3.3.1.1 PART 1 - INCLUSION CRITERIA

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

2. Measurable disease as defined in Appendix 10.5

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

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

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

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

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

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

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

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

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

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

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

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

f) PTT / aPTT <1.5 x ULN

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

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

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

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

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

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


3.3.1.3 PART 2 – INCLUSION CRITERIA

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

3.3.1.3.1 Arm D Melanoma: 2L

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

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

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

3.3.1.3.2 Arm E PDAC: 2L

16. Diagnosis of pancreatic ductal adenocarcinoma

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

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

19. Verification within 72 hours prior to first treatment:

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

3.3.1.3.3 Arm F CRC: Refractory and other solid tumors

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

3.3.1.3.4 Arm G HNSCC: 1L

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

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

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

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

3.3.1.2 PART 1 - EXCLUSION CRITERIA

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

14. Live vaccination within 28 days of first treatment.

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

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

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

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

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

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

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

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


3.3.1.4 PART 2 EXCLUSION CRITERIA

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

3.3.1.4.1 Additional Exclusion Criteria for Part 2

23. Any of the following cardiac criteria:

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

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

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

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

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

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

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

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

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

3.3.1.4.2 Arm D Melanoma: 2L

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

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

3.3.1.4.3 Arm E PDAC: 2L

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

32. Prior history of receiving immune checkpoint inhibitors.

3.3.1.4.4 Arm F CRC: Refractory and other solid tumors

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

34. Prior history of receiving immune checkpoint inhibitors.

3.3.1.4.5 Arm G HNSCC: 1L

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

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

37. Prior immune checkpoint inhibitor therapy.

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

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

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

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

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

4 Are = 18 years of age.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Part-specific criteria

Parts A, B, and C

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

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

Part D

20 Have a histologically confirmed diagnosis of PDAC.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

11 Have a history of leptomeningeal carcinomatosis.

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

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

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

15 Have a diagnosis of Gilbert’s syndrome.

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

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

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

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

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

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

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

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

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

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

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

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

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

1. Be 18 years or older.

2. Be male or non-pregnant females who agree to comply with applicable contraceptive requirements of the protocol (see Table 12. Acceptable Contraceptive Methods). Women of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception with a less than 1% failure rate consistently and correctly.

3. Histologically and/or cytologically confirmed gastrointestinal tumours that are metastatic or unresectable, and are subject to receive FOLFOX +/- bevacizumab as SOC per investigator’s judgement. Participants will have received at least one line of chemotherapy in the metastatic setting

- Colorectal cancer: Patients must have received at least 1 prior line of therapy prior to enrollment in this study.

- Pancreatic cancer: Patients must have received at least 1 prior line of therapy.

- Gastric cancer: Patients who have not received prior treatment may be included in this study.GEJ (gastroesophageal junction) cancer patients are considered eligible to enter this trial.

- Cholangiocarcinoma: locally advanced or metastatic biliary tract cancer (intra or extrahepatic cholangiocarcinoma or gallbladder cancer) are eligible to enter this trial. Patients must have
received at least 1 prior line of therapy (with gemcitabine-based chemotherapy).

- Colorectal cancer (ARM VI): Patients must have received at least 2 prior lines of therapy prior to enrollment in this study, one of which was a 5-FU based regimen.

- Refer to Appendix 8 updated information on Arm VI.

- Colorectal cancer (ARM VII): Patients must have received only 1 prior line of therapy in the metastatic setting prior to enrollment in this study. Prior oxaliplatin therapy is permitted in the following two situations:

1) Patients who have received oxaliplatin in the adjuvant setting.
2) Patients who have received oxaliplatin in the first line metastatic setting but did not progress on treatment or within 3 months of oxaliplatin treatment cessation.

Refer to Appendix 9 for updated information on Arm VII

4. Have measurable disease according to RECIST v1.1 (at least one measurable lesion).

5. Have an anticipated survival of at least 16 weeks.

6. Be ambulatory, with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1

7. Have adequate organ function, defined as:
a. Hematologic: ANC = 1.5 x 10^9/L, Hgb = 9.0 g/dL and platelet count = 100 x 10^9/L
b. Hepatic: total bilirubin = 1.5 x ULN (or = 3 x ULN for subjects with Gilbert’s Syndrome); transaminases = 2.5 x ULN (may be up to = 5 x ULN if clearly due to liver metastases) and ALP = 2.5 x ULN (or = 3 x ULN if liver metastases)
c.Renal: serum creatinine = 1.5 x ULN or creatinine clearance = 50 mL/min.
d. Urine protein is 0, trace, or +1 on dipstick urinalysis, or < 1.0 gram on 24-hour urine protein analysis

8. Be on stable doses of any drugs that may affect hepatic drug metabolism or renal drug excretion (e.g., non-steroidal anti-inflammatory drugs, corticosteroids, barbiturates, diphenylhydantoin, narcotic analgesics, probenecid). Such drugs may be initiated while the subject is participating in this study.

9. Resolved acute effects of any prior therapy before the start of treatment to baseline severity or grade = 1 CTCAE 5.0 except for adverse events not constituting a safety risk by investigator judgment (such as alopecia)

10. Able to take oral medications (for pre-medications and supportive management)

11. Understand and be able, willing, and likely to fully comply with study procedures and restrictions.

12. Be fully informed about their illness and the investigational nature of the study protocol and sign a REB-approved Informed Consent Form (ICF).

13. (ARM VII): BRAF wild-type tumour status

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

1. Neuropathy > grade 2

2. Previous intolerance to or significant reaction secondary to fluorouracil or oxaliplatin or
bevacizumab (if indicated).

3. Cerebrovascular accident within the past 6 months before the start of treatment.

4. History or presence of central nervous system (CNS) metastasis or leptomeningeal tumours as
documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam.

5. Any serious medical conditions that might be aggravated by treatment or limit compliance. This includes, but is not limited to uncontrolled psychiatric disorders, serious infections, active peptic
ulcer disease and bleeding diathesis or coagulopathy

6. Any history of serious cardiac illness including (but not confined to):
- Previous or active myocardial infarction < 6 months before the start of treatment
- Congestive cardiac failure (NYHA III or IV)
- History of unstable angina pectoris < 6 months before the start of treatment
- Recent coronary artery bypass grafting < 6 months before the start of treatment
- Uncontrolled hypertension (systolic = 140 mmHg or diastolic = 90 mmHg)
- Ventricular arrhythmia < 6 months before the start of treatment
- Left ventricular ejection fraction (LVEF) < 50% as measured either by radionuclide angiography or echocardiogram
- QTc interval > 470 msec
- Arterial or venous thrombotic or embolic events within 6 months of study initiation

7. Hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months before the start of treatment

8. Any other known malignancy within 3 years before the start of treatment (with the exception of non-melanoma skin cancer that had undergone curative treatment, cervical cancer in situ, or ductal/lobular carcinoma in situ of the breast that has underwent local treatment

9. Active gastrointestinal tract disease with malabsorption syndrome.

10. History of gastrointestinal perforation or fistulae (tracheoesophageal, bronchopleural, biliary, vaginal, renal or bladder).

11. Non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease.

12. Treatment with radiation therapy or surgery within 4 weeks prior to starting treatment.

13. Recent history of weight loss > 10% of current body weight in past 3 months before the start of treatment

14. Current (within 1 week of the start of the study) or regular use of any medication (including OTC, herbal or homeopathic preparations) that could affect (improve or worsen) the cancer being studied, or could affect the action or disposition of BOLD-100, or its clinical or laboratory assessment, e.g., Coumadin therapy, due to high competitive protein binding.

15. HIV-positive subjects on combination anti-retroviral therapy due to the potential for PK interactions with the study agent.

16. Any condition potentially decreasing compliance to study procedures.

17. Concurrent use of another investigational therapy or anti-cancer therapy within 4 weeks before the start of treatment.

18. (ARM VII): Patients considered resistant to Oxaliplatin:
- Patients who have received oxaliplatin in the adjuvant setting who have progressed / relapsed within 6 months of their last oxaliplatin administration.
- Patients with advanced colorectal cancer who have progressed (based on RECIST 1.1) while on or within 3 months of their last administration of oxaliplatin.

19. (ARM VII): Prior exposure to BOLD-100

20. (ARM VII): Subjects with microsatellite-high (MSI-H) Tumours

21. (ARM VII): Concurrent monoclonal antibody therapy for mCRC (anti-EGFR, or anti-HER2)

22. Currently breastfeeding

23. Dihydropyrimidine Dehydrogenase (DPD) deficiency (Note: when tested/required prior to administration of 5-fluorouracil (5-FU) as per Principal Investigator’s best medical judgement and
based on the local practice guidelines and 5-FU local prescribing instructions. In the EU, DPD testing is required, while in other countries it may be recommended. )

24. Current or prior treatment with potent inhibitors of Dihydropyrimidine Dehydrogenase (DPD)

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

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

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

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

4. Patients with one of the following indications:

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

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

Phase I:

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

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

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

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

Phase II:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Highly effective contraception methods include:

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

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

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

19. Pregnant or nursing (breast feeding) women.

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.

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

Patients must meet the following criteria for study entry:

- Documentation of informed consent
Patients must have the capacity to provide informed consent and participate in the study.

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

- Ability to comply with the study protocol
Patients must not have potential impediments to study compliance (e.g., geographical, social, or psychological barriers).

- For patients enrolling in France: PDAC management must undergo multidisciplinary assessment prior to enrollment

- Preoperative diagnosis of resectable PDAC tumor, as demonstrated by preoperative imaging with computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) scan per institutional standard for imaging evaluation of pancreas (e.g., CT pancreas protocol) and defined as meeting all of the following radiographic criteria:

- Clear fat plane around the celiac and superior mesenteric arteries
- Patent superior mesenteric and portal veins
- No encasement of the superior mesenteric vein or portal veins
- No encasement of the superior mesenteric or hepatic arteries
- Absence of metastatic disease
- Absence of extra-regional nodal disease

- Histologically confirmed diagnosis of PDAC

Patients with adenosquamous carcinoma of the pancreas are eligible for the study.
Patients with intraductal papillary mucinous neoplasm associated PDAC are not eligible for the study.
Patients with other types of tumors of the pancreas, including endocrine tumors or acinar cell adenocarcinoma, cystadenocarcinoma, and malignant ampulloma are not eligible for the study.

- Pancreatic cancer tumor, lymph node, metastasis (TNM) pathological staging values of T1 T3, N0 N2, and M0 per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition (Amin et al. 2017)

Patients with staging values of Tx, T4, Nx, or M1 are not eligible for the study.

- Macroscopically complete (R0 or R1) resection of PDAC

- Unequivocal absence of disease after surgery as assessed by the investigator and based on review of all available data including mandatory imaging (CT or MRI scans; see Section 4.5.5), biochemical data, and clinical findings within 28 days prior to randomization

- CA19-9 level measured within 14 days prior to initiation of study treatment
Enrollment of patients with CA19-9 levels >= 180 U/mL (measured within 14 days prior to initiation of study treatment) will be limited to 24 patients (approximately 9%).

- Presence of at least five tumor neoepitopes as identified from blood and tumor tissue submitted during screening Part A (see Section 3.1.2)

The laboratory manual should be referenced for tumor tissue requirements prior to submission of specimen.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

- Interval of between 6 and 12 weeks since resection of PDAC

- Full recovery from surgery and ability to receive atezolizumab, autogene cevumeran, and mFOLFIRINOX in the investigator's judgment

- Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:

- ANC >= 1.5 x 10^9/L (>= 1500/MikroL) without granulocyte colony-stimulating factor support, with one exception:

Patients with benign constitutional neutropenia (referred to as Duffy-null associated neutrophil count and previously referred to as benign ethnic neutropenia): ANC >= 1.3 x 10^9/L (1300/MikroL)
Constitutional neutropenia is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al. 2019). It has increased prevalence in people of African descent and other specific ethnic groups.

- WBC count >= 2500/MikroL

- Lymphocyte count >= 0.5 x 10^9/L (>= 500/MikroL)

- Platelet count <= 100 x 10^9/L (>= 100,000/MikroL) without transfusion

- Hemoglobin >= 90 g/L (>= 9 g/dL)
Patients may be transfused to meet this criterion.

- AST, ALT, and ALP <= 2.5 x upper limit of normal (ULN)

- Total bilirubin <= 1.5 x ULN

– Creatinine clearance >= 50 mL/min (calculated through use of the Cockcroft Gault formula)

- Albumin >= 25 g/L (>= 2.5 g/dL)

- For patients not receiving therapeutic anticoagulation: INR and aPTT <= 1.5 x ULN

- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

- Negative HIV test at screening

- No evidence of active hepatitis B, defined as having a positive hepatitis B surface antigen (HBsAg) test) at screening

Patients with past or resolved hepatitis B infection (defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test are eligible, however, a hepatitis B virus (HBV) DNA test must be obtained prior to initiation of study drug and must demonstrate absence of active infection.

- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening

- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below:

Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 28 days after the final dose of autogene cevumeran, for 9 months after the last dose of chemotherapy (15 months after the final dose of oxaliplatin in Korea), and for 5 months after the final dose of atezolizumab. Women must refrain from donating eggs for 9 months after the last dose of chemotherapy (15 months after the final dose of oxaliplatin in Korea).

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

Examples of contraceptive methods that can achieve a failure rate of < 1% per year when used consistently and correctly include the following: combined hormonal (estrogen- and progestogen-containing) contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable, intrauterine device), intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence.

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

Women of childbearing potential receiving mFOLFIRINOX should be advised regarding the possibility of fertility preservation because of the risk of irreversible infertility resulting from therapy with mFOLFIRINOX.

- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below:

With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 28 days after the final dose of autogene cevumeran and for 6 months after the last dose of chemotherapy (12 months after the final dose of oxaliplatin in Korea). Men must refrain from donating sperm during this same period.

Male patients receiving mFOLFIRINOX should be advised regarding the conservation of sperm prior to treatment because of the risk of irreversible infertility resulting from therapy with mFOLFIRINOX.

With a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 28 days after the final dose of autogene cevumeran and for 6 months after the last dose of chemotherapy, to avoid exposing the embryo.

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

Patients who meet any of the following criteria will be excluded from study entry:

- Prior adjuvant, neoadjuvant, or induction treatment for pancreatic cancer, including cytotoxic chemotherapy, immunotherapy, investigational therapy, or radiation therapy

- Plan for further adjuvant anti-cancer therapy for PDAC (e.g., radiotherapy and/or chemotherapy), not mandated per protocol, to be initiated after completion of mFOLFIRINOX treatment

Patients being considered for further adjuvant anti-cancer therapy after completion of mFOLFIRINOX treatment must undergo review, prior to study enrollment, by the relevant specialty doctor (e.g., radiation oncologist) for determination of need for further therapy.

- Absence of spleen (due to splenectomy, splenic injury/infarction, or functional asplenia)

Distal pancreatectomy with splenectomy is exclusionary.

- Preexisting Grade >= 2 neuropathy

- Known complete dihydropyrimidine dehydrogenase (DPD) deficiency including homozygous or compound heterozygous mutations of DPYD genetic locus associated with DPD deficiency

- Unresolved >= Grade 3 postoperative complication(s) per the Clavien-Dindo Classification of Surgical Complications (see Appendix 8)

- Disorders of the colon or rectum, or postoperative complication leading to Grade >= 2 diarrhea

- Occlusion or subocclusion of the intestine

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

- Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 28 days after the final dose of autogene cevumeran, 5 months after the final dose of atezolizumab, or 9 months after the last dose of chemotherapy (15 months after the final dose of oxaliplatin in Korea), whichever period ends later

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

- Major surgical procedure, other than for diagnosis or for resection of disease under current study, within < 6 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study

Placement of a central venous access catheter (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted.

- Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

- Clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse as determined by the investigator

- Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barre syndrome, or multiple sclerosis (see Appendix 6 for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions:

Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

- Rash must cover < 10% of body surface area.
- Disease is well controlled at baseline and requires only low-potency topical corticosteroids.
- There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

- Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T-negative severe combined immunodeficiency [SCID]) or combined T- and B-cell immunodeficiencies (e.g., T- and B-negative SCID, Wiskott-Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency)

- History of malignancy within 5 years prior to screening, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis (e.g., 5-year RFS rate > 90%) or death, such as adequately treated carcinoma in situ of the cervix, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer

- Treatment with monoamine oxidase inhibitors (MAOIs) within 3 weeks prior to initiation of study treatment or requirement for ongoing treatment with MAOIs

- Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment

- Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

- Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.

- Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose corticosteroids (defined as <= 10 mg oral prednisone per day or daily equivalent) for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

- Treatment with brivudine, sorivudine, or their chemically-related analogues, which are inhibitors of DPD, within 4 weeks prior to initiation of study treatment

- Current or planned treatment with strong inhibitors or inducers of CYP3A4 and/or UGT1A1 (see Section 4.4.3)

- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

- Known active or latent tuberculosis

If the investigator considers a potential patient to be at an increased risk for infection with Mycobacterium tuberculosis, latent tuberculosis diagnostic procedures must be followed according to local practice standards during the screening period.

- Recent acute infection, defined as severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety

- Prior allogeneic stem cell or solid organ transplantation

- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications

- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab

Influenza vaccination should be given during influenza season only.

- Receipt of any mRNA vaccine (e.g., COVID-19 vaccine) within 7 days prior to start of study treatment

- Current treatment with anti-viral therapy for HBV

- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins

- Known hypersensitivity to Chinese hamster ovary cell products or any component of the atezolizumab formulation

- Known hypersensitivity or allergy to any component of the autogene cevumeran or mFOLFIRINOX formulations, including known hereditary fructose intolerance

Geschlecht: Alle
Mindestalter: 18 Jahre
Höchstalter: kein Höchstalter

Weitere Einschlusskriterien:

- Patienten, die sich einer elektiven Operation in kurativer Intention wegen vermuteter oder durch Biopsie nachgewiesener Malignome der Leber, der Gallenwege/Gallenblase, des periampullären Bereichs oder der Bauchspeicheldrüse unterziehen

- Alter von mindestens 18 Jahren

- Eastern Cooperative Oncology Group (ECOG) - Leistungsstatus 0 oder 1

- Fähigkeit, einen 6MWT mit einer klinisch akzeptablen Herzfrequenz und Blutdruckreaktion sicher zu absolvieren

- Freigabe zur körperlichen Betätigung auf der Grundlage eines Physical Activity Readiness Questionaire (PAR-Q) -Screenings (negatives PAR-Q oder ärztliche Freigabe bei positivem Ergebnis)

- Schriftliche Einverständniserklärung

- Geplante zwei- oder mehrzeitige Operationen innerhalb von 6 Wochen

- Patientinnen während der Schwangerschaft und Stillzeit

- Begleiterkrankungen, die nach Einschätzung des Prüfarztes die Teilnahem an einem Bewegungsprogramm ausschließen

- Vorgeschichte anderer behandelter oder unbehandelter bösartiger Tumoren in den letzten 2 Jahren

- Beeinträchtigter geistiger Zustand oder Sprachbarriere

- vermutete mangelnde Compliance

- Major abdominal surgery for confirmed or suspected gastrointestinal malignancies
- Age >= 18 years
- Written informed consent

- American Society of Anesthesiologist (ASA) classification >= 4
- Planned re-operation within 30 days after index operation
- Mental impairment that prevents an understanding of nature, type and scope of the research project
- Allergies to rosemary oil (rosemary essential oil, virgin olive oil), citrus oil (citrus essential oil, virgin olive oil), solum oil (peat extract, lavender essential oil, horse chestnut extract, horsetail extract, virgin olive oil, white petrolatum, wool wax) or melissa oil (caraway essential oil, fennel essential oil, melissa, marjoram, refined peanut oil) as used oils for the integrative nursing interventions or hypersensitivity to skincare products
- Acute skin disorders at the abdomen or legs
- Emergency Operations
- Pregnancy or breastfeeding
- Participation in another interventional trial with interference on intervention and/or outcome of this trial
- Expected lack of compliance

Patients are eligible to be included in the study only if all of the following criteria apply:
1. Age =18 years at the time of signing informed consent.

2. Karnofsky Performance Status of 70 or higher with no clinically significant deterioration over the previous 2 weeks.

3. Life expectancy minimum of = 12 weeks.

4. Patients diagnosed with histologically or cytologically confirmed advanced solid tumors.

a. Phase 1a darlifarnib (KO-2806) monotherapy (US only): dose escalation and pharmacodynamic (Pd) cohorts

Patients with histologically or cytologically confirmed advanced solid tumors with the following:

- HRAS-mutant and/or amplified tumors (any solid tumor type)
- HRAS overexpression (only for HNSCC tumors)
- KRAS and/or NRAS and/or HRAS-mutant and/or amplified for the following:
- NSCLC
- CRC
- KRAS-mutant and/or amplified PDAC

Patients must have progressed on or be refractory to SOC therapies, be unsuitable for standard therapy, or for which no standard therapy exists.

b. Phase 1a cabozantinib combination dose escalation and Pd cohorts in RCC (Pd cohorts, US only)

- ccRCC: Patients must have received at least 1 prior systemic therapy with IO-based treatment (Note: treatment with prior cabozantinib and/or other TKIs is permitted) for locally advanced or metastatic RCC with predominantly clear cell subtype

- Other non-ccRCC: Patients can be treatment-naive or have received any prior systemic treatment for locally advanced or metastatic RCC.

c. Phase 1a adagrasib combination dose escalation and Pd cohorts in NSCLC, PDAC, and CRC (Pd cohorts, US only)

Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC, PDAC or CRC who have received at least 1 prior systemic therapy for advanced or metastatic disease (Note: any prior type and number KRAS G12C inhibitor is permitted, including prior adagrasib, sotorasib, and experimental [non-approved] KRAS G12C inhibitors). Patients, as assessed by the treating physician, should have received all available approved SOC treatments for advanced or metastatic NSCLC, PDAC or CRC, unless deemed inappropriate or unsuitable (eg. due to toxicity or comorbidities). Specific treatments should include:

- NSCLC: Patients must have received at least 1 prior line of systemic treatment including platinum-based chemotherapy and/or an immune checkpoint inhibitor (given concurrently or sequentially in two different lines of treatment). Patients may have or not received adagrasib or sotorasib.

- PDAC: Patients must have received at least 1 prior line of systemic treatment including platinum-based or gemcitabine chemotherapy and olaparib (as potential 1st line maintenance treatment). Additionally, patients may have had an immune checkpoint inhibitor (if microsatellite instability-high, deficient DNA mismatch repair, or tumor mutational burden-high [> 10 mutations per megabase]).

- CRC: Patients must have received at least 1 prior line of systemic treatment including oxaliplatin and irinotecan-based chemotherapy with or without antiangiogenic or anti-EGFR targeted therapy (given concurrently or sequentially in two different lines of treatment -in patients suitable for intensive chemotherapy). Patients may have or not received adagrasib or sotorasib in combination with cetuximab or panitumumab.

d. Phase 1b cabozantinib combination and cabozantinib monotherapy dose expansion in ccRCC

Patients must be cabozantinib-naive and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies including neoadjuvant, adjuvant, and subsequent therapies. Patients must have had treatment failure on their immediate prior therapy.

e. Phase 1b adagrasib combination dose expansion in NSCLC

Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC who have received at least 1 prior systemic therapy for advanced or metastatic NSCLC (Note: exact patient population for expansion may be restricted to KRAS G12C naive patients or limit it one or more prior KRAS G12C treatment depending on emerging safety and efficacy data from dose-escalation). Patients, as assessed by the treating physician, should have received all available approved SOC treatments for advanced or metastatic NSCLC, unless deemed inappropriate or unsuitable (eg. due to toxicity or comorbidities). Specific treatments should include:

- NSCLC: Patients must have received at least 1 prior line of systemic treatment including platinum-based chemotherapy and/or an immune checkpoint inhibitor (given concurrently or sequentially in two different lines of treatment). Patients may have or not received adagrasib or sotorasib.

5. Adequate organ function, as evidenced by the following laboratory results:

- Hematologic (criteria listed cannot be met with recent blood transfusions or require ongoing growth factor support within 2 weeks of starting study treatment):

i. Absolute neutrophil count > 1500 cells/mm^3.
ii. Platelet count > 100,000 cells/mm^3.
iii. Hemoglobin > 9.0 g/dL within 2 weeks prior to first dose. Note: patients with a Hb > 8.0 g/dL may be transfused within 2 weeks of first dose and included if Hb is > 9.0 g/dL.
Only applicable for patients who are NOT chronically anemic (Hb less than 8.0 g/dL) and transfusion-dependent prior to study entry)

- Hepatic:

i. Total bilirubin (TBL) = 1.5 x upper limit of normal (ULN), except in patients with previously documented Gilbert’s syndrome or in patients with liver metastases, in which case the TBL should be = 3 x ULN.
ii. AST (via serum glutamic oxaloacetic transaminase) and ALT (serum glutamic pyruvic transaminase) = 2.5 x ULN; < 5 x ULN in patients with liver metastases
iii. ALP = 2.5 x ULN; ALP < 5 x ULN for patients with hepatic and/or bone metastases

- Renal:

i. For darlifarnib (KO-2806) monotherapy and adagrasib combination, calculated creatinine clearance = 60 mL/min using the Cockcroft-Gault equation. For cabozantinib combination and cabozantinib monotherapy, calculated creatinine clearance = 40 mL/min using the Cockcroft-Gault equation.

6. Patients must have at least 1 measurable lesion according to RECIST v1.1, which must be confirmed by local radiology prior to patient entry:

a. A previously irradiated lesion can be considered a target lesion (TL) if the lesion is well defined, measurable per RECIST v1.1, and has clearly progressed.

b. Patients without available archival tissue must have a non-target lesion (NTL) that can be biopsied at acceptable risk (if biopsy is required for enrollment) as judged by the Investigator or, if no other lesion is suitable for biopsy, then a RECIST v1.1 TL used for biopsy must be = 2 cm in longest diameter.

7. The results of imaging done up to 6 months prior to screening (eg, = 1 additional time point before baseline assessment) are to be made available to the Sponsor for evaluation of the kinetics of tumor progression if allowed by country.

8. All patients must consent to providing archival tumor specimens for correlative biomarker studies if tumor tissue is available. If an archival specimen is not available, patients may consent to a fresh biopsy.

9. For patients enrolled in the Pd cohorts, paired fresh tumor biopsies at screening and at Days 18 to 21 are mandatory.

10. Capable, according to the Investigator, of complying with the study’s requirements and restrictions including sunlight restrictions: prolonged exposure to sunlight should be avoided during treatment. In addition, patients should take other measures to avoid ultraviolet exposure, such as wearing sunscreen and sunglasses, wearing protective
clothing, and avoiding tanning beds.

11. Able and willing to provide written informed consent prior to any study-related procedure (other than those provided in the course of normal care).

12. Both female patients of childbearing potential and male patients with female partners of childbearing potential must agree to use a highly effective method of contraception along
with a barrier method (eg, condom) from the time of screening and must agree to use such precautions for 180 days after last dose of IMP (see Appendix 2).

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

1. Any use of anticancer therapy (SOC or investigational therapy) within 14 days or 5 half-lives (whichever is shorter) of Cycle 1 Day 1 (darlifarnib [KO-2806] monotherapy and cabozantinib combination and monotherapy arms) or start of adagrasib lead-in (adagrasib combination arm). Note: this criterion does not apply to patients rolling over from cabozantinib monotherapy to cabozantinib+darlifarnib (KO-2806) combination therapy.

2. Received prior treatment with an FTI or HRAS inhibitor.

3. Phase 1a dose escalation and Phase 1b dose expansion (combination):

Cabozantinib combination:

- Clinically significant hematuria or any other hemorrhagic sign/symptom
- Other clinically significant disorders such as:
- Serious non-healing wound/ulcer/bone fracture needing surgical intervention or gaping wound.
- Moderate to severe hepatic impairment (Child-Pugh B or C) (Appendix 10)
- Requirement for hemodialysis or peritoneal dialysis
- History of solid organ transplantation

Adagrasib combination:

- Ongoing need for a medication with any of the following characteristics that cannot be switched to alternative treatment prior to study entry: known risk of QT prolongation or Torsades de Pointes; substrate of cytochrome p450 (CYP)3A with narrow therapeutic index; strong inducer of CYP3A4; and potent inhibitor of BCRP (Appendix 3).

4. Major surgery (as defined by the Investigator) within 28 days prior to first dose or still recovering from prior surgery. Note: Local procedures (eg, placement of a systemic port, core needle biopsy, and prostate biopsy) are allowed if completed at least 24 hours prior to the administration of the first dose of study treatment.

5. Known severe hypersensitivity to the product or similar chemical structure and class to the drug evaluated in the study or one of the active or inactive excipients.

6. Concurrent enrollment in another therapeutic clinical study. Enrollment in observational studies will be allowed.

7. Any toxicity (excluding alopecia) from prior therapy that has not been completely resolved to baseline at the time of consent. Patients with NCI CTCAE v5.0 Grade 1 or 2 toxicities that are deemed stable or irreversible can be enrolled on a case-by-case basis with prior consultation and agreement with the Medical Monitor (eg, Grade 1 peripheral neuropathy from prior oxaliplatin, Grade 1 skin toxicity from prior cetuximab).

8. Any spinal cord compression, leptomeningeal disease, or clinically active CNS metastases. Clinically active CNS metastases are defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Note: Patients with active/symptomatic CNS metastases must have previously completed local therapy.

a. Patients with previously treated CNS metastases are allowed if asymptomatic or neurologically stable (either without the use of steroids or on a steroid dose of = 10 mg/day of prednisone or its equivalent) and have recovered from the acute toxic effects of prior therapy.

b. Patients with CNS metastases treated by radiation must be:
i. = days since stereotactic radiosurgery or gamma knife prior to enrollment.
ii. =14 days since whole-brain radiation therapy prior to enrollment.

9. Any concurrent chemotherapy, immunotherapy, biologic, hormonal or radiation therapy and surgery, for the primary disease under study. Concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and hormone replacement therapy for postmenopausal symptoms) is allowed.

a. Patients are allowed after they have completed a minimum 7-day washout period for radiation to non-CNS locations prior to the start of study treatment.

10. Active autoimmune or inflammatory disorders within the past 5 years prior to the start of treatment. Patients whose condition is well controlled, does not require prohibited systemic immunosuppressive therapy (see Section 5.5.2), and is not expected to interfere with study treatment or endpoint assessment per Investigator opinion are allowed. Note:
The following are some exceptions to this criterion:

a. Vitiligo or alopecia.
b. Hypothyroidism (eg, following Hashimoto syndrome) stable and on hormone replacement.
c. Any chronic skin condition, including psoriasis, that does not require systemic therapy.
d. Celiac disease controlled by diet alone.

11. Any active infection including but not limited to:

a. Hepatitis B virus (HBV): known positive hepatitis B surface antigen (HBsAg) result.
Note: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.

b. Hepatitis C virus (HCV): Note: Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

c. HIV: Known or active HIV infection (HIV testing not required unless required by local regulations). Note the following exceptions:

i. Patients are eligible if CD4 count is > 350 cells/mm^3 and they are on an antiretroviral regimen with evidence of at least 2 undetectable viral loads within the past 6 months on this same regimen; the most recent undetectable viral load must be within the past 12 weeks.

ii. For patients who received chemotherapy in the past 6 months, a CD4 count of < 350 cells/mm^3 during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy.

iii. Patients must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months.

12. Uncontrolled intercurrent illness, including but not limited to the following: ongoing or active infection, interstitial lung disease, cavitating pulmonary lesion(s) or known endobronchial disease manifestation, lesions invading major pulmonary blood vessels, uncontrolled diabetes, serious chronic GI conditions associated with diarrhea, GI conditions associated with a risk of perforation or fistula formation, and psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent.

13. Other invasive malignancy within 2 years. Note: Noninvasive malignancies (eg, cervical carcinoma in situ, in situ prostate cancer, nonmelanomatous carcinoma of the skin, or cured ductal carcinoma in situ of the breast) are permitted after discussion with the Medical Monitor.

14. Refractory nausea and vomiting, chronic GI diseases, inability to swallow the formulated product, malabsorption syndrome and/or previous significant bowel resection that would preclude adequate absorption of study treatments.

15. Cardiac and vascular criteria:

a. Mean QTcF =470 ms calculated from 3 ECGs (within 5 minutes at 1 minute apart, manually read).

b. Presence of acute coronary syndrome, including myocardial infarction or unstable angina pectoris, other arterial ischemic or thrombotic event (not including venous thrombotic events), including cerebrovascular accident or transient ischemic attack, within 6 months prior to enrollment.

c. New York Heart Association class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or uncontrolled hypertension (= 160 mmHg systolic and/or = 100 mmHg diastolic blood pressure [BP]), despite appropriate antihypertensive medication.

d. History of hypertensive crisis/hypertensive encephalopathy within the past 6 months prior to the scheduled first dose of study treatment.

16. Receipt of live attenuated vaccines within 28 days prior to the first dose of study treatment.

17. Any condition that, in the opinion of the Investigator or Sponsor, would interfere with safe administration or evaluation of the IMP, interpretation of patient safety, or study results.

18. Significantly altered mental status that would limit the understanding or rendering of informed consent and compliance with the requirements of this protocol. Unwillingness or inability to comply with the study protocol for any reason.

19. Involvement in the planning and/or conduct of the study (applies to both Sponsor staff and/or staff at the study site).

20. Female patients who are pregnant, lactating, or intend to become pregnant during their participation in this study.

1. Age = 18 years and = 80 years

2. histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas

3. medical and technical operability of the primary tumor

4. limited synchronous liver metastatic status (= 3 resectable/ablatively treatable liver metastases)
OR
limited metachronous liver metastatic status (= 3 resectable/ ablatively treatable liver metastases), but must have completed adjuvant chemotherapy at least 6 months before start of study treatment

5. Previous neo-/adjuvant anti-cancer therapy for non-metastatic PDAC with last dose administered = 6 months before the start of study treatment are allowed

6. adequate hematological (WBC = 3000/µl, platelets = 100.000/µl, hemoglobin = 8 g/dl), hepatic (bilirubin = 2.5 x mg/dl) and renal function (creatinine clearance > 50 ml/min) parameters

7. ECOG performance status = 1

8. Written informed consent obtained according to international guidelines and local laws.

9. measurable disease according to RECIST v1.1. prior to induction therapy

1. Unresectable pancreatic cancer

2. Prior chemotherapy within 6 months or prior radiation therapy within 28 days (e.g. in adjuvant settings).
Exception for previous systemic anti-cancer treatment for metastatic PDAC: Patients with need of immediate treatment (high tumour load, symptoms) may have received one cycle of FOLFIRINOX or modified FOLFIRINOX prior to study entry (Cycle 0) and may be enrolled after Coordinating Investigator approval has been obtained.

3. Concurrent malignancy other than the disease under investigation with exception of malignancy that was treated curatively and has not recurred within 2 years prior to the date of screening. Fully resected basal or squamous cell skin cancers and any carcinoma in situ are eligible

4. Patients with either peritoneal carcinomatosis or > 3 liver metastases or extrahepatic metastasis)

5. Known hypersensitivity to the active substances or any of the excipients

6. Impaired cardiac function or clinically significant cardio-vascular disease, such as: – Congestive heart failure requiring treatment (NYHA grade > 2), or clinically significant arrhythmia (including uncontrolled atrial flutter/fibrillation) – Acute myocardial infarction, unstable angina pectoris, coronary stenting, or bypass surgery < 3 months prior to study entry

7. Simultaneous participation in other interventional trials which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed

8. Inability to understand the study and/or comply with the protocol procedures;

9. Subject pregnant or breast feeding, or planning to become pregnant within 6 months

10. Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: hormonal contraception [estrogen and progesterone combined, oral, intravaginal, transdermal; progesterone-only, oral, injectable, implantable], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence from heterosexual intercourse)

11. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. These conditions should be discussed with the patient before registration in the trial.

12. Person either performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical trials, or persons in residential care institutions.

13. Subjects dependent upon the sponsor, investigator or trial site

- 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

Inclusion criteria for patients
- Planned open or minimally-invasive distal pancreatosplenectomy - - - - -
- Resectable cancer of the pancreatic body or tail
- Age = 18 years
- ASA = III
- Ability to understand character and individual consequences of the trial
- Written informed consent

Exclusion criteria for patients

Preoperative exclusion criteria:
- Distant metastases of pancreatic cancer
- Tumor infiltrating surrounding organs or visceral arteries (except of splenic artery), i.e. stage T4 according to the 8th edition of the American Joint Committee on Cancer staging system
- Surgery for secondary tumors or metastases involving the pancreas
- Participation in another intervention-trial with interference of intervention and/or outcomes of this study

Intraoperative exclusion criteria:
- Intraoperative diagnosis of previously occult metastases that prohibit curative surgical resection
- Tumor resection technically impossible (local unresectability)

Alter > 18 Jahre
Zustimmung zur Studienteilnahme
Geschäftsfähigkeit
elektive Operation an Pankreas, Leber, Magen oder Ösophagus
Verlegung von einer anästhesiologischen Überwachungsstation (PACU/IMC/Intensivstation) auf Normalstation

Zurückziehen der Einwilligung
Wunsch auf Studienbeendigung
Sprachbarriere
Verletzung beider Gehörgänge, Schwerhörigkeit beidseits
Intensivstationäre Therapie aufgrund eines Organversagens vor Randomisierung
Vorliegen einer palliativen Behandlungssituation
Ablehnung durch die Patienten

- Adult patients (age = 18 years) scheduled to undergo PD for highly suspected or histologically proven, resectable PDAC, DCC, and/or ampullary cancer (pancreaticobiliary type), (Stages I-III)

- Suspected pancreas anastomosis at high-risk for development of a POPF (grade “D according to Schuh et al.): Estimation by CT scan, MRI, and/or Endoscopic Ultrasound

- Written informed consent

- Stage IV disease, duodenal carcinoma, ampullary cancer (intestinal type), neuroendocrine tumors, benign tumors, chronic pancreatitis

- Medical conditions that do not allow appreciation of the nature, scope, and possible consequences of the trial as judged by the investigator

- Pregnancy. A beta-Human Chorionic Gonadotropin (bHCG) pregnancy test must to be performed for women of child-bearing potential (defined as premenopausal women who have not undergone surgical sterilization)

- Inability to follow the study procedures, e.g., due to psychological disorders, dementia, etc.

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