QTcF =470 ms calculated from 3 ECGs (within 5 minutes at 1 minute apart, manually read).

b. Presence of acute coronary syndrome, including myocardial infarction or unstable angina pectoris, other arterial ischemic or thrombotic event (not including venous thrombotic events), including cerebrovascular accident or transient ischemic attack, within 6 months prior to enrollment.

c. New York Heart Association class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or uncontrolled hypertension (= 160 mmHg systolic and/or = 100 mmHg diastolic blood pressure [BP]), despite appropriate antihypertensive medication.

d. History of hypertensive crisis/hypertensive encephalopathy within the past 6 months prior to the scheduled first dose of study treatment.

16. Receipt of live attenuated vaccines within 28 days prior to the first dose of study treatment.

17. Any condition that, in the opinion of the Investigator or Sponsor, would interfere with safe administration or evaluation of the IMP, interpretation of patient safety, or study results.

18. Significantly altered mental status that would limit the understanding or rendering of informed consent and compliance with the requirements of this protocol. Unwillingness or inability to comply with the study protocol for any reason.

19. Involvement in the planning and/or conduct of the study (applies to both Sponsor staff and/or staff at the study site).

20. Female patients who are pregnant, lactating, or intend to become pregnant during their participation in this study.

Subjects meeting all of the following criteria will be considered for admission to the trial:

1. Must be = 18 years at the time of signing the informed consent.

2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.

3. Patients with a "good risk" status as defined by the NCCN guidelines (version 1.2021)

4. Tumor board protocol confirming:
- a clinical recommendation for intrathecal therapy and evaluation of trial enrollment
- a statement on the potential necessity of additional systemic treatment of metastatic tumor outside the CNS

5. Able to adhere to the study visit schedule and other protocol requirements.

6. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.

7. Patients with Karnofsky performance score > 50%

8. Diagnosis of LMD by CSF and/or MRI

a. A thorough CSF evaluation must be performed in every patient prior to the inclusion in this trial. The reason is that a positive CSF cytology is considered the gold standard for LMD diagnosis. Furthermore, a thorough CSF evaluation will allow the thorough assessment of potential differential diagnoses (for example viral meningitis, bacterial meningitis, aseptic meningitis, sarcoidosis etc.)

b. Presence of malignant cells on CSF cytology. The frequency of CSF evaluation is based on guideline of the German Society of Neurology: Please note that the first lumbar puncture is only 50-60% sensitive. Repeat collection increases sensitivity up to approximately 80%. Thus, a negative first CSF evaluation should at least be repeated once. According to guidelines from the German Society for Neurology each CSF collection should draw enough, i.e. at least 5-10 ml CSF and should be processed within one hour of collection.

c. MRI diagnosis of LMD: pial enhancement, pial nodular manifestations (as defined per LANO criteria, see appendix).

d. A positive CSF cytology and an MRI evidence is enough to determine the LMD diagnosis.

e. Please note that approximately 20% of patients with symptomatic LMD might lack positive CSF cytology even upon repeated puncture. In these cases, the LMD diagnosis can also be performed based on cerebral/spinal MRI manifestations and by exclusion of differential diagnosis.

f. In the absence of diagnostic findings for LMD in the CSF: patients must present with typical clinical and MRI signs of LMD (Le Rhun et al., 2017). If the CSF has signs of pleocytosis (BUT NOT any malignant, atypical or suspicious cells) the differential diagnosis for CSF pleocytosis (aseptic meningitis, viral meningitis, bacterial meningitis) must be excluded.

g. Some centers perform biopsies of leptomeninges for obtaining a LMD diagnosis. The LMD diagnosis will be based on histology and should be documented accordingly. Yet, a histological diagnosis of LMD is NOT required for the inclusion in this trial.

9. If radiation therapy had occurred: Please make sure that a documentation of the past
radiation therapy is available (including applied dosage and radiation therapy fields):
a. Participants eligible for IT-PD1 should have completed their radiation therapy due to clinical indication > 2 weeks prior to enrollment into the trial.
b. All LMD patients without an indication for radiation therapy (per investigator's choice) can be enrolled immediately

10. Neurological examination (NANO scale) (Nayak et al., 2017).

11. MRI: the assessment at baseline and for subsequent time points should be based on the LANO scorecard (see appendix) according to (Le Rhun et al., 2019).

12. Ability to undergo intrathecal therapy via an intraventricular catheter (e.g. Ommaya reservoir).

13. Primary tumor tissue for the assessment of PD-1 and PD-L1 is optional at the timepoint of inclusion and enrollment but does need to be shipped before end of the trial.

14. Female Patient of childbearing potential1 and male patients with female partner of
childbearing potential1 is willing to use highly effective contraceptive methods during
treatment and for 150 days (male or female, see SmPC) after the last dose.
Recommendations highly effective contraceptive methods are:
a. combined hormonal contraception associated with inhibition of ovulation (oral-, intravaginal, -transdermal)
b. progestogen-only hormonal contraception associated with inhibition of ovulation (pral injectable, implantable),
c. intrauterine device (IUD),
d. intrauterine hormone - releasing system (IUS),
e. bilateral tubal occlusion,
f. vasectomized partner2,
g. sexual abstinence3

^1 For the purpose of this document, a female is considered of childbearing potential (FCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. For the purpose of this document, a man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.

^2 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success

^2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

Subjects presenting with any of the following criteria will not be included in the trial:

1. Women during pregnancy and lactation.

2. Previous intrathecal Nivolumab application.

3. Patient at "poor risk" (NCCN guidelines version 1.2021).

4. The following differential diagnoses to LMD are exclusion criteria:
a. Aseptic meningitis
b. Viral meningitis
c. Bacterial meningitis

5. History of hypersensitivity to monoclonal antibodies.

6. Participation in other clinical AMG or MDR trials or observation period of competing trials or if there is otherwise a high risk of insurance law issues intervening between two studies and if the participation affects the primary endpoint of the IT-PD1 study. In case of uncertainty, competing insurances must be contacted prior to participation

7. A clinical condition that in the opinion of the investigator would interfere with the evaluation or interpretation of patient safety or trial results or that would prohibit the understanding of informed consent and compliance with the requirements of the protocol.

8. Any treatment-related toxicities from prior systemic anti-tumor or immune therapy not having resolved to CTCAE version 5.0 grade 1, with the exception of alopecia.

9. Patient with confirmed hisory of current autoimmune disease.

10. Patients with any disease resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy.

11. Clinically significant active infection, for example:
a. Presence of human immunodeficiency virus
b. Active hepatitis B virus/hepatitis C virus. HIV infection or active Hepatitis B or C infectionor active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients' blood or tissue (e.g. rabies) *.

12. Inability to undergo MRI with contrast agent.

13. The underlying primary tumor has not a registered and authorized indication in the European Union for intravenous treatment with Nivolumab, Pembrolizumab or Atezolizumab. The solide tumor registered are, i.e. melanoma, non-small cell lung cancer (NSCLC), Malignant pleural mesothelioma (MPM),renal cell carcinoma (RCC), Classical Hodgkin lymphoma (cHL), squamous cell cancer of the head and neck (SCCHN), urrothelial carcinoma, muscle invasive urothelial carcinoma (MIUC), colorectal cancer (CRC) with Mismatch repair deficient (dMMR) or microsatellite
instability-high (MSI-H), esophageal squamous cell carcinoma (ESCC), Adjuvant treatment of esophageal cancer (EC) or gastro-oesophageal junction cancer (GEJC), Gastric gastro- oesophageal junction (GEJ) or oesophageal adenocarcinoma, triplenegative breast carcinoma. In addition, leptomeningeal disease of solid tumors with a high tumor mutational burden is also eligible.

14. Abnormal laboratory values for the following values in haematology, coagulation parameters, liver and renal function:
a. Haemoglobin < 8 g/dl
b. White blood cell count < 2.0 x 10^9/L)
c. Platelet count decrease < 50 x 10^9/L
d. Bilirubin > 2.5 x upper limit of normal (ULN) according to the performing laboratory's reference range. Note that benign hereditary hyperbilirubinemia e.g. Gilbert's syndrome is permitted.
e. Alanine aminotransferase > 3 x ULN
f. Aspartate aminotransferase > 3 x ULN
g. Serum creatinine increase > 1.5 x ULN

15. Patients who have received live or attenuated vaccine therapy used for prevention of infectious disease within 4 weeks of the first IT application of Nivolumab.

16. Patients requiring chronic systemic corticosteroid therapy (> 10 mg prednisone or equivalent per day) or any other immunosuppressive therapies (including anti-TNF-a therapies).

*) These parameters are necessary in immunotherapy studies, as they in turn may have an impact on immune parameters (independent of study treatment)