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.

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.

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.).

MODULE 1 INCLUSION CRITERIA

1. Written (signed and dated) informed consent, and capable of co-operating with IMP (and AxMP) administration and follow-up.

2. Histologically or cytologically confirmed diagnosis of PDAC with metastatic disease.

3. Consent for pre- and on-treatment tumour biopsy samples for assessment of molecular markers, including, but not limited to, SMAD4 and gremlin-1. Pre- and on-treatment tumour samples are mandatory in the first instance. These tumour samples may become optional as considered appropriate by the Sponsor and Investigators based on review of emerging data during the trial. Participants must have disease amenable to biopsy as deemed safe by the Investigator. If there is only 1 measurable lesion, then this should not be used for pre- and on-treatment biopsies and inclusion should be discussed with Sponsor. Archival tumour tissue can be used if adequate tissue for planned analysis is confirmed prior to trial inclusion. Archival tissue sample must be = 3 months old, with no subsequent treatment and adequate tissue confirmed prior to trial inclusion. Please refer to the Study Laboratory Manual for details on assessment of adequacy of material.

4. Measurable disease according to RECIST Version 1.1 (Appendix 2), with at least 1 measurable lesion (not in a previously irradiated area unless radiological progression has occurred) and not previously biopsied at screening.

5. ECOG performance status of = 1 (to be confirmed at screening and within 7 days prior to first dose of IMP and SoC chemotherapy [Day 1]).

6. Haematological and biochemical indices within the ranges shown below. These measurements should be performed to confirm the patient’s eligibility to participate in the trial.

Laboratory Test: Value required

Haemoglobin (Hb): = 90 g/L
No transfusional support within 7 days prior to Cycle 1 Day 1

ANC: = 1.5 x 10^9/L
No growth factor support within 10 days prior to
Cycle 1 Day 1

Platelet count: = 100 x 10^9/L
No transfusional support within 7 days prior to
Cycle 1 Day 1

Total bilirubin: = 1.5 x upper limit of normal (ULN)
Patients with known Gilbert’s syndrome: total bilirubin = 3 x ULN

ALT and AST: = 3 x ULN, or = 5 x ULN if raised due to the presence of liver metastases

Renal function – estimated creatinine clearance: = 50 mL/min (Cockcroft-Gault)

Coagulation – PT (or INR) and aPTT: < 1.5 x ULN unless on warfarin or a direct oral anticoagulant

7. Aged 18 years or over at the time consent is given.


MODULE 2 INCLUSION AND EXCLUSION CRITERIA

A substantial amendment confirming the chosen MEK inhibitor and providing further details of the investigational plan for Module 2 will be submitted to the relevant Regulatory Authority/ies and Ethics Committee/s prior to commencement of Module 2.

MODULE 1 EXCLUSION CRITERIA

1. Prior radiotherapy to the only measurable index lesion unless radiological progression has occurred following completion of radiotherapy.

2. Radiotherapy (for non-metastatic disease) within the last 6 months prior to first dose of IMP with the exception of palliative treatment (= 10 Gy single fraction or 25 Gy fractionated total) that has been completed at least 7 days prior to first dose of IMP.

3. Prior chemotherapy for unresectable disease.

4. Previous investigational therapy for the treatment of metastatic PDAC.

5. Previous concurrent anti-cancer treatment within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of IMP (e.g., cytoreductive therapy, radiotherapy, immunotherapy, biologic therapy, or cytokine therapy [with the exception of erythropoietin]).

6. Live vaccinations will not be permitted within 28 days before trial enrolment.

7. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma.

8. Prior neo-adjuvant, peri-operative, or adjuvant chemotherapy for non-metastatic pancreatic adenocarcinoma with curative intent unless recurrent (i.e. metastatic) disease is documented more than 6 months since the last dose of systemic therapy.
Prior treatment with 5-FU, gemcitabine or capecitabine administered as a radiation sensitiser is allowed, provided that disease progression has occurred more than 6 months since completion of the last dose of chemotherapy or radiotherapy.

9. Clinically significant/symptomatic third space fluid accumulation (e.g. ascites or pleural effusion).

10. Ongoing toxic manifestations of previous treatments considered by the Investigator to make the patient unsuitable for the trial.

11. Brain or leptomeningeal metastases.

12. Clinically significant ongoing pulmonary disease, including but not limited to interstitial lung disease, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis.

13. History of pulmonary embolism or deep vein thrombosis unless continuing anticoagulant treatment as clinically indicated.

14. Women of childbearing potential^6. However, those women of childbearing potential who are not already pregnant or breastfeeding, or who agree to discontinue breastfeeding, or who meet the following points are considered eligible:

- Have a negative highly sensitive serum pregnancy test within 7 days before Day 1 and either:

- Agree to one form of highly effective contraception, such as:

i. oral, intravaginal or transdermal combined (oestrogen and progestogen) containing hormonal contraception associated with inhibition of ovulation;
ii. oral, injectable or implantable^7 progestogen-only hormonal contraception associated with inhibition of ovulation;
iii. intrauterine device^7;
iv. intrauterine hormone-releasing system^7;
v. bilateral tubal occlusion^7;
vi. vasectomised partner^7,^8
or agree to sexual abstinence.^9

Effective from the date of the negative pregnancy test, throughout the trial and for 6 months after the last administration of IMP or SoC chemotherapy agents (whichever component is administered last).

15. Male patients with partners of childbearing potential or who are pregnant or breastfeeding. However, those patients who meet the following points are considered eligible:

- Agree to take measures not to father children by using a barrier method of contraception (condom) or sexual abstinence9 effective from the date of first administration of IMP and SoC chemotherapy agents, throughout the trial and for 6 months after the last administration of IMP or SoC chemotherapy agents (whichever component is administered last).

- Non-vasectomised male patients must also be willing to ensure that any partner who is of childbearing potential uses a highly effective method of contraception (as detailed for exclusion criterion 14) or agrees to sexual abstinence9 for the same duration.

- Male patients with pregnant or breastfeeding partners must be advised to use barrier method contraception (male condom) to prevent exposure of the foetus or neonate.

Please Note: All male patients must refrain from donating sperm throughout the trial and for 6 months after the last administration of IMP or SoC chemotherapy agents (whichever component is administered last).

^6 A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level in the post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

^7Contraception methods that in the context of this guidance are considered to have low user dependency.

^8Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success.

^9Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

16. Major thoracic or abdominal surgery from which the patient has not yet recovered.

17. At high medical risk because of non-malignant systemic disease, including active uncontrolled infection. Patients with previous HCV exposure but no current infection are eligible to participate. Any uncontrolled active systemic infection requiring systemic IV treatment that was completed =7 days before first dose of IMP.

18. Known to be serologically positive for HBV, HCV or HIV. Patients who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have an undetectable HCV RNA by PCR or HBV DNA (by PCR) that is < 500 IU/mL before enrolment. Patients who are HBV core antibody positive should continue tenofovir during trial treatment.

19. Known hypersensitivity to any of the ingredients/excipients in the IMP to be administered.

20. Significant cardiovascular disease, defined as:
a. History of congestive heart failure requiring therapy (New York Heart Association III or IV) or LVEF <40% (moderate or severe);
b. History of unstable angina pectoris or myocardial infarction within 6 months prior to trial entry, or current poorly controlled angina (symptoms weekly or more);
c. Presence of symptomatic or severe valvular heart disease (severe by local echocardiographic criteria or American Heart Association/American College of Cardiology Stage C or D);
d. History of a clinically significant cardiac arrhythmia within 6 months prior to trial entry (asymptomatic atrial fibrillation or asymptomatic first-degree heart block is permitted).

21. Baseline corrected QTcF >450 ms measured on triplicate ECG (if an average QTcF of > 450 ms then the patient is ineligible).

22. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase II trial of ginisortamab. Participation in an observational trial or interventional clinical trial that does not involve administration of an IMP and that would not place an unacceptable burden on the patient, in the opinion of the Investigator, would be acceptable.

23. Current or prior malignancy that could affect safety or efficacy assessment of the IMP or compliance with the protocol or interpretation of results. Patients with curatively treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinomas-in-situ are generally eligible.

Patients with asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy, or who require only hormonal therapy and have had normal prostate-specific antigen for > 1 year prior to the start of therapy, are eligible for participation in the trial.

24. Patients with any congenital or acquired immunodeficiency syndrome or who are receiving immunosuppressive therapy (including any dose of systemic corticosteroids), or who are immunosuppressed post-organ transplant. However, patients receiving inhaled corticosteroids and patients with a history of allergy (other than anaphylaxis) are eligible, as are patients with a history of autoimmune disease.

25. Any other condition that, in the Investigator’s opinion, would mean that the trial is not in the best interests of the patient.


MODULE 2 INCLUSION AND EXCLUSION CRITERIA

A substantial amendment confirming the chosen MEK inhibitor and providing further details of the investigational plan for Module 2 will be submitted to the relevant Regulatory Authority/ies and Ethics Committee/s prior to commencement of Module 2.

- Alter = 18 Jahre

- Indikation zur elektiven pyloruserhaltenden Pankreatikoduodenektomie

- offene operative Entfernung des Pankreaskopfes (Resektion) bei malignen Tumoren und/oder Zysten des Pankreaskopfes

- ASA I-III

- Mündliche und schriftliche Einwilligung

- Fähigkeit, den Studieninhalt und -umfang zu verstehen und diesen umsetzen zu können

- Notfallmäßige PPPD

- Pylorusresektion bzw. Whipple Operation

- Teilnahme an einer anderen Studie, die das Studienergebnis beeinträchtigt

- > ASA III

- chronische Pankreatitis,

- ECOG > II,

- chronische Schmerzsyndrome, die eine routinemäßige Analgetikatherapie erfordern

- Teilnahme an einer interventionellen Studie

Cohort-specific criteria

C1 : Locally Advanced/Metastatic Unresectable Pancreatic Ductal Adenocarcinoma 1L (Closed to enrolment as of protocol amendment 5.0)
Patients with histologically or cytologically confirmed, locally advanced/metastatic unresectable PDAC who are eligible for 1L SOC chemotherapy with gemcitabine plus nab-paclitaxel

C2: Metastatic Colorectal Cancer 1L (MSI-H/dMMR) (Closed to enrolment on 19 October 2023)
Patients with histologically or cytologically confirmed metastatic colorectal adenocarcinoma (mCRC) with MSI-H/dMMR tumors and no prior systemic treatment for metastatic disease.

C3: Metastatic Colorectal Cancer 3L (Closed to enrolment as of protocol amendment 5.0)
Patients with histologically or cytologically confirmed mCRC, independent of MSI/dMMR status, who failed (and/or did not tolerate) 2 prior lines of treatment, including oxaliplatin, irinotecan, 5-FU, +/- targeted agents such as bevacizumab and/or an anti- EGFR antibody who are eligible for 3L SOC chemotherapy with trifluridine/tipiracil

C4: Locally Advanced/Metastatic Unresectable Anal Cancer >=2L
Patients with histologically or cytologically confirmed locally advanced/metastatic unresectable SCCA of viral (HPV) or non-viral origin who failed (and/or did not tolerate) prior systemic chemotherapy.

C5: See Section 5.2 of the Cohort 5 Appendix


Patients must:

1. Provide written informed consent prior to study participation.

2. Be at least 18 years of age on the day of providing consent.

3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days of start of treatment.

4. Have measurable lesions per RECIST v1.1

5. Have adequate organ function at the time of enrollment as defined by:
- Absolute neutrophil count >=1200/mm^3
- Platelet count >=7.5 x 104/mm^3
- Hemoglobin >8 g/dL (blood transfusion >2 weeks before testing is permitted)
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) <=2.5 x the upper limit of normal (ULN; <=5 x ULN in patients with liver metastasis)
- Total bilirubin <=1.5 x ULN
- Creatinine <=1.5 x ULN
- Lipase <=1.5 x ULN
- International normalized ratio (INR) <=1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) <=1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g. heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring per local SOC will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local SOC.

6. Have recovered to <= grade 1 or baseline for all AEs due to previous therapies or surgeries.

7. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly-effective form(s) of contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 6 months after the last dose of study drug.

Patients must not have:

1. Undergone systemic chemotherapy, radiotherapy, or surgery, <4 weeks before study treatmentIn Cohort 3 only: patients must not have received previous treatment with trifluridine/tipiracil

2. Received previous treatment with immune checkpoint inhibitors.

3. Uncontrolled hypertension (systolic blood pressure >=150 mmHg and diastolic blood pressure >=90 mmHg) despite treatment with hypotensive agents.

4. Acute coronary syndrome (including myocardial infarction and unstable angina), and/or a history of coronary angioplasty or stent placement performed within 6 months of enrollment.

5. A large amount of pleural effusion or ascites requiring more than weekly drainage.

6. A history of (non-infectious) pneumonitis that required steroids or currently active pneumonitis.

7. A >= grade 3 active infection according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

8. Symptomatic brain metastasis. (Patients with asymptomatic and stable brain metastasis are eligible for study enrollment.) Patients with a history of brain metastasis must be assessed using MRI during screening.

9. Interstitial lung disease with symptoms or signs of activity.

10. In Cohort 1, Cohort 2, and Cohort 3 only: known active Hepatitis B (HBV) or Hepatitis C (HCV) infection that requires anti-viral treatment. Testing for HBV/HCV is not required in the absence of clinical suspicion.

In Cohort 4 only: Prior infection with HIV, if the CD4+ T cell is <300 cells/µl.* Testing for HIV status is required.

* To be eligible, HIV+ patients must have an undetectable viral load and be receiving highly active antiretroviral therapy (HAART). Patients must be on established HAART therapy for at least 4 weeks prior to study entry.

11. Autoimmune disease that has required systemic treatment in the past 2 years with disease modifying agents, corticosteroids, or immunosuppressive drugs. [Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment].

12. A history or findings of =grade 3 congestive heart failure according to the New York Heart Association functional classification.

13. A seizure disorder that requires pharmacotherapy.

14. Proteinuria =grade 3 (using spot testing; if grade 3, repeat with mid-stream urine; if still grade 3, then urine collection for 24 hours to confirm grade) as per NCI CTCAE.

15. A medical contraindication to undergoing biopsies.

16. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.

17. A non-healing wound, non-healing ulcer, or non-healing bone fracture within 4 weeks prior to the start of study drug.

18. Women who are pregnant or breastfeeding.

19. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing >10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study drug.

20. Any vaccine within 28 days prior to the first treatment or during the first cycle of treatment.

21. Legal incapacity or limited legal capacity.

22. Life expectancy less than 3 months

1. Elective abdominal operation via a midline laparotomy

2. Planned clean or clean-contaminated operations according to the Centre for Disease Control (CDC) definition (1)

3. Patient age >= 18 years

4. Ability to understand the nature and extent of the trial and to give written informed consent.

5. Written informed consent

6. Life expectancy >= 2 years

1. American Society of Anaesthesiologists (ASA) grade > 3

2. Pregnant or lactating woman

3. Midline laparotomy within the last 60 days prior to trial intervention

4. Previous incisional abdominal hernia or fascial dehiscence

5. Planned relaparotomy via the midline incision within 2 years after trial intervention

6. Concurrent abdominal wall infections

7. Participation in another intervention-trial with interference of intervention and/or outcome of this study

- Zytologisch oder histologisch gesichertes duktales Adenokarzinom des Pankreas oder CT grafisch hochgradiger Verdacht auf Adenokarzinom des Pankreas (z.B. im Rahmen der präoperativen Diagnostik) mit postoperativer histologischer Sicherung
- Alter >= 18 Jahre
- Schriftliches Einverständnis zur Teilnahme an der Studie

- Papillenkarzinome
- Neuroendokrine Neoplasien des Pankreas
- Azinuszellkarzinome des Pankreas
- Tumor spezifische Vortherapie, außer Tumorresektion
- Schwere neurologische oder psychiatrische Störungen die eine Einwilligungsfähigkeit beeinträchtigen
- Kein Einverständnis für die Registrierung, Lagerung und Handhabung der personenbezogenen Krankheitsdaten

1. Patients diagnosed with cancer

2. Patients planned to undergo or undergoing neoadjuvant treatment before planned curative resection

3. Adult patients (>= 18 years of age)

4. Written informed consent

5. Ability to understand character and individual consequences of the clinical trial

Additional for the online program

6. Stable internet connection

7. Laptop of similar

8. Poultieces utensils and utensils for the other applications

9. Sports mat or similar

1. Participation in another interventional trial with interference on intervention and outcome of this trial

2. Immobility or inability to walk unaided

3. Expected lack of compliance

- Patientinnen und Patienten, die eine viszeralchirurgische Operation mit kurativer In-tention aufgrund eines primären oder sekundären Malignom erhalten

- vorliegender Tumorboardbeschluss

- Alter = 18 Jahre

- Mündliche und schriftliche Einwilligungserklärung

- Schwangerschaft

- ASA = 4

- Geistige Einschränkung, welche eine Erfassung von Wesen, Art und Umfang des For-schungsprojekt verhindert

- Zu erwartende fehlende Wahrnehmung der Empfehlungen

- Fehlende Einwilligungsfähigkeit

- Teilnahme an einer anderen Studie, die das Studienergebnis beeinträchtigt

To be included in the study, each potential patient must meet all of the following inclusion criteria.

Patient Characteristics:

1. At least 18 years of age and has provided informed consent. Follow local regulatory requirements if the legal age of consent for study participation is > 18 years old.

2. ECOG performance status 0 or 1. Rescreening is required if ECOG is > 1 for any reason prior to initiation of study treatment.

3. Life expectancy = 3 months, in the opinion of the Investigator.

Disease Characteristics:

4. Histologically or cytologically confirmed PDAC with metastatic disease, including adenosquamous carcinoma and poorly differentiated carcinoma.

5. Documented disease progression on most recent prior therapy.

6. Measurable disease assessed by computed tomography (CT) or magnetic resonance imaging (MRI) scans per RECIST 1.1 based on local assessment. Previously radiated lesions are not considered measurable unless they have progressed after radiation.

7. One prior line of systemic therapy in the metastatic setting which must include either a fluoropyrimidine-based or gemcitabine-based regimen. Patients with known driver mutations (eg, BRAF V600E, microsatellite instability-high [MSI-H]/mismatch repair deficient [dMMR], NTRK gene fusion, etc.) for which there is local regulatory approval must have received appropriate targeted therapy. If prior therapy was received in the neoadjuvant or adjuvant setting, and metastatic disease was diagnosed < 6 months from last dose, this will be considered first-line treatment. Maintenance therapy as part of first-line treatment is not considered an additional line of therapy, including maintenance chemotherapy or PARP inhibitor (eg, olaparib).

8. Documented RAS mutation status, either mutant or wild-type. Eligible RAS mutations are defined as nonsynonymous mutations in KRAS, NRAS, or HRAS at codons 12, 13, or 61 (G12, G13, or Q61). Mutation status must have been previously identified (independent of this trial) by an assay on circulating tumor DNA (ctDNA) or tumor tissue (obtained within 5 years of consent), and performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (US) or equivalent per local regulation (eg, International Organization for Standardization [ISO]).

9. Patient must submit tumor tissue, as specified in the protocol, for retrospective central laboratory testing of RAS mutation status and exploratory biomarker analysis.

Organ Function:

10. Adequate bone marrow function defined as:
a. Absolute neutrophil count (ANC) = 1.5 x 10^9/L (without growth factor support within 7 days of randomization)
b. Hemoglobin = 8.0 g/dL (without red blood cell [RBC] transfusion or erythropoietin use within 2 weeks of randomization)
c. Platelet count = 100 x 10^9/L (without platelet transfusion within 2 weeks of randomization)

11. Adequate kidney function defined as estimated glomerular filtration rate (eGFR) = 60 mL/min, calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation or other equation per institutional guidelines, or based on 24-hour urine collection.

12. Adequate hepatic function defined as:
a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x the upper limit of normal (ULN), or < 5 x ULN in the presence of liver metastasis
b. Serum bilirubin < 1.5 x ULN or < 2 x ULN for patients with Gilbert syndrome
c. Serum albumin = 3 g/dL

13. Adequate coagulation function defined as: prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) < 1.5 x ULN, or = 2 x ULN for patients on anticoagulant therapy.

Other Inclusion Criteria:

14. Able to take oral medications and willing to keep daily adherence record.

To be included in the study, potential patients must not have any of the following exclusion criteria.

Disease Characteristics:

1. Prior therapy with any direct RAS-targeted therapy (eg, degraders and/or inhibitors).

2. History of or known central nervous system metastatic disease.

3. Diagnosed or treated for cancers other than PDAC = 5 years prior to randomization, except:

a. Cancers for which no systemic anticancer treatment is required and were treated with successful definitive resection (eg, non-melanoma skin cancer, carcinoma in situ of the breast or cervix, or other in situ cancers).

b. Cancers that have been treated with curative intent, with no evidence of disease recurrence within 5 years of initiation of curative therapy, and judged by the Investigator to be at low risk for recurrence.

4. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage within 4 weeks prior to randomization.

5. Anticancer therapies that have been discontinued before randomization must follow these washout periods:
a. Chemotherapy or targeted therapy = 21 days or 5 half-lives (whichever is shorter) of randomization
b. Radiotherapy to = 30% of bone marrow or wide field radiation = 4 weeks of randomization; stereotactic radiotherapy or whole brain radiotherapy = 2 weeks of randomization.

6. Clinically relevant toxicity associated with prior anticancer therapy that in the opinion of the Investigator has not recovered to Grade 1, baseline, normal, or to the levels dictated by the inclusion/exclusion criteria, including ongoing Grade = 2 peripheral neuropathy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0, except for alopecia, or endocrine disorder stably maintained with appropriate replacement therapy.

Medical Disorders:

7. Significant cardiovascular disease defined as:

a. Acute coronary syndrome (eg, unstable angina, myocardial infarction) within 6 months of randomization.

b. Symptomatic congestive heart failure (New York Heart Association Class II to IV) within 4 weeks of randomization.

c. Left ventricular ejection fraction (LVEF) < 50% within 4 weeks of randomization, per echocardiography or multigated acquisition scan (MUGA).

d. Significant cardiac conduction abnormalities:
- Corrected QT interval (QTc) > 470 msec (unless a pacemaker is in place), averaged from 3 electrocardiogram (ECGs), using the screening clinic ECG machine-derived QT interval corrected by Fridericia’s formula (QTcF) value.
- Any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG, eg, second-degree heart block, third-degree heart block, complete left bundle branch block, PR interval > 250 msec.
- Any increased risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, hypomagnesemia, or congenital long QT syndrome.

8. History of interstitial pneumonia, pneumonitis, pulmonary fibrosis, or radiation pneumonitis which required steroid treatment within 6 months of randomization, or any evidence of active interstitial lung disease on screening imaging.

9. Any conditions that may affect the ability to take or absorb study treatment, eg, refractory nausea and vomiting, malabsorption, significant bowel resection (note: patients with prior Whipple procedure are eligible), or uncontrolled inflammatory gastrointestinal disease such as Crohn disease or ulcerative colitis.

10. Patients with the following active infections will be excluded if any of the following conditions are met:

a. For patients with known human immunodeficiency virus infection:
- CD4+ T-cell (CD4+) counts = 350 cells/µL and history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the preceding 12 months prior to randomization.
- If CD4+ T-cell (CD4+) counts > 350 cells/µL or in the absence of AIDS-defining opportunistic infections in the preceding 12 months prior to randomization, enrollment may be considered if the patient is on established antiretroviral therapy for at least 4 weeks prior to randomization and treatment regimen does not conflict with other study restrictions, and patient has a viral load of < 400 copies/mL prior to enrollment.

b. For patients positive for hepatitis B core antibody (HBcAb) at screening: Positive hepatitis B surface antigen or positive hepatitis B virus (HBV) deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) test

c. For patients positive for hepatitis C virus (HCV) antibody at screening: Positive HCV ribonucleic acid (RNA) by PCR test

11. Any uncontrolled, active systemic infection including any infection requiring systemic IV treatment which was completed = 7 days prior to randomization.

12. Any serious medical condition or psychiatric condition (eg, uncontrolled hypertension, bleeding diatheses) or organ system dysfunction, that, in the Investigator’s opinion, could compromise the patient’s safety or put the study outcomes at undue risk.

Prior/Concomitant Medications:

13. Requires treatment with strong or moderate CYP3A4 inhibitors/inducers, or consumed Seville oranges, grapefruit, or grapefruit products from 14 days prior to cycle 1 day (C1D1). Patients randomized to Arm A (RMC-6236) must continue to refrain from such treatments/products through the end of treatment.

14. Requires treatment with strong or moderate P-glycoprotein (P-gp) inhibitor from 14 days prior to C1D1. Patients randomized to Arm A (RMC-6236) must continue to refrain from
such treatments through the end of treatment.

15. Requires treatment with sensitive or narrow therapeutic index substrate of cytochrome P450 (CYP) 3A4, P-gp, organic anion-transporting polypeptide B3 (OATP1B3), or breast cancer resistance protein (BCRP) from 7 days prior to C1D1. Patients randomized to Arm A (RMC-6236) must continue to refrain from such treatments through the end of treatment.

16. Requires systemic treatment with cyclosporine A or derivative.

Other Exclusion Criteria:

17. History of allergy or known hypersensitivity to any of the chemotherapy study treatments or any of their excipients, or contraindication to any of the study treatments as outlined in the local prescribing information (eg, USPI).

18. Major surgery = 28 days of randomization.

19. On other therapies or participating in other trials that may interfere with the conduct or interpretation of data from the current study.

20. Women who have a positive pregnancy test at screening or C1D1; are pregnant or breastfeeding; or are planning to become pregnant or breastfeed during treatment and for up to 15 months after the last dose of study treatment.

21. Women of childbearing or reproductive potential, or men, unwilling to use highly effective forms of contraception (Appendix 3) or avoid intercourse during treatment, and for at least 15 months after the last dose of study treatment for women; at least 12 months after the last dose of study treatment for men. Refer to Section 9.1.9 for contraceptive guidance for female of WOCBP partners of male participants.

22. Women or men unwilling to abstain from donating egg or sperm during treatment, and for at least 15 months after the last dose of study treatment for women; at least 12 months
after the last dose of study treatment for men.

23. Patient is unable or unwilling to comply with all protocol-required study visits or procedures, in the judgment of Investigator.

24. Patient is incapacitated, regardless of possession of legal representative, or committed to an institution by virtue of an order by a court or governmental authority.

Preoperative inclusion criteria:

- Patients with suspected or histologically verified resectable, borderline or locally advanced pancreatic cancer of the pancreatic head (i.e. pancreatic ductal adenocarcinoma, IPMN (Intraductal Papillary Mucinous Neoplasms) carcinoma or periampullary cancer of the pancreatobiliary-type)

- Patients scheduled for elective partial pancreatoduodenectomy (irrespective of neoadjuvant therapy)

- Assumed resectability in accordance with the surgical protocol for experimental and control intervention as judged by the treating surgeon

- Ability of subject to understand character and individual consequences of the clinical trial

- Written informed consent

- Age =18 years


Intraoperative inclusion criteria (prior to randomisation):

- No distant metastases

- No paraaortic lymph node metastases

- Intraoperative confirmation that the patient can be operated according to both surgical methods (experimental or control group)

- Participation in another interventional trial with interference of intervention and outcome of this trial

- American Society of Anesthesiologists (ASA) grade > 3

- Distant metastatic disease

Patients may be included in the trial only if they meet all the following criteria:

GENERAL INCLUSION CRITERIA:

1. Signed informed consent according to ICH/GCP and national/local regulations (informed consent is given for both part I and part II of the trial at enrolment; participation in translational research is voluntary)

2. ECOG performance status 0-1

3. Age = 18 years

INCLUSION CRITERIA - TRIAL PART I (establishing organoids):

4. Suspected pancreatic ductal adenocarcinoma (PDAC), resectable according to NCCN criteria, Ca19-9 <500 U/ml (without relevant cholestasis), = cT3 with no prior tumor specific treatment

5. No evidence of metastases to distant organs (e.g. liver, peritoneum, lung)

6. Suitable for adjuvant treatment with mFOLFIRINOX

INCLUSION CRITERIA - TRIAL PART II (organoid-based treatment):

7. Histologically confirmed PDAC

8. R0 or R1 resection

9. Start of adjuvant chemotherapy within 12 weeks after tumor resection

10. No evidence of postoperative tumor recurrence/metastases by radiological assessment

11. Clinically eligible for all adjuvant treatment regimens foreseen in this trial

12. Sufficient convalescence from surgery and revision surgeries if applicable

13. Postoperative Ca19-9 < 180 U/ml (starting from POD 14)

14. Organoid-based chemotherapy recommendation available

15. Creatinine clearance >= 30 ml/min

16. Serum total bilirubin level 1.5 - 3 x ULN

17. ALT and AST <= 2.5 x ULN

18. White blood cell count = 3.5 x 10^6/ml, neutrophil granulocytes count = 1.5 x 10^6/ml, platelet count = 100 x 10^6/ml

19. Women of Childbearing Potential (WOCBP, defined as not postmenopausal and not surgically or congenitally sterile) whose male partners are potentially fertile (e.g. no vasectomy) or males that are potentially fertile with WOCBP partner must use highly effective contraception methods for the duration of the trial and for at least 15 months (male or female) after last dose of trial drug (IMP). Postmenopausal is defined as no menses for 12 months without an alternative medical cause. Highly effective birth control methods that result in a failure rate of less than 1% per year include hormonal contraception, intrauterine device, bilateral tubal occlusion, vasectomized partner. Sexual abstinence is only considered a highly effective method if defined as refraining from heterosexual intercourse in the defined period. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the patient.

Patients will be excluded from the trial for any of the following reasons:

GENERAL EXCLUSION CRITERIA:

1. R2 resection or metastatic PDAC by radiological criteria or macroscopic aspect intraoperatively

2. Neoadjuvant treatment for PDAC

3. Chronic infectious diseases, immune deficiency syndromes, including evidence of clinically relevant, active hepatitis B, C or HIV infection

4. Premalignant hematologic disorders, e.g. myelodysplastic syndrome

5. Disability to understand and sign written informed consent document

6. Past (last 3 years) or current history of malignancies except for the indication under this trial and curatively treated:
a. Basal and squamous cell carcinoma of the skin
b. In-situ carcinoma of the cervix
c. Other malignant disease without recurrence after at least 2 years of follow-up

7. Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrolment

8. History of or evidence upon physical examination of CNS disease unless adequately treated (e.g. primary brain tumor, seizure not controlled with standard medical therapy or history of stroke).

9. Pre-existing neuropathy > grade I (NCI CTCAE V 5.0)

10. Known dihydropyrimidine dehydrogenase (DPD) deficiency (will be tested in all patients receiving fluoropyrimidine treatment)

11. Severe non-healing wounds, ulcers or bone fractures

12. Evidence of bleeding diathesis or coagulopathy

13. Patients not receiving therapeutic anticoagulation must have an INR = 1.4 and PTT = 40 sec within 28 days prior to enrolment. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution)

14. Pregnant, lactating or women of childbearing potential without a negative pregnancy test (serum) within 7 days prior to trial inclusion, irrespective of the method of contraception used

15. Patients with known allergies to the trial drugs or to any of its excipients

16. Clinically relevant interstitial lung disease, e.g. non-infectious pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease

17. Participation in another clinical trial affecting endpoints (within the last 14
days prior to enrolment or 5 plasma half-lives of the used investigational drug,
whatever is longer)

18. Any psychological, familial, sociological or geographical condition potentially compromising compliance with the trial protocol and the follow-up schedule; those conditions should be discussed with the patient prior to enrolment in the trial

19. Person of legal age who is incapable of comprehending the nature, significance and implications of the clinical trial and of determining his/her will in the light of these facts

EXCLUSION CRITERIA - TRIAL PART II

20. Patients not treated according to recommendation of Organoid Board