Each potential participant must satisfy all of the following criteria (except as indicated for specific cohort[s])to be enrolled in the study:

1. Criterion modified per Amendment 4

1.1 >=12 years of age.

NOTE: Adolescent participants (defined as >12 and <18 years of age) are only eligible for the R/R Cohort (Arm A, Cohort A4)

2. Criterion modified per Amendment 1

2.1 Criterion modified per Amendment 2

2.2 Criterion modified per Amendment 3

2.3 Criterion modified per Amendment 4

2.4 Diagnosis of acute myeloid leukemia (AML) according to World Health Organization criteria:

- De novo or secondary AML

- Relapsed /refractory (Arm A only) or newly diagnosed AML


- Participants mayreceive emergency leukapheresis and/or cytarabine as cytoreductive therapy according to local practice guidelines prior to first dose of study treatment to control hyperleukocytosis (see Section 6.8.1). If possible, these treatments should not be given until after the screening bone marrow assessment; however, these treatments must be discontinued >=24 hours prior to start of study treatment).

- Harboring KMT2A, NPM1, NUP98, or NUP214alterations

3. Updated per Amendment 1

3.1 COHORT B1 ONLY: Must be newly diagnosed and INELIGIBLE for intensive chemotherapy based on the following criteria:
- >=75 years of age or

- >=18 to <75 years of age with >=1 of the following comorbidities:

- Eastern Cooperative Oncology Group (ECOG) performance status of 2 (see Appendix 11.12)

- Cardiac comorbidity NYHA Class I or II

- Severe pulmonary comorbidity (baseline pulmonary disease), defined as documented pulmonary disease with lung diffusing capacity for carbon monoxide <=65% of expected or forced expiratory volume in 1 second <=65% of expected

- Comorbidity that, in the investigator’s opinion, makes the participant unsuitable for intensive chemotherapy, which must be documented and approved by the sponsor before enrollment

4. COHORT C1 ONLY: Must be >=18 to <75 years of age, newly diagnosed and ELIGIBLE for intensive chemotherapy

5. Criterion modified per Amendment 2

5.1 Pretreatment clinical laboratory values meeting the following criteria -listed below:

HEMATOLOGY

- White blood cell (WBC) count: <=25 x 10^9/L (hydroxyurea may be used to lower WBC count at screening and during study; cytoreductive therapy may be considered with sponsor approval; see Criterion 2.2 and Section 6.8.1)

CHEMISTRY

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): <= 2.5 x upper limit of normal (ULN)

- Total bilirubin: < 1.5 x ULN (participants with elevated bilirubinemia, such as Gilbert’s syndrome, may enroll if conjugated bilirubin is within clinically acceptable range and total bilirubin <= 3 x ULN).

- Renal function: Estimated or measured glomerular filtration rate >= 40 mL/min per MDRD formula (Levey 2006; see Section 11.14).

6. Criterion modified as per Amendment 4

6.1 ECOG performance status grade of 0, 1 or 2 (See Appendix 12; Oken 1982).

Note: Adolescent participants only: Performance status >70 by Lansky scale (for participants <16 years of age) or >70 Karnofsky scale (for participants >16 years of age) (Appendix 13)

7. Criterion modified as per Amendment 4

7.1 A female of childbearing potential must have a negative highly sensitive serum ß-human chorionic gonadotropin at screening and within 48 hours prior to the first dose of study
treatment

8. Criterion modified per Amendment 1

8.1 Criterion modified per Amendment 2

8.2 Criterion modified as per Amendment 4

8.3 A female of childbearing potential must agree to all the following during the study and for 6 months after the last dose of study treatment (see Appendix 5: Contraceptive and
Barrier Guidance):

- Use a barrier method of contraception
- Use a highly effective preferably user-independent method of contraception
- Not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction
- Not plan to become pregnant
- Not to breast-feed

9. Criterion modified per Amendment 2

9.1 A male must agree to all the following during the study and for 3 months after the last
dose of study treatment or for 6 months following the last dose of daunorubicin:

- Wear a condom when engaging in any activity that allows for passage of ejaculate to another person.
- Not to donate sperm or freeze for future use for the purpose of reproduction.
- In addition, the participant should be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak.

10. Criterion modified as per Amendment 4

10.1 Must sign an informed consent form (ICF) indicating participant (or their LAR) understands the purpose of the study and procedures required for the study and is willing to
participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the participant’s disease.

Note: If the participant is an adolescent, the legal guardian (as defined in Section 2) and the participant, if capable, must provide informed consent/assent, as described in Section 11.3.

11. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Criterion modified per Amendment 4

1.1 Acute promyelocytic leukemia, diagnosis of Down syndrome associated leukemia or juvenile myelomonocytic leukemia according to WHO 2016 criteria (Arber 2016).

2. Leukemic involvement of the central nervous system

3. Recipient of solid organ transplant

4. Criterion modified per Amendment 2

4.1 Any prior treatment with a menin-KMT2A inhibitor (exception: participants with prior menin-KMT2A inhibitor exposure may be considered for enrollment with sponsor approval)

5. Criterion modified per Amendment 2

5.1 Cardiovascular disease that is uncontrolled, increases risk for Torsades de Pointes or that was diagnosed within 6 months prior to the first dose of study treatment including, but not limited to:

a. Myocardial infarction
b. Severe or unstable angina
c. Clinically significant cardiac arrhythmias, including bradycardia (<50 beats per minute)
d. Currently uncontrolled (persistent) hypertension: systolic blood pressure >=140 mm Hg; diastolic blood pressure >90 mm Hg
e. Acute neurologic events such as stroke or transient ischemic attack, intracranial or subarachnoid hemorrhage, intracranial trauma
f. Venous thromboembolic events (eg, pulmonary embolism) within 1 month prior to the first dose of study treatment (uncomplicated Grade <=2 deep vein thrombosis is not considered exclusionary)
g. Congestive heart failure (NYHA class III to IV) (AHA 1994)
h. Pericarditis or clinically significant pericardial effusion
i. Myocarditis
j. Endocarditis
k. Clinically significant hypokalemia, hypomagnesemia, hypocalcemia (corrected for hypoalbuminemia)

l. COHORT C1 ONLY:

- Reached cumulative dose of any combination of anthracyclines or anthracenediones of 550 g/m^2
- LVEF < 50%

6. QTc according to Fridericia’s formula (QTcF) for males >=450 msec or for females >=470 msec. Participants with a family history of Long QT syndrome are excluded.

NOTE: For participants with documented wide QRS interval (eg, due to a bundle branch block), alternate methods of calculating a corrected QT interval may be
appropriate for eligibility determination if recommended by a consulting cardiologist and approved by the sponsor, provided there is no evidence or history of a repolarization abnormality.

7. Any toxicity (except for alopecia, stable peripheral neuropathy, thrombocytopenia, neutropenia, anemia) from previous anticancer therapy that has not resolved to baseline or to Grade 1 or less.

8. Pulmonary compromise that requires the need for supplemental oxygen use to maintain adequate oxygenation.

9. Reported temperature >100.4 F/38 C within 48 hours prior to the first dose of study treatment.

10. Known allergies, hypersensitivity, or intolerance to any assigned study treatment (combination agent or bleximenib), or its excipients.


11. Exclusion criteria related to stem cell transplant:

- Received prior treatment with allogenic bone marrow or stem cell transplant <=3 months before the first dose of study treatment
- Has evidence of graft versus host disease
- Received donor lymphocyte infusion <=1 month before the first dose of study treatment
- Requires immunosuppressant therapy (exception: daily doses <=10 mg prednisone or equivalent are allowed for adrenal replacement)

NOTE: Participants must discontinue all immunosuppressive therapy, including calcineurin inhibitors, at least 4 weeks before the first dose of study treatment and remain clinically stable.

12. Criterion modified per Amendment 2

12.1 Chemotherapy, targeted therapy, immunotherapy, or radiotherapy within 2 weeks or 5 half-lives (whichever is longer) before the planned first dose of study treatment
(EXCEPT when used as cytoreductive therapy to control hyperleukocytosis as detailed in inclusion criterion 2 above).

13. Administration of:

- live-attenuated vaccine within 4 weeks before the first dose of study treatment or planned during the course of study treatment; or
- investigational vaccine within 2 weeks before the first dose of study treatment.

NOTE: Approved non-live vaccines (eg, influenza) or non-live vaccines authorized for emergency use (eg, SARS-CoV-2 [COVID-19]) by local health authorities are allowed.

14. Received investigational treatment or used an invasive investigational medical device within 2 weeks before the planned first dose of study treatment or is currently receiving
active treatment on an investigational study.

15. Major surgery (eg, requiring general anesthesia) within 2 weeks prior to first dose of study treatment or has not recovered from surgery. Must not have major surgery
planned during the time the participant is receiving study treatment. Participants with recent or planned surgical procedures utilizing only local anesthesia may participate.

16. Requires a prohibited medication that cannot be discontinued or substituted, or temporally interrupted during the study.

17. Criterion Modified per Amendment 3

17.1 Known to be positive or tests positive at screening for HIV, unless viral load is undetectable and CD4 count is above 200 on stable highly active antiretroviral therapy
(see Section 6.8.2 for prohibited and restricted medications).

18. Active or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (as defined below) or clinically active infectious liver disease:

a. Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HbsAg).

NOTE: Participants with a prior history of HBV demonstrated by positive hepatitis B core antibody are eligible if they have at screening

1) a negative HbsAg and
2) a HBV DNA (viral load) below the lower limit of quantification, per local testing.
Participants with a positive HbsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing.

b. Positive hepatitis C antibody (anti-hepatitis C virus [HCV]).
NOTE: Participants with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.

19. Any serious underlying medical or psychiatric conditions, such as seizure disorder or psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status.

20. Evidence within 7 days prior to the first dose of study treatment of any active or uncontrolled infection.

21. Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of an oral agent. Such conditions include, but are not limited to, malabsorption syndrome, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or resection of the stomach or small bowel. If any of these conditions exist, the investigator should discuss with the sponsor to determine participant eligibility.

22. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

23. Criterion modified per Amendment 3

23.1 Received strong cytochrome P450 3A (CYP3A) inducers or inhibitors within 7 days prior to initiation of bleximenib.

24. Criterion modified per Amendment 3

24.1 Concurrent or recently diagnosed or treated malignancies present at the time of screening. Exceptions are squamous and basal cell carcinoma of the skin, carcinoma
in situ of the cervix, and any malignancy that is considered cured or has minimal risk of recurrence within 1 year of first dose of study treatment in the opinion of both the
investigator and the sponsor’s medical monitor.

25. Criterion added per Amendment 4

25.1 Participants with diagnosis of Fanconi anemia, Kostmann syndrome, Shwachman Diamond syndrome, or any other known bone marrow failure syndrome.

NOTE: Investigators must ensure that all study enrollment (inclusion/exclusion) criteria have been met at screening, and prior to the first dose of study treatment. If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study treatment is given such that the participant no longer meets all eligibility criteria, then the participant must be excluded from participation in the study and the sponsor notified. Section 5.4, Screen Failures, describes options for retesting. The required source documentation to support meeting the enrollment criteria are noted in Appendix 3: Regulatory, Ethical, and Study Oversight Considerations.

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 extramedullary disease) defined according 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.
OR
Patients with diagnosis of relapsed/refractory MDS/AML with 10-19% bone marrow blasts at initial diagnosis and >=5% bone marrow blasts, and/or >=1% peripheral blood blasts at screening defined according to 2022 ICC criteria 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 written approval by the oordinating investigator.
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT), <= 3.0 x ULN, unless considered due to leukemic involvement of the liver - following written approval by the coordinating investigator.

6. Adequate renal function as evidenced by creatinine clearance = 30 mL/min based on the CKD-EPI formula 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 postmenopausal 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 negative estrogen test, both at screening

or

- Patient is documented surgically sterile by bilateral tubal ligation or bilateral oo phorectomy 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 consistently 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 intrauterine 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 effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.

* List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control per the requirements of the CTFG Guidance document Recommen dations related to contraception and pregnancy testing in clinical trials’, September 2020 (and any updates thereof) during the protocol
defined period. Since ivosidenib may decrease the concentrations of hormonal contraceptives, it is recommended 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 contraception 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 administration.

12. Patient agrees not to participate in another interventional 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 investigational medication (see Appendix I), unless the patient can be transferred to other
medications prior to enrolling or unless the medications can be properly monitored during the study.

11. Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transportersensitive substrate medications (see Appendix J) unless the patient can be transferred to other medications within >= 5 half-lives prior to administration of molidustat and ivosidenib, 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 screening. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal 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 administered with proper monitoring.

19. Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion 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 screening.

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 hampering compliance with the study protocol and follow-up schedu

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.

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 19):

a. AML, nonacute promyelocytic leukemia and either of the following disease activity criteria:

i. TN and unfit for intensive chemotherapy as defined by one of the following (TN AML patients who are unfit for intensive chemotherapy may not be enrolled in countries such as the US, France, Germany, Italy, and Spain, if a Bcl-2 inhibitor is available as standard of care; in other countries, patients with no access or who havecontraindications to available standard of care may be eligible per investigator’s assessment of benefit/risk):
(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 < 50 mL/min
(5) Liver disease with bilirubin > 1.5 x upper limit of normal (ULN) unless patient has documented Gilbert syndrome

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 12). In France, patients with R/R AML with FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutation confirmed using a validated test, after induction chemotherapy, must have received gilteritinib, if eligible.

iii. HMA-failure AML – received >= 1 cycle of hypomethylating agent and had disease progression (Döhner et al 2017, see Appendix 12) or no >= partial remission (PR) or hematologic improvement (HI) after 4 cycles after receiving > 75% of planned dose

b. MDS (bone marrow blast > 5% and that 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 BGB-11417 monotherapy cohort.

ii. R/R to >= 1 prior lines of systemic therapy as defined by modified International Working Group (IWG) 2006 criteria for relapse, or failure, or disease progression (Cheson et al 2006, see Appendix 14)

iii. HMA-failure MDS– received >= 1 cycle of hypomethylating agent and had disease progression (Cheson et al 2006, see Appendix 14) or no >= PR or HI after 4 cycles after receiving > 75% of planned dose

c. MDS/MPN including chronic myelomonocytic leukemia (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 BGB-11417 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 14)
iii. HMA-failure MDS/MPN– received at least 1 cycle of hypomethylating agent and had disease progression (Cheson et al 2006, see Appendix 14) 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 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 (µmol/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 (or <= 3 x ULN in unfit AML cohort) unless patient has documented Gilbert syndrome. Total bilirubin may exceed this value for patients with documented Gilbert syndrome, but direct bilirubin must be <= 1.5 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, for the duration of the study treatment period, and for >= 90 days after the last dose of BGB-11417 and >= 180 days after the last dose of azacitidine. See Appendix 18 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. See Appendix 18 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. Prior malignancy within the past 2 years, except for curatively treated 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. White blood cell (WBC) count > 25 x 10^9/L (treatment with hydroxyurea 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 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 or azacitidine

a. For R/R AML patients: prior therapy with a Bcl-2 inhibitor or azacitidine except for HMA-failure (see inclusion criteria 3a)

b. For R/R MDS or MDS/MPN patients: prior therapy with a Bcl-2 inhibitor or azacitidine except for HMA-failure (see inclusion criteria 3b and 3c)

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 includes 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 9)

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 6.11.4).

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 6.11.4).

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 BGB-11417 (see Appendix 10)

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

20. History of hypersensitivity to an excipient of the BGB-11417 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. Receiving treatment with drugs known to prolong the QT/QTc interval (see Appendix 17)

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 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 10^9 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 = 90 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 longer. They must also have a negative serum pregnancy test result = 7 days before randomization (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 1)

12. Nonsterile male patients must be willing to use a highly effective method of birth control and refrain from sperm donation for the duration of the study and for = 90 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 longer.

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 (Appendix 1).

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.
- 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:
- Malignancies treated with curative intent and with no known active disease present for = 3 years before randomization.
- 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 for a = 4 weeks before enrollment. 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.

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/strongCYP3A 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.

Each patient who is eligible to participate in this study must 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 covalently binding 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. Phase 2 Cohort 2 only: confirmed availability of the baseline tumor tissue samples for retrospective central pathology confirmation of MCL diagnosis.

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 covalently binding 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 except if discontinued earlier for intolerance.
(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 covalently binding 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, all patients must have been treated with a covalently binding 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.
(1) After 85 patients without prior treatment with a noncovalent BTKi (eg, pirtobrutinib or nemtabrutinib) have been enrolled in Phase 2 Cohort 1, all subsequent patients will be required to have received prior treatment with both a covalent and a noncovalent BTKi. This requirement is not applicable to Part 1d.

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/µL) 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 F or 38 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, and Japanese sites ONLY: patients must also have been treated with a covalently binding 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:
- Non-Germinal 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 covalently binding 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. For 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 covalently binding 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 noncovalently binding 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 only: Received only 1 regimen containing a covalently binding BTKi (Note: Patients may have received treatment with 2 different covalently binding BTKi if the initial covalently binding BTKi was 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]).
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); patients with platelet count < 50 x 10^9/L (< 50,000/mm^3) secondary to bone marrow infiltration by the underlying malignancy are eligible for the study if their platelet count is = 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 as above if the reduced hemoglobin is secondary to bone marrow infiltration by the underlying malignancy.

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’s 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 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 (µmol/L).

ii. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (2021):
(1) eGFR =142*min(standardized Scr/K, 1)alpha *max(standardized Scr/K, 1)^-1.200 *0.9938^Age*1.012 [if female].
(a) Scr (serum creatinine) = mg/dL; K (Baschkirisch) = 0.7 (females) or 0.9 (males).
(b) alpha = -0.241 (females) or -0.302 (males).
(c) min = indicates the minimum of Scr/K (Baschkirisch) or 1, and
(d) max = indicates the maximum of Scr/K (Baschkirisch) or 1.

iii. CKD-EPI Creatinine-Cystatin Equation (2021).
(1) eGFRcr-cys = 135 x min(Scr/K (Baschkirisch), 1)^alpha x max(Scr/K (Baschkirisch), 1)^-0.544 x min(Scys/0.8, 1)^-0.323 x max(Scys/0.8, 1)^-0.778 x 0.9961^Age x 0.963 [if female].
(a) K (Baschkirisch) = 0.7 (females) or 0.9 (males).
(b) alpha = -0.219 (female) or -0.144 (male).
(c) min(Scr/K (Baschkirisch), 1) is the minimum of Scr/K (Baschkirisch) or 1.0.
(d) max(Scr/K (Baschkirisch), 1) is the maximum of Scr/K (Baschkirisch) or 1.0.
(e) Scys = standardized serum cystatin C in mg/L.

iv. Nuclear medicine scan.

v. 24-hour urine collection.

f. Adequate pancreatic function.

i. Serum or plasma amylase = 1.5 x ULN.

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’s syndrome) and direct bilirubin level = 1.0 x ULN for patients with documented Gilbert’s 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 22 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 22 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 Criteria 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, post-transplant 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. Receiving treatment with a strong CYP3A inhibitor (< 7 days or 5 half-lives, whichever is longer) or strong CYP3A inducer (= 14 days or 5 half-lives, whichever is longer) before the first dose of BGB-16673 OR requiring long-term use of strong CYP3A inhibitors or inducers. For a list of selected strong CYP3A inhibitors or inducers, see Appendix 14.

12. Except in Part 1f: Receiving treatment with proton-pump inhibitors = 5 days before the first dose of BGB-16673. Patients receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study; refer to Section 8.3 for detailed instructions.

13. 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.

14. 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.

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

16. 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).

17. 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.

18. Known infection with human immunodeficiency virus (HIV) or serologic status reflecting active hepatitis A virus (HAV), 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 6.12.6). 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 6.12.6).

c. Presence of HAV IgM antibody (patients with a history of HAV infection that has resolved are eligible for the study).

19. Pregnant or lactating women.

20. 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.

21. Inability to comply with study procedures.

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

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

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

25. 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.

26. 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’s syndrome due to WM), or history of spontaneous bleeding requiring blood transfusion or other medical intervention.

27. NOTE: Original exclusion criterion 27 has been removed.

28. 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.

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

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

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

Main Study Inclusion Criteria

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 reappearance of any disease-related symptoms (including but not limited to clinical, biological or radiological), progression of the disease during treatment, or 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 (Hallek et al 2018)
i. R/R CLL/SLL is defined as disease that relapsed after, or was refractory to, = 1prior lines of therapy [= 2 prior lines of therapy in EU] (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)

b. DLBCL meeting all the following criteria:
i. 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 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 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 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
ii. Meeting = 1 criterion for treatment according to consensus panel criteria from the Eleventh International Workshop on Waldenstrom Macroglobulinemia (Treon et al 2023)
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
g. Symptomatic cryoglobulinemia
h. Cold agglutinin anemia
i. Immune-mediated hemolytic anemia and/or thrombocytopenia or nephropathy related to WM
j. Amyloidosis related to WM
k. Hemoglobin = 10 g/dL
l. 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 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 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 (Hallek et al 2018)
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 R/R CLL/SLL: = 1 lymph node measuring > 1.5 cm in the longest diameter and measurable in 2 perpendicular dimensions (assessed by CT/MRI).
NOTE: For patients with CLL in Part 1a and Part 1b only, the presence of measurable disease is NOT required.
b. For patients with NHL: = 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).
c. For patients with MZL: Isolated splenomegaly is considered measurable disease for the purposes of eligibility for this study (assessed by CT/MRI).
d. For patients with R/R MCL in Parts 1a and 1b: Isolated splenomegaly is considered measurable disease for the purposes of eligibility for this study (assessed by CT/MRI).
e. For patients with WM: Serum or plasma IgM level > 0.5 g/dL.

5. Patients with CLL/SLL must agree to collection of bone marrow samples (FFPE block or approximately 20 freshly cut unstained FFPE slides and bone marrow biopsy). Refer to Section 8.7 for additional details

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

Main Study Exclusion Criteria

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

1. Patients with treatment-naive B-cell malignancies.

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 12weeks must be achieved prior to enrollment.

9. Patients with HIV infection, if known. As an exception in Substudies 1 and 2, patients with known 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

15. 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).

16. 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).

17. Patients who are treated with a moderate or strong CYP3A inhibitor (7 days or 5 half lives, whichever is longer) or moderate or strong CYP3A inducer (14 days or 5 half-lives,
whichever is longer) before the first dose of study treatment or who require ongoing treatment with a moderate or strong CYP3A inhibitor or a strong CYP3A inducer.

18. 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.

19. 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.

20. 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.

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

22. Patients receiving a vitamin K antagonist or Factor Xa inhibitor.

23. 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.

24. 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.

25. Female patients who are pregnant or are breastfeeding.

26. 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.

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

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.

STUDY POPULATION
Approximately 137 participants with R/R CLL will be enrolled in this study. Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

SHARED INCLUSION CRITERIA

Participants across all Arms (unless noted) are eligible to be included in the study only if all the following criteria apply:

- Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the Informed Consent Form and in this protocol

- Age >= 18 years at the time of signing the Informed Consent Form

- South Korea applicable only: The South Korean subject must be >= 19 years of age, at the time of signing the informed consent for this protocol

- Ability to comply with the study protocol and procedures and required hospitalizations, in the investigator’s judgement

- Have a diagnosis of CLL requiring treatment according to the iwCLL criteria (Hallek et al. 2018)

- Participants must meet the following criteria for R/R CLL per iwCLL 2018 criteria
- 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 or as progression within 6 months from the last dose of therapy

- Previously treated with at least two lines of therapy, including at least one prior BTKi and/or venetoclax-based regimen

- Screening flow cytometry or immunohistochemistry (IHC) evidence of CD20 positive disease as per local review (dim expression of CD20 is acceptable)

- Eastern Cooperative Oncology Group (ECOG) performance score (PS) of <= 2

- Adequate BM function independent of growth factor or transfusion support, within 2 weeks of screening, at screening as follows unless cytopenia is clearly due to marrow involvement of CLL:
- Platelet count >= 75,000/mm^3; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet count should be >= 30,000/mm^3
- ANC >= 1000/mm^3 unless neutropenia is clearly due to marrow involvement of CLL (per the discretion of the investigator)
- Total hemoglobin>= 9 g/dL unless anemia is due to marrow involvement of CLL(per the discretion of the investigator)

- Adequate liver function as indicated by a total bilirubin, AST, and ALT <= 2 times the institutional ULN value

- In patients with CLL involvement of the liver; AST and ALT < 5 times institutional ULN and total bilirubin < 3 times institutional ULN

- In patients with Gilbert’s syndrome; total bilirubin < 3 times institutional ULN

- Measured or estimated creatinine clearance >= 45 mL/min by institutional standard method

- Life expectancy > 6 months

- Resolution to Grade <= 1 for clinically significant toxicities attributable to prior therapies before commencement of the first study drug administration with the following exceptions:

- Any grade alopecia or vitiligo

- Grade 2 peripheral sensory or motor neuropathy

- Endocrinopathy managed and controlled using replacement therapy

- Patients who have a negative HIV test at screening, with the following exception, applicable to Arms A and B only:

Patients with a positive HIV test at screening are eligible provided that, prior to enrollment, they are stable on anti-retroviral therapy for at least 4 weeks, have a CD4 count >= 200/µL, have an undetectable viral load, and have not had a history of an opportunistic infection attributable to AIDs within the past 12 months.

- For biologically female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, and agreement to refrain from donating eggs, during the treatment period and for at least 3 months after the last dose of mosunetuzumab, 3 months after the last dose of tocilizumab (if applicable), and 30 days after the last dose of venetoclax (Arm C only).

A biologically female participant is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (>=12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

- For biological males: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:

With a biological female partner of childbearing potential or pregnant partner, men must remain abstinent or use a condom during the treatment period and for 2 months after the final dose of tocilizumab (if applicable) and within 90 days after the last dose of venetoclax (Arm C only), to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.

INCLUSION CRITERIA SPECIFIC TO ARM B

In addition to the above inclusion criteria, participants considered for Arm B must meet the following inclusion criterion:

- Participants must have been taking a BTKi for at least 12 months, have demonstrated evidence of progressive disease while receiving the BTKi and require additional salvage therapy as assessed by their treating physician. Participants should be able to continue their previously prescribed BTKi at a stable dose throughout the study screening period and for the first two cycles of mosunetuzumab administration.

SHARED EXCLUSION CRITERIA

Participants across all Arms (unless noted) are excluded from the study if any of the following criteria apply:

- Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of mosunetuzumab and tocilizumab or within 30 days after the final dose of venetoclax (if applicable)

Biologically female participants of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. If a serum pregnancy test has not been performed within 14 days prior to receiving first study treatment, a negative urine pregnancy test result (performed within 7 days prior to study treatment) must be available.

- Participants who have received any of the following treatments prior to study entry:

- Treatment with mosunetuzumab or other CD20/CD3-directed bispecific antibodies

- Allogeneic stem cell transplant

- Participants who have received any of the following treatments, whether investigational or approved, within the respective time periods prior to initiation of study treatment:

- Radiotherapy within 2 weeks prior to the first dose of study treatment

- Autologous stem cell transplant within 100 days prior to first study treatment

- CAR T-cell therapy within 30 days before first study treatment

- Prior use of any monoclonal antibodies, radioimmunoconjugates, or antibody-drug conjugates for anti-CLL treatment within 4 weeks before first dose of study treatment

- Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to first dose of study treatment

Systemic corticosteroid treatment <= 20 mg/day prednisone or equivalent and inhaled corticosteroids are permitted.

Administration of acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea or B-symptoms) is permitted.

The use of mineralocorticoids for management of orthostatic hypotension and corticosteroids for management of adrenal insufficiency is permitted.

- Any other anti-cancer therapy, whether investigational or approved, including but not limited to chemotherapy, with washout periods as follows:

Arm A: Washout period is within 4 weeks prior to initiation of study treatment.

Arm C: Washout period is within 4 weeks, or 5 half-lives, whichever is shorter, prior to initiation of study treatment.

Except participants to be enrolled into Arm B where overlapping therapy with an approved BTKi is permitted (Section 5.1.1)

- Prior cancer immunotherapy not explicitly described in this protocol
Eligibility is determined by the investigator. The Medical Monitor is available to advise as needed

- Received a live, attenuated vaccine within 4 weeks before first dose of study treatment, or in whom it is anticipated that such a live attenuated vaccine will be required during the study period or within 5 months after the final dose of study treatment

- Transformation of CLL to aggressive NHL (e.g., Richter’s transformation, prolymphocytic leukemia, or diffuse large B cell lymphoma [DLBCL]) or CNS involvement by CLL

- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins)

- Presence of idiopathic, autoimmune, or drug-induced interstitial lung disease (ILD) and drug induced or auto-immune pneumonitis

- Contraindication to tocilizumab

- History of prior malignancy, except for conditions as listed below if patients have recovered from the acute side effects incurred as a result of previous therapy:

- Malignancies treated with curative intent and with no known active disease present for >= 2 years before enrollment

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

- Adequately treated cervical carcinoma in situ without evidence of disease

- Surgically/adequately treated low grade, early stage, localized prostate cancer without evidence of disease

- Participants with infections requiring IV treatment with antibiotics or hospitalization (Grade 3 or 4) within the last 4 weeks prior to enrollment or known active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment

- Evidence of any significant, concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to:

- Significant cardiovascular disease (e.g., New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina)

- Significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm)

- Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis

- Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease

Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no residual neurologic deficits as judged by the investigator are allowed.

Participants with a history of epilepsy who have had no seizures in the past 2 years with or without anti-epileptic medications can be eligible only for the expansion cohort

- History of confirmed progressive multifocal leukoencephalopathy (PML)

- Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology)
Participants with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening.
These participants must be willing to undergo monthly DNA testing and appropriate prophylactic antiviral therapy as indicated.

- Acute or chronic hepatitis C virus (HCV) infection
Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation.

- Known or suspected chronic active Epstein-Barr virus infection

- Known or suspected history of HLH

- History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 6)

Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.

Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

Participants with a history of disease-related immune thrombocytopenic purpura or autoimmune hemolytic anemia may be eligible

Participants with a remote history of, or well-controlled autoimmune disease, with a treatment-free interval from immunosuppressive therapy for 12 months may be eligible after review by the investigator. The Medical Monitor is available to advise as needed.

- Evidence of other clinically significant uncontrolled condition(s) including but not limited to active or uncontrolled systemic infection (e.g., viral, bacterial, or fungal)

- Recent major surgery within 4 weeks prior to first study treatment administration, with the exception of protocol-mandated procedures (e.g., tumor biopsies and bone marrow biopsies)

- Participants with a left ventricular ejection fraction (LVEF) < 40%

- Participants who are in dependence to the Sponsor or an investigator

- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study

- Positive SARS-CoV-2 test within 7 days prior to enrollment. PCR or rapid antigen test result is acceptable.

EXCLUSION CRITERIA SPECIFIC TO ARM C
In addition to the above exclusion criteria, participants considered for Arm C are excluded if the following criteria are met:

- Have received venetoclax therapy within 12 months prior to first study treatment administration

- Patients with known infection with HIV or human T-cell leukemia virus 1 (HTLV1)

- In countries where mandatory testing by health authorities is required, HIV testing will be performed.

- HTLV testing is required in patients from endemic countries (Japan, countries in the Caribbean basin, South America, Central America, sub-Saharan Africa, and Melanesia).

- Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

- Patients who have received the following agents:

- Strong and moderate CYP3A inhibitors within 7 days prior to the initiation of study treatment

- Strong and moderate CYP3A inducers within 7 days prior to the initiation of study treatment

- Steroid therapy for anti-neoplastic intent with the exception of inhaled steroids for asthma, topical steroids, or replacement/stress corticosteroids within 7 days prior to the first dose of study drug administration

- Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study drug and throughout venetoclax administration

- Inability to swallow a large number of tablets

- Malabsorption syndrome or other condition that precludes enteral route of administration

- Known allergy to both xanthine oxidase inhibitors and rasburicase

1) Signed Written Informed Consent

a) Participants or their legally acceptable representatives (see Appendix 2), must have signed and dated an (IRB)/Independent Ethics Committee (IEC)–approved written ICF in
accordance with regulatory, local, and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal
patient care.

b) Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.

2) Type of Participant and Target Disease Characteristics

a) A fresh pre-treatment and on-treatment tumor biopsy must be provided for biomarkeranalysis. Participants must have a tumor that can be biopsied at an acceptable clinical risk
as judged by the investigator to be eligible. An unsuccessful fresh tumor biopsy at screening will not exclude participants from receiving study treatment. For participants in Parts 2A and 2B, a repeat biopsy at screening or on-treatment from the same or an alternative site will be required if clinically feasible (at the discretion of the investigator), and the initial attempt was unsuccessful in obtaining adequate tissue for biomarker analysis. Only 1 repeat attempt may be performed at each time point, if clinically feasible. An unsuccessful fresh tumor biopsy at screening (whether or not repeat is clinically feasible) will not exclude participants from receiving study treatment. Please refer to the laboratory manual for additionaldetails. The biopsy must be a core biopsy, an excisional biopsy, or a surgical specimen.

b) Participants must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix 5) and, in addition, have at least 1 lesion accessible for biopsy. Fine needle biopsy, cytology, and bone lesion biopsies are not acceptable.

c) Participants must have an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (Appendix 6).

d) Participants must have experienced radiographically documented progressive disease on or after the most recent therapy.

e) Study participants will be expected to have received standard-of-care therapies (except forPart 1C, where participants with prior docetaxel use for the advanced/metastatic setting will be excluded), including an available PD-(L)1 inhibitor known to be effective in the tumor type for which they are being evaluated.

f) Participants must have advanced or metastatic disease and have received, be refractory to, not be a candidate for, or be intolerant to existing therapy(ies) known to provide clinical benefit for the condition of the participant. Eligible tumor types for each Part are listed below:
- Parts 1A and 1B: NSCLC, SCCHN, MSS-CRC, gastric/GEJ adenocarcinoma, cervical cancer (SCC or adenocarcinoma), RCC, UC, PDAC, melanoma, OC, orTNBC.
- Parts2A and 2B: NSCLC, SCCHN, gastric/GEJadenocarcinoma, orup to 3 additional tumor types from Parts 1A and 1B may be considered based on emerging data.
- Part 1C: NSCLC, SCCHN, gastric/GEJ adenocarcinoma, OC, or TNBC.

g) Participants with NSCLC:
i) Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV, or recurrent disease.
ii) Participants must have recurrent or progressive disease during or after platinum doublet-based chemotherapy for advanced or metastatic disease, OR must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy for local disease.
iii) Participants must have received and progressed on or after anti-PD-(L)1 therapy, if available.
iv) Status for actionable mutations (eg, epidermal growth factor [EGFR], anaplastic lymphoma kinase [ALK], ROS oncogene 1 [ROS1], rearranged during transfection [RET], etc.) must be known (when testing is available as per country/region standard of care practices); participants with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for standard tyrosine kinase inhibitors (as available per country/region standard-of-care practices)

h) Participants with SCCHN:
i) Participants must have histologically confirmed, recurrent, or metastatic SCCHN (oral cavity, pharynx, larynx), andnot amenable to local therapy with curative intent. Any other cancers of the head and neck, including nasopharyngeal cancer, salivary gland, and neuroendocrine tumors, are excluded.
ii) Participants must have progressed on or after, or been intolerant to a platinum containing regimen.
iii) Prior curative radiation therapy must have been completed at least 4 weeks prior to first study drug administration. Prior focal palliative radiotherapy must have been completed at least 2 weeks before study drug administration.
iv) Historical human papillomavirus (HPV) status for oropharyngeal cancers must be documented. HPV status should have been determined using p16 immunohistochemistry (IHC) or HPV polymerase chain reaction (PCR).
v) Participants must have received and progressed on or after anti-PD-(L)1 therapy, if available.

i) Participants with MSS-CRC:

i) Participants must have received and then progressed on or after, or have been intolerant or refractory to at least 1 standard systemic therapy for metastatic and/or unresectable disease (or have progressed within 6 months of adjuvant therapy).
(1) Prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan given as a single regimen or over multiple regimens is required.
(2) Prior treatment with an anti-angiogenic therapy (eg, bevacizumab) is required.

ii) Participants must have known MSI status or mismatch repair status.
(1) If the MSI molecular test and MMR IHC test results are both available, then both MSS and MMR proficiency will be required for study entry. Patients with MSIhigh or MSI-low or MMR deficiency will not be eligible.

iii) KRAS, NRAS and BRAF status, if known, should be documented.
(1) If RAS wild-type, prior treatment with an anti-EGFR therapy (eg, cetuximab or panitumumab) is required.

j) Participants with gastric/GEJ adenocarcinoma:

i) Participants must have received and then progressed, relapsed, or been intolerant to at least 1 standard treatment regimen in the advanced or metastatic setting (or have progressed within 6 months of adjuvant therapy).

ii) Participants with known human epidermal growth factor receptor 2 (HER2)-positive gastric cancer must have received prior treatment with a HER2 inhibitor (eg, trastuzumab).

iii) If available, MSI status or mismatch repair status should be documented.

k) Participants with cervical cancer (SCC or adenocarcinoma):

i) Must have received and then progressed, relapsed, or been intolerant to platinum-based chemotherapy with or without bevacizumab in the advanced or metastatic setting.

ii) If available, MSI status or mismatch repair status should be documented.

l) Participants with renal cell carcinoma (RCC):

i) Participants must have histologically confirmed, recurrent, or metastatic RCC, and not amenable to local therapy with curative intent.

ii) Participant had progression or refractory disease during or after at least 2 lines of therapy, including a prior anti-PD-(L)1 therapy.

m) Participants with urothelial carcinoma (UC):

i) Participants must have histologically confirmed, recurrent, or metastatic UC, and not amenable to local therapy with curative intent.

ii) Must have received and then progressed, relapsed, been intolerant to, or ineligible for at least 1 platinum-containing chemotherapy regimen OR be within 12 months of perioperative (neo-adjuvant or adjuvant) treatment with a platinum agent in the setting of cystectomy for localized muscle-invasive UC.

iii) Must be resistant or refractory to anti-PD-(L)1-based immunotherapy.

n) Participants with pancreatic adenocarcinomas (PDAC):

i) Participants must have histologically confirmed, recurrent, unresectable or metastatic PDAC, and not amenable to local therapy with curative intent.

ii) Participants must have received and progressed or been intolerant to (or not be a candidate for) at least 1 prior standard
chemotherapy.

o) Participants with melanoma:

i) Participants must have cutaneous, acral, mucosal, or unknown primary melanoma.Participants with uveal/ocular melanoma are not eligible.

ii) Participants must have histologically confirmed, recurrent, or metastatic melanoma, and not amenable to local therapy with curative intent.

iii) Participants must have received and then progressed, relapsed, or been intolerant to at least 1 standard treatment regimen in the advanced or metastatic setting, including a prior anti-PD-(L)1 therapy, if available.

iv) Participants must have known BRAF status. If indicated, participants must have been offered mutation-directed therapy that has proven survival benefit.

p) Participants with ovarian carcinomas (OC):

i) Participants must have histologically or cytologically confirmed, recurrent, or metastatic epithelial ovarian cancer, primary peritoneal carcinoma or fallopian tube cancer, and not amenable to local therapy with curative intent.

ii) Participants must have received and then progressed, relapsed, or been intolerant to platinum-based chemotherapy, OR must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy.

iii) Participants with BRCA1/2 mutation must have received treatment with a PARP inhibitor, if available.

q) Participants with triple negative breast cancer (TNBC):

i) Participants must have histologically confirmed, recurrent, or metastatic TNBC, and not amenable to local therapy with curative intent.

ii) Must have progression or refractory disease during or after at least 1 chemotherapy regimen for the treatment of locally advanced or metastatic disease.

iii) Participants with BRCA1/2 mutation must have received treatment with a platinum-containing regimen (if eligible) and a PARP inhibitor, if available.

iv) If PD-L1 positive (defined as combined positive score = 10), prior treatment with immune checkpoint inhibitor is required.

3) Age and Reproductive Status

Investigators shall counsel women of childbearing potential (WOCBP) on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study drug to a developing fetus.

- The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.

- Local laws and regulations may require the use of alternative and/or additional contraception methods.

a) Female Participants

i) Females, ages = 18 or local age of majority at the time of consent.

ii) Women who are not of childbearing potential are exempt from contraceptive requirements.

iii) Women participants must have documented proof that they are not of childbearing potential.

iv) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours prior to the start of study treatment. An extension up to 72 hours prior to the start of study treatment is permissible in situations where results cannot be obtained within the standard 24-hour window.

v) Additional requirements for pregnancy testing during and after study treatment are located in Section 2, Schedule of Activities.

vi) 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.

vii) WOCBP must agree to follow instructions for method(s) of contraception defined in Appendix 4 and as described below and included in the ICF.

viii) WOCBP are permitted to use hormonal contraception methods (as described in Appendix 4).

ix) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:

(1) Is not a WOCBP OR

(2) Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in Appendix 4 during the treatment period and for at least 3 months after the last treatment with BMS-986340 monotherapy or for at least 6 months after the last dose of study treatment if receiving BMS 986340 in combination with nivolumab or with docetaxel and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period.

b) Male Participants

i) Males, age = 18 years or local age of majority at the time of consent.

ii) Male participants receiving BMS-986340 monotherapy and BMS-986340 in combination with nivolumab should maintain their usual practice with regard to contraception (if any); however, no specific contraceptive measures are required.

iii) Male participants receiving BMS-986340 in combination with docetaxel who are sexually active with a WOCBP must agree to follow instructions for method(s) of contraception as defined in Appendix 4 and as described below.

(1) Male participants will be required to always use latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the participants have undergone a successful vasectomy or if their partner is already pregnant or breastfeeding. Males should continue to use a condom during the intervention period and for at least 3 months after the last dose of study intervention.

(2) Female partners of males participating in the study should be advised to use highly effective methods of contraception during the intervention period and for at least 3 months after the last dose of study intervention in the male participant.

(3) Male participants must refrain from donating sperm during the intervention period and for at least 3 months after the last dose of study intervention.

(4) Breastfeeding partners should be advised to consult their health care providers about using appropriate highly effective contraception during the time participant is required to use condoms.

1) Medical Conditions

a) Women who are pregnant or breastfeeding.

2) Medical History and Concurrent Diseases

a) Primary central nervous system (CNS) malignancy.

b) Untreated CNS metastases. Participants are eligible if CNS metastases have been treated and participants have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment). In addition, participants must have been either off corticosteroids, or on a stable or decreasing dose of = 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to the first dose of study treatment. Imaging performed within 28 days prior to the first dose of study treatment must document radiographic stability of CNS lesions and be performed after completion of any CNS-directed therapy

c) Leptomeningeal metastases.

d) Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment (ie, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before the first dose of study treatment and the participant has no evidence of disease). Participants with history of prior early-stage basal/squamous cell skin cancer or noninvasive or in situ cancers who have undergone definitive treatment at any time are also eligible.

e) Participants with an active, known, or suspected autoimmune disease. Participants with type 1 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 enroll.

f) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

g) Prior organ or tissue allograft.

h) Toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery, unless the toxicity is either resolved, returned to baseline or Grade 1, or deemed irreversible.

i) Any major surgery within 4 weeks of study drug administration. Participants must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment.

j) Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

i) Myocardial infarction or stroke/transient ischemic attack within the past 6 months.

ii) Uncontrolled angina within the past 3 months.

iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia,ventricular fibrillation, or torsades de pointes).

iv) History of other clinically significant heart disease (eg, cardiomyopathy, congestiveheart failure with New York Heart Association functional classification III to IV pericarditis or significant pericardial effusion).

v) Cardiovascular disease-related requirement for daily supplemental oxygen therapy.

vi) QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation> 480 msec, except for right bundle branch block.

vii) History of myocarditis, regardless of etiology.

k) History of or with active interstitial lung disease or pulmonary fibrosis.

l) Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy = 7 days prior to the first dose of study treatment (except for viral infections that
are presumed to be associated with the underlying tumor type required for study entry).

m) Known human immunodeficiency virus (HIV) positive with an acquired immune deficiency syndrome (AIDS)-defining opportunistic infection within the last year, or a current CD4 count <350 cells/µL. Participants with HIV are eligible if:

i)They have received antiretroviral therapy for at least 4 weeks prior to the first dose of study treatment, as clinically indicated, while enrolled on study.

ii) They continue on antiretroviral therapy as clinically indicated while enrolled on study.

iii) CD4 counts and viral load are monitored per standard of care by a local health care provider.

NOTE: Testing for HIV must be performed at sites where mandated locally. HIV positive participants must be excluded where mandated locally.

n) Participants with serious or uncontrolled medical disorders.

o) Receipt of packed red blood cells or platelet transfusion within 2 weeks of the first dose of study treatment.

p) Any significant acute or chronic medical illness which would interfere with study treatment or follow-up.

q) Any known or underlying medical or psychiatric condition and/or social reason that, in the opinion of the Investigator or Sponsor, could make the administration of studytreatment hazardous to the participants or could adversely affect the ability of the participant to comply with or tolerate the study.

r) Any condition, including active or uncontrolled infection, or the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

s) Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to Cycle 1 Day 1.

i) Acute symptoms must have resolved, and, based on investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving study treatment.

3) Prior/Concomitant Therapy

a) Cytotoxic agents, unless at least 4 weeks have elapsed from last dose of prior anti-cancer therapy and prior to the first administration of study drug.

b) Non-cytotoxic agents, unless at least 4 weeks or 5 half-lives (whichever is shorter) have elapsed from the last dose of prior anti-cancer therapy and prior to the first administration of study drug. If 5 half-lives is shorter than 4 weeks, agreement with the Sponsor/Medical Monitor (or designee) is mandatory.

c) Prior immune therapy treatments, unless at least 4 weeks or 5 half-lives (whichever is shorter) have elapsed from the last dose of immune therapy and initiation of study therapy.
See Section 6.1 for additional requirements for prior immunotherapy treatments.

d) Treatment with any live / attenuated vaccine within 30 days of first study treatment.

e) Previous SARS-CoV-2 vaccine within 7 days of Cycle 1 Day 1. For vaccines requiring more than 1 dose, the full series (eg, both doses of a 2-dose series) should be completed prior to Cycle 1 Day 1, when feasible, and when a delay in Cycle 1 Day 1 would not put the study participant at risk.

f) Has participated in a study of an investigational agent and has received study therapy or has used an investigational device within 28 days or 5 half-lives (whichever is shorter) of administration of BMS-986340.

g) Treatment with complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks prior to first study treatment. Refer to Section 7.7.1 for prohibited therapies.

h) Prior radiation therapy within 2 weeks prior to first study treatment. Participants must have recovered (ie, Grade = 1 or at baseline) from radiation-related toxicities prior to first study treatment.

i) Prior therapy with an anti-CCR8 antibody.

j) For Part 1C only: Participants must not have been previously treated with docetaxel in the unresectable or metastatic setting.

4) Physical and Laboratory Test Findings

a) White blood cells (WBC) < 2000/µL.

b) Neutrophils < 1500/µL (stable off any growth factor within 4 weeks of first study treatment administration).

c) Platelets < 100 x 10^3/µL (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration).

d) Hemoglobin < 9.0 g/dL (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration).

e) Serum creatinine > 1.5 x ULN, unless creatinine clearance = 40 mL/min (measured or calculated using the Cockroft-Gault formula).

f) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): > 3.0 x ULN. For participants in Part 1C receiving docetaxel: AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN.

g) Total bilirubin > 1.5 x ULN (except participants with Gilbert’s syndrome, who must have a total bilirubin level of < 3.0 x ULN). For participants in Part 1C receiving docetaxel: total bilirubin > 1 x ULN.

h) Any positive test result for hepatitis B virus (HBV) indicating presence of virus; eg, hepatitis B surface antigen (HBsAg, Australia antigen) positive.

i) Any positive test result for hepatitis C virus (HCV) indicating presence of active viral replication (detectable HCV-RNA). Note: Participants with positive HCV antibody and an undetectable HCV RNA are eligible to enroll

5) Allergies and Adverse Drug Reaction

a) History of allergy, hypersensitivity, or serious adverse reaction to monoclonal antibodies or related compounds.

b) History of life-threatening toxicity related to prior immune therapy (eg, anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hypothyroidism).

c) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity) except for history of infusion reaction to paclitaxel or oxaliplatin.

d) History of allergy or hypersensitivity to study drug components.

6) Other Exclusion Criteria

a) Prisoners or participants who are involuntarily incarcerated. (Note: Under specific circumstances and only in countries where local regulations permit, a person who has been
imprisoned may be included as a participant. Strict conditions apply and BMS approval is required.)

b) Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.

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.

Dose escalation

Participants are eligible to be enrolled in the dose escalation study only if all of the following criteria apply:

Demographic characteristics

1. Male or female participant aged = 18 years of age.

General criteria

2. Estimated life expectancy = 3 months.

3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

Sex and contraceptive/barrier requirements

4a. Women of childbearing potential (WOCBP) must use a highly effective method of birth control (described in Appendix 7) during study treatment and for at least 6 months after the last dose of S095035 when administered as a single agent, and for at least 7 months after the last dose when S095035 is given in combination with TNG462. In case of oral contraceptive use, women should have been stable on the same contraceptive drug (i.e., same active principle) for at least 3 months prior to the first IMP administration. Ovum donation will not be allowed during the study and for at least 6 months after the last dose of S095035 when administered as a single agent, and for at least 7 months after the last dose when S095035 is given in combination with TNG462.

5b. Male participants with WOCBP partners must use a condom during the study and until at least 3 months after the last dose of S095035 when administered as a single agent, and for at least 4 months after the last dose when S095035 is given in combination with TNG462. In addition, the same contraception duration should be considered for their female partners. Sperm donation will not be allowed during the study and for at least 3 months after the last dose of S095035 when administered as a single agent, and for at least 4 months after the last dose when S095035 is given in combination with TNG462.

Contraceptive measures do not apply if the participant is sterile, has undergone a vasectomy or hysterectomy or is sexually abstinent from heterosexual contact.

Please refer to Appendix 7 for further contraception considerations.

Informed consent

6. Obtained prior to any study-specific procedure as described in Section 13.3 of the protocol.

Medical and therapeutic criteria

7b. Participants with histologically confirmed advanced or metastatic solid tumors (excluding CNS tumors other than IDHwt glioblastoma [as per World Health Organization (WHO) 2021 classification]), with measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria for participants with IDHwt glioblastoma, that have progressed (documented disease progression) after receiving at least one prior treatment regimen given for advanced/metastatic disease, and for whom additional effective standard therapy is not available. For this study, effective standard therapy is defined as treatment that has been shown to be curative and/or to prolong survival. In addition, participants who are considered to not be candidates for standard therapy are eligible for this study; in such cases, documentation of the reason for omitting a standard therapy is required.

8. Participants with pre-existing documented MTAP homozygous gene deletion in their tumor tissue, determined using an NGS IVD test (please refer to the laboratory manual for the tests authorized by the Sponsor in the frame of this clinical study) prior to screening.

9a. Participants, except those with IDHwt glioblastoma, must be willing to provide newly collected tumor biopsies prior to Cycle 1 Day 1 (C1D1), and while receiving treatment (i.e., at C1D28 +/- 6 days) unless not medically feasible. Participants with IDHwt glioblastoma must provide archival tissue from their most recent surgery or biopsy, collected before screening.

10. Adequate hematological function based on the last assessment performed within 7 days prior to the first IMP administration, defined as:
- Absolute neutrophil count (ANC) = 1.10^9/L.
- Hemoglobin = 9 g/dL. In case of blood transfusion, the hemoglobin assessment must be performed 2 weeks or more after the transfusion.
- Platelet count = 100 x 10^9/L.

11a. Adequate coagulation function, defined as international normalized ratio (INR), prothrombin time (PT) or activated partial thromboplastin time (aPTT) = 1.5 x the upper limit of normal (ULN) unless participant is receiving anticoagulant therapy and the PT or aPTT is within the therapeutic range for such anticoagulants. For participants receiving coumadin/warfarin, the INR should be determined and = 2.0 x ULN.

12a. Adequate renal function, defined as a glomerular filtration rate (GFR) or creatinine clearance (CrCl) =60 mL/min, must be confirmed based on the most recent assessment conducted within 7 days prior to the first administration of IMP. Renal function may be assessed using the Cockcroft-Gault formula, the Modification of Diet in Renal Disease (MDRD) formula, or the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula.

13. Adequate hepatic function based on the last assessment performed within 7 days prior to the first IMP administration, defined as:
- Total serum bilirubin <- 1.5 x ULN.
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN.
- AST and/or ALT = 5 x ULN if increase due to underlying liver metastasis.

36. Participants with IDHwt glioblastoma must be stable. If they are on corticosteroids for reasons related to their CNS tumor, they must be on a stable or decreasing dose (= 4mg/day of dexamethasone or equivalent) for = 5 days before the first IMP administration.

Dose expansion

Participants are eligible to be enrolled in one of the single-agent or combination dose expansion Arms only if they meet all of the inclusion criteria listed in Section 5.1.1, unless otherwise specified, as well as the criteria (general and cohort-specific) listed below:

37. Participants in dose expansion, except those with IDHwt glioblastoma, must provide newly collected tumor biopsies at screening, unless not medically feasible and archival tissue was collected within 3 months before study entry and no treatment has been received since the most recent biopsy.

38. Participants with IDHwt glioblastoma must provide archival tissue from their most recent surgery or biopsy, collected before screening, even if that occurred > 3 months before study entry.

Inclusion criteria specific to S095035 single-agent dose expansion

Arm 1a:

39b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 1b:

40b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced BTC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 1c:

41b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced PDAC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 1d:

42b. Participants with locally advanced or metastatic malignancies with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1 or RANO 2.0 criteria for participants with IDHwt glioblastoma, who have received and progressed of experienced recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Enrollment in Arm 1d will be limited to the following tumor types: IDHwt glioblastoma (as per WHO 2021 classification), gastroesophageal cancer, urothelial cancer, head and neck (including salivary) cancers, and melanoma. However, other locally advanced or metastatic homozygously MTAP deleted solid tumor types may be considered following discussion with the Sponsor. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Inclusion criteria specific to S095035–TNG462 combination dose expansion

Arm 2a:

43b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced BTC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 2b:

44b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced gastroesophageal cancer with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 2c:

45b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced PDAC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Dose escalation

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

General criteria

14. Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of the IMP. Examples of medical conditions that may affect IMP absorption include (but are not limited to) inflammatory bowel disease (e.g., Crohn’s disease) and gastrointestinal diseases such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea and malabsorption syndrome.

15. Pregnant or lactating women.

16. WOCBP who have a positive pregnancy test within 7 days prior to the first day of IMP administration.

17. Unlikely to cooperate in the study.

18. Participation in another interventional study at the same time or less than 5 half-lives of the investigational drug of the other study. Participation in non-interventional registry or epidemiological studies is allowed.

19. Participant already enrolled in the study (informed consent signed) who had received at least 1 dose of IMP.

Medical and therapeutic criteria

20. Active second primary malignancy other than non-melanoma skin cancers, nonmetastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor’s Medical monitor and investigator agree and document that it should not be exclusionary.

21. Known prior severe hypersensitivity to any component of the IMP(s) formulation.

22. Failure to recover to = Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0) from acute non-hematologic toxicity (or to = Grade 2 for neuropathy or alopecia), due to previous therapy, prior to screening.

23. Major surgery within 4 weeks prior to the first IMP administration or participants who have not recovered from side effects of the surgery.

24. Have a known history of Gilbert’s syndrome.

25. History of gastrointestinal perforation and /or fistula or aorto-esophageal fistula within 6 months prior to first IMP intake.

26. Severe or uncontrolled active acute or chronic infection.

27. Participants with a known clinically significant cardiovascular disease or condition, including:
- Uncontrolled arterial hypertension per the investigator’s judgment.
- Congestive heart failure (corresponding to New York Heart Association class III or IV).
- Congenital or substance-induced long QT defined as heart rate–corrected QT (QTc) interval > 470 ms according to Frederica’s formula.
- Uncontrolled cardiac arrhythmia (e.g., participants with rate-controlled atrial fibrillation are eligible).
- Severe conduction disturbances (e.g., 3rd degree heart block).
- Acute coronary syndrome (including unstable angina pectoris, acute myocardial infarction), coronary angioplasty or bypass grafting within 6 months prior to the first IMP administration.

28. Participants with thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to first IMP administration.

29. Active brain metastases, i.e., symptomatic brain metastases or known leptomeningeal disease. Asymptomatic brain metastases are allowed if they meet the following criteria:
- Have been treated and have been stable for = 4 weeks as documented by radiographic imaging.
- Have not required increasing doses of corticosteroids within 2 weeks prior to initiation of study treatment.
- Participants who have had complete surgical resection or received stereotactic radiosurgery or whole brain radiotherapy may enroll in the study provided that they have completed treatment > 2 weeks prior to initiation of study treatment, have recovered, are clinically/neurologically stable and do not require escalating corticosteroid therapy as noted above. If local treatment was completed > 4 weeks prior to study entry, participants must not have new findings on CNS imaging.

30. Participants who have received systemic anticancer treatment or radiotherapy less than 2 weeks before the first dose of IMP. Continuation of supportive therapy with bisphosphonates or denosumab is allowed, regardless of the underlying malignancy.

31. Any clinically significant medical condition (e.g., organ dysfunction) or laboratory abnormality likely to jeopardize the participant’s safety or to interfere with the conduct of the study, in the investigator’s opinion.

32. Participants who have already received a MAT2A or PRMT5 inhibitor.

33. For prohibited concomitant medication, refer to Section 6.3.

35. A medical condition that results in increased clinically significant photosensitivity (e.g., solar urticaria, lupus erythematosus, etc.).

Inclusion criteria

Subjects 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. Subject is currently enrolled in a pre-defined Novartis-sponsored study and is receiving spartalizumab as single agent or in combination with other study treatment.

3. Subject is currently deriving clinical benefit from the study treatment, as determined by the investigator.

4. Subject has demonstrated compliance, as assessed by the investigator, with the parent protocol requirements.

5. Subject is willing and able to comply with the scheduled visits and treatment plans.

Exclusion criteria

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

- Subject has been permanently discontinued from spartalizumab in the parent protocol for any reason other than enrollment in the CPDR001X2X01B study.

- Subject does not meet the criteria specified in the parent protocol criteria for continued study treatment.

- Subject not willing to comply with the contraception requirements outlined in the exclusion criteria of the parent protocol.

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.

1. Histologically confirmed locally advanced (not manageable with curative intent) or metastatic solid tumor

Specification for Stratum C: Only patients with NSCLC adenocarcinomas, (squamous or adenosquamous not permitted) who are scheduled to receive platin + pembrolizumab +
pemetrexed standard treatment (only for Stratum C)

Specification for Stratum E: Including only metastatic or irresectable locally advanced urothelial carcinomas – also refer to IC 14 below (only for Stratum E)

2. Tumor is accessible for repeated injections and biopsies (only for Stratum A)

3. Peritoneal carcinomatosis (only for Stratum B)

4. Patient failed standard therapy or refused standard therapy or is intolerable towards standard therapy (Strata A, B, and D) or who receives Standard-of-Care first line treatment comprising platin + pembrolizumab + pemetrexed (only for Stratum C)

5. Patient has not received more than 4 prior lines of therapy. Neoadjuvant/adjuvant treatment is not counted unless progression occurs <6 months after completion of the treatment. In these cases, neoadjuvant/adjuvant treatment is counted as one prior line (only for Stratum D).

Specification for Stratum C: Only patients receiving first line Standard-of-Care therapy (platin + pembrolizumab + pemetrexed; only for Stratum C)

Specification for Stratum E: Refer to IC 14 below with regards to previous lines of therapy; only for Stratum E)
Note exclusion criterion 7 on exclusion of defined previous cancer immunotherapy (only for Strata D and E)

6. Patients >= 18 years. Patients in reproductive age must be willing to use highly effective contraception during the study and 4 months after the end of the study (appropriate
contraception is defined as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomized partner, bilateral tubal occlusion, sexual
abstinence. If an oral contraception is used, a barrier method of contraception (e.g., male condom, female condom, cervical cap, diaphragm, contraceptive sponge) has to be applied
additionally.). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.

7. ECOG 0 or 1

8. Adequate hematological, hepatic and renal function parameters:

- ANC (absolute neutrophil count) >= 1,500/µL
- Leukocytes >= 3,000/µL
- Platelets >= 75,000/µL (for Stratum D: >= 100,000/µL)
- Serum creatinine <= 1.5 x upper limit of normal, or GFR >= 50 mL/min (not applicable for patients not eligible for platinum-based therapy in Stratum E)
- Bilirubin <= 1.5 - 3 x upper limit of normal (for Stratum D: <= 1.5 x ULN)
- AST and ALT <= 3 x upper limit of normal (<= 5 x if liver metastases are present) (for Stratum D: AST and ALT <= 2.5 x ULN; <= 5 x if liver metastases are present)
- Alkaline phosphatase <= 6 x upper limit of normal
- Hemoglobin >= 9 g/dL

9. Adequate coagulation functions as defined by International Normalized Ratio (INR) <=1.5, and a partial thromboplastin time (PTT) <= 5 seconds above the ULN (unless receiving
anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin (new oral anticoagulants (NOACs) are permitted) and have
achieved stable coagulation profile.

10. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

11. Evidence of measurable disease as defined by RECIST v1.1 (only for Strata C, D and E) or assessable disease as defined by RECIST v1.1 (only for Stratum C)

12. Expected survival > 3 months

13. Resolution of toxicity associated with prior or current therapy to grade <2 (except for alopecia and transaminases in case of liver metastases)

14. Patient is eligible if one of the following settings applies (only for Stratum E):

- did not receive any prior systemic therapy for metastatic disease AND would be eligible for platinum-based therapy AND has a PD-L1 CPS =10 or
- did not receive any prior systemic therapy for metastatic disease AND is not eligible for platinum-based therapy, independent from PD-L1 CPS status or
- did suffer disease progression during/directly after a platinum-based chemotherapy for metastatic disease AND did not receive avelumab maintenance therapy after platinum based chemotherapy, independent from PD-L1 CPS status

1. Inability to understand the aims of the study and/or protocol procedures

2. Bleeding ulcerative tumors or tumors requiring intratumoral injections of study drug into parenchymatous organs such as, but limited to liver, spleen or pancreas (only for Stratum A)

3. Patients with contraindication versus a laparoscopy or refusing a laparoscopy (only for Stratum B)

4. Hypersensitivity towards eftilagimod alpha, avelumab (only for Strata D and E), or any ingredient of the injection/infusion solutions

5. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

6. Any concurrent other antineoplastic treatment including irradiation, or targeted small molecule therapy, or biological cancer therapy. (only Strata A, B, D and E)

7. Prior PD-1/PDL-1 targeted therapy (only for Strata D and E).
NOTE: For Stratum E only, patients can be enrolled if they received prior PD-1/PD-L1 targeted therapy during neoadjuvant treatment. HOWEVER, only after at least a free interval of at least 12 months after neoadjuvant PD-1/PD-L1 addressed- therapy.

8. Cirrhosis of the liver (Child > Grade A), pronounced alcohol abuse with anticipated detoxification, severe pulmonary infection with considerable reduction of pulmonary function

9. Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV (for Stratum D: >= NYHA II) within 6 months prior to first dose of study treatment including: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of current NCI CTCAE version Grade >2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, ventricular arrhythmias requiring medication or symptomatic pulmonary embolism

10. Cerebral or leptomeningeal metastases
Note: Subjects with previously treated brain metastases may participate if they meet the following criteria: 1) are stable for at least 28 days prior to the first dose of study treatment
and if all neurologic symptoms returned to baseline; 2) have no evidence of new or enlarging brain metastases; and 3) have not been using steroids for at least 7 days prior to first dose of study treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

11. Chronic inflammatory bowel disease

12. Active infection requiring systemic therapy at the start of study treatment or chronic infection or serious intercurrent infection within 4 weeks prior to first dose of study treatment

13. QTcF >480 ms, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP)

14. Uncontrolled electrolyte disorders that can worsen the effects of a QTc-prolonging drug (e.g., hypocalcaemia, hypokalaemia, hypomagnesemia)

15. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. Testing is not required in the absence of history.
Participants with known human immunodeficiency virus (HIV) infections are eligible if the following criteria are met:

a. If clinically indicated participants must be stable on antiretroviral therapy (ART) for at least 4 weeks and agree to adhere to ART. If not clinically indicated, consult Principal Investigator (LKP).
b. Participants with HIV infection should have no evidence of documented multidrug resistance that would prevent effective ART.
c. Have an HIV viral load of < 400 copies/mL at Screening.
d. If prophylactic antimicrobial drugs are indicated, patient may still be considered eligible upon agreement with the Principal Investigator (LKP)

16. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test) or hepatitis C Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV
infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible. Note: Patients positive for hepatitis C virus (HCV)
antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA). Testing is not required in the absence of history.

17. History or evidence of interstitial lung disease, active non-infectious pneumonitis or active tuberculosis

18. Active or prior autoimmune disease requiring immunosuppressive therapy that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.

19. Known history of immune-mediated colitis, pneumonitis, pulmonary fibrosis (only for Strata D and E).

20. Administration of a live, attenuated vaccine (including Covid-19 vaccination with live, attenuated vaccine) within four weeks prior to start of treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study.

21. Any condition requiring continuous systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 4 weeks
prior to first dose of study treatment. Intranasal, inhaled or topical steroids, eye drops or local steroid injection (e.g., intra-articular injection), steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication) and physiological replacement doses of up to 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.

22. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is shorter, prior to start of study treatment

23. Any previous venous thromboembolism > National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 within the last 6 months

24. Past history of severe allergic episodes and/ or Quincke’s oedema

25. Prior organ transplantation or stem cell transplantation

26. On-treatment participation in another clinical study in the period 30 days prior to start of study treatment and during the study

27. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)

28. Pregnancy or lactation

29. Planned intratumoral injections in parenchymatous organs (e.g. liver, spleen, adrenal gland, pancreas)

30. Life-threatening illness unrelated to cancer

31. History of irAEs of CTCAE Grade 4 requiring steroid treatment (only for Strata C, D and E)

32. Persisting toxicity related to prior therapy (NCI CTCAE current version Grade > 1); however, alopecia, sensory neuropathy Grade <=2, or other Grade <=2 AEs not constituting a
safety risk based on investigator's judgment are acceptable (only for Strata D and E)

33. Other severe acute or chronic medical conditions, psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities
that may increase the risk associated with study participation or study treatment 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

Inclusion Criteria; HLA (S1), and Tumor Tissue Collection (S2) and Treatment Eligibility Assessment (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 and/or metastatic cutaneous melanoma, uveal melanoma, endometrial carcinoma (excluding uterine carcinosarcoma), epithelial ovarian, fallopian tube or primary peritoneal cancer restricted to serous, clear cell, and endometrioid subtypes, with the exception of primary platinum-refractory disease, synovial sarcoma, or sqNSCLC.

Phase IIa: Patients must have pathologically confirmed and documented advanced and/or metastatic cutaneous melanoma.

Note: Depending on trial progress, the patient's tumor indication should be considered to meet the requirements of the planned treatment cohort (i.e., basket population for dose Phase Ia escalation/de-escalation and in Phase Ib extension cohorts; indication specific extension cohorts in Phase IIa (see Section 2.2.2). S1 - X

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).

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. 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. Absolute neutrophil count (ANC) = 1.0 x 10^9/L (without granulocyte colony-stimulating factor [G CSF] support); platelets = 75,000/µL; hemoglobin = 8 g/dL; absolute lymphocyte count (ALC) = 0.5 x 10^9/L (repeat assessment allowed). S2 - X^5, VA - X^1

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 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). 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) unless patient is on stable dose of anticoagulants, the interruption of which for the purpose of obtaining the biopsy is medically feasible. S2 - X^3,5, VA - X^1

11 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 (e.g., radiation, surgery, chemotherapy, immunotherapy or targeted therapy). 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 (e.g., chronic peripheral neuropathy) and such toxicities are not anticipated to worsen with the IMA402 therapy. VA - X

13 Male patients must agree to use highly effective contraception or be abstinent while on treatment and for 1 month after the last infusion of IMA402. VA - X

14 Female patients of childbearing potential must use highly effective contraception or be abstinent during screening, while on treatment and until 1 month after the last infusion of IMA402. S1 - X, S2 - X, 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. 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.

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. 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). S1 - X, VA - X

9. History of, or current, immunodeficiency disease or prior treatment relevantly compromising immune function, at the discretion of the investigator. S1 - 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 IMA402 therapy systemic corticosteroids (= 10 mg/day prednisone or equivalent), major surgery, any 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.

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 IMA402 treatment after signature of ICF2. VA - X

14. Patients with active CNS metastases.
Note: Patients with a history of newly detected CNS metastases are eligible if 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. 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 intend are not considered. The evaluation should be conducted at S2 (if applicable, before a biopsy is taken). Any number of prior systemic treatment lines in the platinum-sensitive setting is allowed.
Note: Additionally applied systemic anti-tumor treatment lines after S2 are allowed. S2 - X

16. Patients with LDH > 2.0-fold ULN. S2 - X, 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 PRAME- or MAGEA4/8-directed TCR-based therapy. VA - X

21. For combination therapy only: Patients with hypersensitivity or a history of toxicity leading to permanent discontinuation of prior CPI treatment, or contraindications for pembrolizumab administration according to current PI/SmPC. 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 the regulatory agency's approval. An interim report (including but not limited to safety, PK, pharmacodynamics, and preliminary efficacy data and the foreseen RDE[s]) will be submitted for review before dose expansion parts are initiated in one treatment group.

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 a qualified local laboratory of CALR exon-9 mutation (preferably obtained by next-generation targeted sequencing or PCR).

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-2 or high-risk DIPSS MF (according to IWG-MRT criteria, Passamonti et al 2010).
- Must be JAK inhibitor–naive (TxN) and have an indication for initiation of ruxolitinib treatment.

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 or platelet count > 1 x 10^12/L 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 hematological 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 7.

Exclusionary Laboratory Values

Laboratory Parameter: Exclusion Criterion

Hematology

a Platelets: TGA-ET: < 450 x 10^9/L TGA-MF: < 50 x 10^9/L TGBs: < 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 m2 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 HBV (or at risk of reactivation), defined as follows: positive HBsAg result (laboratory test required at screening), and/or positive total anti-HBc result (laboratory test required at screening), and/or quantitative HBV-DNA test result greater than the lower limits of detection of the assay (if known; laboratory test not required for eligibility purpose, but can be done as part of screening if available locally).

Note: Participants with no prior history of HBV infection who have been vaccinated against HBV and who have 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).

Subjects must meet all of the following criteria in order to be included in the study. Anything other than a positive response to the questions below will result in exclusion from study participation.

Consent
1. Subjects or their legally authorized representative, if permitted, must voluntarily sign and date an informed consent, approved by an independent ethics committee (IEC)/institutional
review board (IRB), prior to the initiation of any screening or study-specific procedures.

Subjects must not be incarcerated and must be freely willing and able to provide informed consent (e.g., adults under legal protection measure [e.g., under guardianship/curatorship] or
unable to express their consent and select adults under psychiatric care). Investigator's discretion should be applied.

Demographic and Laboratory Assessments

2. Adult male or female, at least 18 years old.

3. Laboratory values meeting the following criteria within the screening period prior to the
first dose of study drug:

- Absolute neutrophil count (ANC) = 1.5 x 10^9/L (growth factor use is allowed if evidence of bone marrow involvement, but subject must not have received growth factor within 14 days prior to screening labs)

- Hemoglobin = 8.0 g/dL (red blood cell transfusions permitted, but subject must not have received blood transfusions within 7 days prior to screening labs)

- Platelet count = 75 x 10^9/L, or = 50 x 10^9/L if bone marrow infiltration or hypersplenism (platelet transfusions permitted, but subject must not have received blood transfusions
within 7 days prior to screening labs)

- Serum aspartate transaminase (AST) AND alanine transaminase (ALT) level = 3 x upper limit of normal (ULN)

- Direct bilirubin must be = 2 x ULN

- Estimated Creatinine Clearance (CrCl) (as calculated by Cockcroft-Gault Formula, modified as needed for factors such as body weight) or eGFR (as calculated by MDRD equation) = 50 mL/min

- Prothrombin time (PT) or International normalized ratio (INR), and Activated partial thromboplastin time (aPTT) = 1.5 x ULN, unless receiving anticoagulation (although INR should not be > 4.0)

4. Subject is willing and able to comply with procedures required in this protocol.

5. Subject must be able to tolerate subcutaneous injections.

6. Subject must have available adequate fresh or paraffin-embedded tissue at Screening.

Disease/Condition Activity

7. Diagnosis of:

- (Arms 1, 2, 3, and 4) DLBCL (de novo or histologically transformed from follicular lymphoma or nodal marginal zone lymphoma) with histologically confirmed CD20+ disease at most recent representative tumor biopsy pathology report, inclusive of the following according to WHO 2016 classification and documented in pathology report:

- DLBCL, NOS

- High-grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 translocations per WHO 2016 ("double-hit" or "triple-hit")

Note: High-grade B-cell lymphomas NOS or other double-/triple-hit lymphomas (with histologies not consistent with DLBCL) are not eligible

- Follicular lymphoma Grade 3B

Or

- (Arm 5) FL with histologically confirmed CD20+ Grade 1 to 3a FL and no evidence of histologic transformation to an aggressive lymphoma at most recent representative tumor biopsy pathology report according to WHO 2016 classification

Or

- (Arms 6 and 7 and 8) MCL with histologically confirmed CD20+ disease at most recent representative tumor biopsy pathology report according to the WHO 2016 classification with evidence of overexpression of cyclin D1 in association with relevant markers by IHC or evidence of t(11;14) assessed by flow cytometry, FISH, or PCR

- A report from the local laboratory is acceptable if available, however, a tumor block or slides must be sent to the central pathology laboratory for confirmation

8. Subject must have no prior treatment with epcoritamab or any other bispecific antibody targeting CD3 and CD20

9. Subject must have 1 or more measurable disease sites:

- A PET-CT scan demonstrating PET-positive lesion(s)

AND

- At least 1 measurable nodal lesion (long axis > 1.5 cm) or = 1 measurable extra-nodal lesion (long axis > 1.0 cm) on CT scan or MRI

10. Subject must be eligible to receive and have a need for treatment initiation based on symptoms and/or disease burden as per investigator assessment.

11. Subject must have ECOG performance status 0-2, except for Arms 6, 7 and 8 where ECOG performance status must be 0-1.

1. For Dose Escalation (Part 1) only*+: Participants with documented diagnosis for one of the following third line or later treatment of B-cell malignancies, from one of the following
WHO-defined histologies (Swerdlow et al 2016):
a) CLL
b) SLL
c) CAR-T/HCT R/R or ineligible DLBCL from the following histologies: DLBCL not otherwise specified (NOS) (GCB and non-GCB DLBCL), T-cell/histiocyte-rich large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic lymphoma kinase positive (ALK+) large B-cell lymphoma, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphoma NOS
d) MCL
e) FL (grades 1-3b)
f) MZL (splenic, extranodal, and nodal)
g) LPL including WM
h) Transformed iNHL

2. For Dose Expansion (Part 2) only*+:Participants with documented diagnosis of CLL/SLL who are in their third line or later treatment including those with BTK mutations or CAR-T/HCT R/R or ineligible non-GCB DLBCL who are in their third line or later treatment with histology based on criteria established by the WHO
*Participants with CLL/SLL should have either received both a BTK inhibitor and venetoclax therapy, been evaluated for and determined to be ineligible for either or both of these therapies, and/or been offered and declined treatment with either or both of these therapies.
+ Participants with CLL and transformed iNHL must meet relevant disease-specific requirements for systemic treatment (e.g., iwCLL or Groupe d'Etude des Lymphomes Folliculaires [GELF] for FL, respectively).

3. Participant must be at least 18 years old.

4. Participant has an ECOG PS of 0, 1, or 2. For EU only: Participant has an ECOG PS of 0 or 1.

5. Participant has a life expectancy >= 12 weeks.

6. Prior BTKi is allowed.

7. Adequate hematologic function independent of growth factor or transfusion support within 14 days prior to enrollment, defined as:

- Hemoglobin > 8 g/dL.
- ANC > 1 x 10^9 /L.
- Platelet count > 50 x 10^9 /L.

8. Adequate renal and hepatic function, defined as:

- ALT <= 2.5 x upper limit of normal (ULN).
- AST <= 2.5 x ULN.
- Total bilirubin <=1.5 x ULN (unless bilirubin rise is due to cases of documented Gilbert's syndrome or of non-hepatic origin, a total bilirubin = 3 x ULN may be allowed).
- Estimated glomerular filtration rate (by Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology [CKD-EPI]) or measured creatinine clearance by 24-hour urine collection >= 40 mL/min.

9. Adequate coagulation factor levels:

- PT <=1.5 x ULN.
- INR <=1.5 x ULN.
- aPTT <=1.5 x ULN.

10. Participant (excluding CLL subtype) must have archival or freshly collected tumor tissue for correlative studies before study enrollment.

11. A female who is not pregnant, breastfeeding, donating eggs (ova, oocytes), or considering becoming pregnant, breastfeeding, or donating eggs (ova, oocytes) during the study or for 180 days after the last dose of study treatment can be enrolled. For men or women of childbearing potential, willing to use adequate contraception for the duration of study and
90 days (men) or 180 days (women) after last dose of study treatment.
Note: For guidance on the use of contraceptives and barriers, see Appendix 4 (Section 10.4).

12. Women of childbearing potential must have negative serum pregnancy test within 14 days prior to first dose of study treatment and a negative confirmational urine (or serum per local guidelines) pregnancy test prior to study drug dosing on Cycle 1 Day 1 (C1D1).

13. Must voluntarily sign and date an informed consent, approved by an IEC/ IRB, before the initiation of any screening or study-specific procedures.

14. Echocardiogram with ejection fraction >= 50%.

15. Able to swallow tablets and no conditions that could interfere with drug absorption including but not limited to short bowel syndrome or malabsorption syndrome.

16. Must be willing and able to comply with procedures required in this protocol.

17. Ability to tolerate uric acid reducing medications (note: participants with known glucose-6-phosphate dehydrogenase [G6PD] deficiency will be excluded).

18. No known history of other malignancy, with the following exceptions:

- No known active disease present for = 3 years before first dose of study treatment and considered to be at risk of low recurrence by the Investigator.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated carcinoma in situ without evidence of disease.

1. Previously treated with a BTK degrader.

2. Known active central nervous system (CNS) disease, or primary CNS lymphoma. Participants with prior CNS disease that have been effectively treated may be eligible.

3. Known bleeding disorders (e.g., von Willebrand's disease or hemophilia).

4. Therapeutic need for anticoagulation therapy with warfarin or Low Molecular Weight Heparin (LMWH).

5. Known history of stroke or intracranial hemorrhage within 12 months prior to first dose of study treatment.

6. Uncontrolled active systemic infection, or active cytomegalovirus infection.

7. Active hepatitis B or C infection or less than 12 weeks since achieving undetectable viral load in cases of prior active hepatitis C.

8. Known history of human immunodeficiency virus (HIV).

9. Radiotherapy within 14 days prior to the first dose of study treatment.

10. Anticancer therapy including chemotherapy, small molecule and investigational agents, or monoclonal antibody therapy within 28 days (or at least 5 half-lives, whichever is shorter), and/or corticosteroids at doses exceeding 20 mg/day of prednisone or equivalent given with anti-neoplastic intent within 7 days prior to first dose of study treatment.

11. The participant requires urgent cytoreductive therapy.

12. Stem cell transplant (SCT) within 90 days prior to the first dose of study treatment and recovery from SCT-related complications is required.

13. Evidence of active graft versus host disease (GVHD) or requirement for immunosuppressants within 28 days prior to first dose of study treatment.

14. Active or uncontrolled autoimmune cytopenias (for 14 or more days) including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP).

15. Ongoing history of clinically significant medical and/or psychiatric conditions or any other reason that, in the Investigator's opinion, could impact the participant's safety or put the study outcomes at risk.

16. History or evidence of current interstitial lung disease or pneumonitis.

17. Currently active, clinically significant cardiovascular abnormalities (unless pacemaker was installed with no subsequent abnormalities) including symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV heart failure), unstable angina pectoris, cardiac arrhythmia, or cardiac infarction within 6 months prior to first dose of study
treatment.

18. Corrected QT interval > 450 msec (males) or > 470 msec (females) based on Fridericia's formula or other significant electrocardiographic abnormalities including second degree
atrioventricular block type II, third degree atrioventricular block, or bradycardia (ventricular rate less than 50 beats/min).

19. Has received any live vaccine within 28 days prior to the first dose of study treatment or has an expected need for a live vaccination during study participation, including at least 28 days after the last dose of study treatment. The first dose of study treatment, when possible, is preferred to be given at least 7 days after SARS-CoV-2 vaccine administration.

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

21. Unresolved toxicity of >= Grade 2 from prior anticancer therapy, except for alopecia.

22. Known hypersensitivity or an allergic reaction to the active ingredient or other components of the study drug and/or other products in the same class.

23. Participant has systemically used proton-pump inhibitors within 7 days prior to the first dose of study treatment.

24. Participant has systemically used known moderate/strong inhibitors of cytochrome P450 3A (CYP)3A enzyme isoform subfamily, or p-glycoprotein (P-gp), within 14 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study treatment.

25. Participant has systemically used known moderate/strong inducers of CYP3A or P gp inducers within 14 days prior to the first dose of study treatment.

26. Participant requires treatment with known moderate or strong inhibitors or inducers of CYP3A, P-gp inhibitors, P-gp inducers, or proton-pump inhibitors from the first dose of study treatment and for the duration of the study.

27. Administration or consumption of any of the following within 3 days prior to first dose of study treatment and while on study treatment: grapefruit or grapefruit products, Seville oranges (including marmalade-containing Seville oranges), and star fruit.

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 potential^1 and male patients with female partner of childbearing potential^1 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 partner^2

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 ormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. For the purpose of this document, aman 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, triple negative 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)