1. Male and female patients* with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 – 16 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower, middle and upper third of the rectum), depending on MRI-defined inclusion criteria (see below).

2. Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.

3. Transrectal endoscopic ultrasound (EUS) is mandatory and used to help discriminate between T1/2 and early T3 tumors.

4. MRI-defined inclusion criteria:

- Lower third (0-6 cm): cT1/2 with clear cN+ based on MRI-criteria (see SOP in chapter 12.3 of the appendix), provided CRM- and EMVI-** (defined as MRI-EMVI score 0-3; see SOP in chapter 12 of the appendix)

- Middle third (= 6-12 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; cT3 with maximum infiltration of 10mm in the perirectal fat, provided no evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM > 2 mm), N0 or N1, EMVI-**

- Upper third (= 12-16 cm): cT1/2 with clear cN+, irrespective of CRM and EMVI; any cT3-4 irrespective of nodal status, CRM and EMVI.

5. Spiral-CT of the abdomen and chest to exclude distant metastases.

6. Aged at least 18 years. No upper age limit.

7. WHO/ECOG Performance Status = 1.

8. Adequate haematological, hepatic, renal and metabolic function parameters:

9. Leukocytes = 3.000/mm^3, ANC = 2.000/mm^3, platelets = 100.000/mm^3, Hb > 9 g/dl

10. Serum creatinine = 1.5 x upper limit of normal

11. Bilirubin = 2.0 mg/dl, SGOT-SGPT, and AP = 3 x upper limit of normal.

12. QTc interval (Bazett**) = 440 ms

13. Informed consent of the patient.

* Thera are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
** defined as MRI-EMVI score 0-3; see SOP in chapter 12 of the appendix
*** Formula for QTc interval calculation (Bazett):

QTc = (QT-Dauer / Wurzel aus RR-Abstand in Sek.) = QT-Dauer / ( Wurzel aus 60 / Frequenz (1/min)).

1. Distant metastases (to be excluded by CT scan of the thorax and abdomen).

2. Prior antineoplastic therapy for rectal cancer.

3. Prior radiotherapy of the pelvic region.

4. Major surgery within the last 4 weeks prior to inclusion.

5. Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.

6. Subject (male or female) is not willing to use highly effective*** methods of contraception during treatment and for 6 months (male or female) after the end of treatment Male patients treated with Oxaliplatin should take legal advice concerning sperm conservation before start of therapy and should additionally use a condom during treatment period. Their female partner of childbearing potential should also use an appropriate contraceptive measure.

7. On-treatment participation in a clinical study in the period 30 days prior to inclusion.

8. Previous or current drug abuse.

9. Other concomitant antineoplastic therapy.

10. Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.

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

12. Chronic diarrhea (> grade 1 according NCI CTCAE).

13. Prior or concurrent malignancy = 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free.

14. Known allergic reactions or hypersensitivity on study medication or to any of the other excipients.

15. Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 5.0 (see appendix).

16. Severe kidney dysfunction (creatinine clearance < 30 ml/min).

17. Recent or concurrent treatment with brivudine.

18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.

19. Known dihydropyrimidine dehydrogenase deficiency (Activity score < 1,5 after genetic testing of DPYD variants). (s. ganz unten)

20. 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).
****highly effective (i.e. failure rate of < 1 % per year when used consistently and correctly) methods: intravaginal and transdermal combined (estrogen and progestogen containing) hormonal contraception; injectable and implantable progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments).

For adjustments of chemotherapy for patients with DPYD activity score = 1,5 see Protocol section 4.2.4.3

3.3.1.1 PART 1 - INCLUSION CRITERIA

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

2. Measurable disease as defined in Appendix 10.5

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

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

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

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

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

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

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

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

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

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

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

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

f) PTT / aPTT <1.5 x ULN

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

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

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

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

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

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


3.3.1.3 PART 2 – INCLUSION CRITERIA

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

3.3.1.3.1 Arm D Melanoma: 2L

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

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

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

3.3.1.3.2 Arm E PDAC: 2L

16. Diagnosis of pancreatic ductal adenocarcinoma

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

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

19. Verification within 72 hours prior to first treatment:

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

3.3.1.3.3 Arm F CRC: Refractory and other solid tumors

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

3.3.1.3.4 Arm G HNSCC: 1L

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

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

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

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

3.3.1.2 PART 1 - EXCLUSION CRITERIA

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

14. Live vaccination within 28 days of first treatment.

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

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

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

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

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

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

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

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


3.3.1.4 PART 2 EXCLUSION CRITERIA

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

3.3.1.4.1 Additional Exclusion Criteria for Part 2

23. Any of the following cardiac criteria:

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

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

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

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

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

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

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

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

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

3.3.1.4.2 Arm D Melanoma: 2L

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

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

3.3.1.4.3 Arm E PDAC: 2L

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

32. Prior history of receiving immune checkpoint inhibitors.

3.3.1.4.4 Arm F CRC: Refractory and other solid tumors

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

34. Prior history of receiving immune checkpoint inhibitors.

3.3.1.4.5 Arm G HNSCC: 1L

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

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

37. Prior immune checkpoint inhibitor therapy.

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

1) Signed Written Informed Consent

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

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

2) Type of Participant and Target Disease Characteristics

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

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

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

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

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

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

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

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

i) Participants with MSS-CRC:

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

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

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

j) Participants with gastric/GEJ adenocarcinoma:

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

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

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

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

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

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

l) Participants with renal cell carcinoma (RCC):

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

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

m) Participants with urothelial carcinoma (UC):

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

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

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

n) Participants with pancreatic adenocarcinomas (PDAC):

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

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

o) Participants with melanoma:

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

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

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

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

p) Participants with ovarian carcinomas (OC):

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

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

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

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

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

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

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

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

3) Age and Reproductive Status

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

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

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

a) Female Participants

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

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

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

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

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

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

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

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

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

(1) Is not a WOCBP OR

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

b) Male Participants

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

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

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

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

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

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

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

1) Medical Conditions

a) Women who are pregnant or breastfeeding.

2) Medical History and Concurrent Diseases

a) Primary central nervous system (CNS) malignancy.

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

c) Leptomeningeal metastases.

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

e) Participants with an active, known, or suspected autoimmune disease. Participants with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

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

g) Prior organ or tissue allograft.

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

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

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

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

ii) Uncontrolled angina within the past 3 months.

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

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

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

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

vii) History of myocarditis, regardless of etiology.

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

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

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

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

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

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

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

n) Participants with serious or uncontrolled medical disorders.

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

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

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

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

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

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

3) Prior/Concomitant Therapy

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

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

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

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

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

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

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

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

i) Prior therapy with an anti-CCR8 antibody.

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

4) Physical and Laboratory Test Findings

a) White blood cells (WBC) < 2000/µL.

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

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

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

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

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

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

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

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

5) Allergies and Adverse Drug Reaction

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

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

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

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

6) Other Exclusion Criteria

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

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

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

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. Patients must be >= 18 years of age.

3. Target disease characteristics:

Dose escalation part:
Patients with advanced unresectable or metastatic MSI^hi or dMMR* solid tumors who have progressed after or are intolerant to prior standard therapy.Patients must have progressed on the most recent therapy for advanced disease.

3a ArmA HRO761 s.a.
- Patient should have received all available lines of standard of care therapy, including chemotherapy and/or targeted therapy, and prior immune checkpoint inhibitor therapy.

3b ArmB HRO781 in combination with tislelizumab
- Patient should have received standard of care therapy, i.e., chemotherapy and/or targeted therapy. Patient should have received checkpoint inhibitor therapy for advanced disease as prior treatment or should be expected to benefit from anti-PD1 checkpoint inhibitor therapy as part of the HRO761 in combination with tislelizumab.
- Prior adjuvant therapy is allowed

3c Arm C HRO761 in combination with irinotecan
- Patient should have received at least one prior line of chemotherapy or targeted therapy, and prior checkpoint inhibitor therapy. Patient should not have previously received irinotecan for advanced disease but should be expected to benefit from irinotecan therapy


Dose optimization (Arm A) and Dose expansion (Arms A, B and C) parts:

3d Arm A - Optimizazion and Expansion Group A1 HRO761 s.a.
- Patients with advanced unresectable or metastatic MSI^hi or dMMR* colorectal cancer (CRC) who have progressed after or are intolerant to prior standard therapy including at least one line of immune checkpoint inhibitor. Patient must have received prior therapy that included fluoropyrimidine and oxaliplatin or irinotecan.
- No more than total 3 prior lines of therapy for advanced disease (prior adjuvant therapy is allowed)

3e Arm A - Optimization and Expansion Group A2 HRO761 s.a.
- Patients with advanced unresectable or metastatic MSI^hi or dMMR* solid tumors (with the exception of CRC) who have progressed after or are intolerant to prior standard therapy. Patient should have received at least one prior line of chemotherapy or targeted therapy, and one prior line of checkpoint inhibitor therapy.
- No more than total 3 prior lines of therapy for advanced disease (prior adjuvant therapy is allowed).

3f Arm B - Group B1 HRO761 in combination with tislelizumab
- patients with advanced unresectable or metastatic MSI^hi or dMMR* colorectal cancer (CRC) who have not received any prior checkpoint inhibitor therapy and no more than one prior line of chemotherapy for advanced disease. Patients should be expected to benefit from anti-PD1 checkpoint inhibitor therapy.
- Prior adjuvant therapy is allowed if completed > 12 months prior to study start.

3g Arm B - Group B2 HRO761 in combination with tislelizumab
- Patients with advanced unresectable or metastatic MSI^hi or dMMR* solid tumors (with the exception of CRC) who have not received any prior checkpoint inhibitor therapy and no more than one prior line of systemic therapy (chemotherapy and/or targeted therapy) for advanced disease. Patients should be expected to benefit from anti-PD1 checkpoint inhibitor therapy.
- Prior adjuvant therapy is allowed if completed > 12 months prior to study start

3h Arm C - Group C1 HRO761 in combination with irinotecan
- Patients with advanced unresectable or metastatic MSI^hi or dMMR* solid tumors who have progressed after or are intolerant to prior standard therapy. Patient should have received at least one prior line of chemotherapy or targeted therapy, and one prior line of checkpoint inhibitor therapy. Patient should not have previously received irinotecan for advanced disease, but should be expected to benefit from irinotecan therapy.

For patients who have received prior definitive chemoradiation, adjuvant or neoadjuvant therapy: if disease progression occurred within = 6 months after completion of last therapy, this will be considered as one line of treatment for advanced disease.

* For dose escalation, dose optimization and dose expansion parts:
MMR deficient (dMMR) or MSIhi status based on local testing will be determined using a test such as:
- For dMMR status: Immunohistochemistry (IHC) including four core MMR proteins (MSH2, MSH6, MLH1 and PMS2).
- For MSI status: PCR analysis including five tumor microsatellite loci (BAT25, BAT26, NR21, NR24, Mono27), or Next Generation Sequencing (NGS).

4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) = 1

5. Measurable disease as determined by RECIST version 1.1 (refer to Section 10.3 Appendix 3). Tumor lesions previously irradiated or subjected to other loco-regional therapy will only be considered measurable if there is documented disease progression at the treated site after completion of therapy.

6. Dose escalation and optimization (Arm A only): Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution’s guidelines. Patients must be willing to undergo a new tumor biopsy at screening and during therapy on the study (Please refer to Table 8-8 for details). A biopsy from the same lesion is preferred if safe and medically feasible. Exceptions may be considered after documented discussion with Novartis.

7. Patients will have available archival tumor tissue obtained prior to study treatment initiation (in addition to newly obtained tumor biopsy at screening), to allow retrospective MSIhi/dMMR status confirmation (If an archival tumor sample is not available at screening, a newly obtained tumor sample is to be collected, please refer to Table 8-8 for details)

EXCLUSION CRITERIA APPLICABLE FOR ALL TREATMENT ARMS
Patients meeting any of the following criteria are not eligible for inclusion in this study:

1. Impaired cardiac function or clinically significant cardiac disease, including any of the following:
- Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade = 2), uncontrolled hypertension or clinically significant arrhythmia
- History of cardiac imaging evidence of cardiac fibrosis or structural remodeling/thickening (heart wall thickness = 15 mm). Patient with mild thickening with preserved ejection fraction (> 50%) can be enrolled after a cardiology consultation which would have assessed the overall benefit/risk of participating to the study.
- QTcF > 470 msec on screening ECG or congenital long QT syndrome

2. History of acute myocardial infarction or unstable angina pectoris

3. Clinically significant eye impairment including any of the following:
- History of acute or chronic glaucoma, anterior chamber defect
- Retinal pathology or retinal vessel impairment
- Clinically relevant high intraocular pressure at screening as per ophthalmologist assessment (e.g., CTCAE Grade = 2 glaucoma criteria)

4. Patients with a primary CNS tumor. Patients with brain metastases may participate in this study if at the time of first study treatment the patient is:
- 2 weeks or more from prior CNS-directed therapy completion (including radiation and/or surgery).
- Clinically stable with respect to the CNS tumor.
- Not receiving steroid therapy or, if receiving glucocorticoid therapy, the patient must have been maintained on a stable dose for at least 4 weeks.
- Not receiving anti-convulsive medications (that were started for brain metastases).

5. (Inclusion criteria not applicable as per protocol amendment v.04, revised and included in Inclusion criteria 5a). Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
- <= 4 weeks for radiation therapy. Limited field radiation for palliation is allowed within :S 2 weeks prior to the first <lose of study treatment.
- <= 4 weeks or :S 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.
- Patients who have undergone major surgery :S 4 weeks prior to first dose of study treatment or who have not recovered from the surgical procedure.

5a. Treatment with any ofthe following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
- <= 4 weeks for radiation therapy. Limited field radiation for palliation is allowed within <= 2 weeks prior to the first <lose of study treatment.
- <= 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.
- Patients who have undergone major surgery <= 4 weeks prior to first dose of study treatment or who have not recovered from the surgical procedure.

6. 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. HIV infection with viral load values consistently greater than 50 copies/mL or CD4+ cell count less than 200/mm^3

8. Active HBV or HCV infection not controlled by antiviral therapy. (Controlled disease is defined as positive anti-HBc and negative HBsAg for HBV and undetectable viral load by real-time PCR for HCV) (Please refer to Table 8-3).

9. Patient with untreated active or latent tuberculosis.

10. Infection requiring systemic antibacterial, antifungal or antiviral therapy within 14 days prior to first dose of study drugs

11. Having out of range laboratory values defined as:
- Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 60 mL/min
- Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
- Alanine aminotransferase (ALT) > 3 x ULN
- Aspartate aminotransferase (AST) > 3 x ULN
- Absolute neutrophil count (ANC) < 1.0 x 10^9/L
- Platelet count < 75 x 10^9/L
- Hemoglobin < 9 g/dL
- Clinically significant serum/plasma electrolyte concentration abnormalities (e.g., sodium, chloride, potassium)

12. History of severe hypersensitivity reactions to any ingredient of study drug(s)

13. Use of any live or attenuated vaccines against infectious diseases within 4 weeks of study treatment initiation.

14. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs, (e.g., severe ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection), presence of intestinal obstruction. Prior gastrectomy is not an exclusion criterion.

15. History of or current drug induced interstitial lung disease or non-infectious pneumonitis grade = 2. Non-drug induced interstitial lung disease or non-infectious pneumonitis grade = 2 within 6 months prior to study treatment.

16. Use of hematopoietic growth factors or transfusion support = 2 weeks prior to start of study treatment. For arms A and B only: 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.

17. Unable or unwilling to swallow the oral drug as per dosing schedule

18. Presence of Grade = 2 toxicity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 5), with the exception of neuropathy (inclusion of patients with neuropathy of Grade 2 or less is permitted) and alopecia

19. Major surgery treatment (except for surgical treatment of cancer, see exclusion criteria 3) within 4 weeks prior to enrollment (mediastinoscopy, insertion of a central venous access device and insertion of a feeding tube are not considered major surgery)

20. Participation in an interventional, investigational study within 2 weeks prior to the first dose of study treatment

21. Patients who are taking a prohibited medication that cannot be discontinued at least seven days prior to the first dose of study treatment and for the duration of the study (see Section 6.8.2)

22. Pregnant or breast-feeding (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test

23. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 7 days (patients assigned to HRO761 s.a. Arm) based on estimated half-life of 9 hours (Please refer to HRO761 investigator Brochure) – 120 days patients assigned to HRO761 in combination with tislelizumab) – 6 months or as per the local approved label (patients assigned to HRO761 in combination with irinotecan) after stopping medication. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception.
- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation 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.
- Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
- Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.

In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of childbearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate [generally age from 40 to 59 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 or bilateral tubal ligation 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 considered to be not of child bearing potential.

24. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 days (patients assigned to HRO761 s.a. Arm and in combination with
tislelizumab) – 3 months or as per the local approved label (patients assigned to HRO761 in combination with irinotecan) after stopping study treatment. A condom is required for all sexually active male patients to prevent them from fathering a child AND 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.

If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.

25. Any medical condition that would, in the investigator’s judgement, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures. Any severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgement of the investigator, would make the patient inappropriate for the study.

EXCLUSION CRITERIA SPECIFIC TO TREATMENT ARM B CONTAINING TISLELIZUMAB

101. Groups B1 and B2: prior treatment with immune checkpoint inhibitors

102. History of severe hypersensitivity reactions to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction

103. Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur may be considered. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.

104. Patients who discontinued prior anti-PD-1 therapy due to an anti-PD-1-related toxicity

105. Systemic chronic steroid therapy (> 10mg/day prednisone or equivalent) or any other immunosuppressive therapy within 7 days of the first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.

106. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within 2 weeks of intervention)

EXCLUSION CRITERIA SPECIFIC TO TREATMENT ARM C CONTAINING IRINOTECAN

108. UGT1A1*28 TA7/7, TA7/8, TA8/8 genetic polymorphisms; known history or clinical evidence of reduced UGT1A1 activity, known Gilbert's syndrome, known Crigler-Najjar syndrome, (testing for UGT1A1 status is not mandatory unless required by local regulations and can be conducted at a local laboratory)

109. Use of hematopoietic growth factors or transfusion support = 2 weeks prior to start of study treatment.

110. Patients requiring treatment with strong inhibitors or strong inducers of CYP3A4 for whom treatment cannot be changed to another appropriate medication

111. History of severe diarrhea or colitis

112. Absolute neutrophil count (ANC) < 1.5 x 10^9/L

113. Platelet count < 100 x 10^9/L

114. Prior pelvic / abdominal radiotherapy

115. Known hypersensitivity to irinotecan or components of the drug

Einschlusskriterien für das Screening
Patienten, die alle folgenden Kriterien erfüllen, können in das Screening eingeschlossen werden:

1) Reseziertes Kolonkarzinom im Stadium II,
ODER
Reseziertes Rektumkarzinom im Stadium II, wenn keine Indikation zur Bestrahlung besteht (z.B. bei einer Lage im oberen Rektumdrittel), so dass die Behandlung der des Kolonkarzinoms entspricht.
Patienten, bei denen das Stadium noch nicht bekannt ist, können in das Screening eingeschlossen werden.

2) Unterzeichnete Einwilligungserklärung für das Screening

Einschlusskriterien für die randomisierte Phase
Patienten, die alle folgenden Kriterien erfüllen, können in die randomisierte Phase eingeschlossen werden:

1) Reseziertes Kolonkarzinom im Stadium II,
ODER
Reseziertes Rektumkarzinom im Stadium II, wenn keine Indikation zur Bestrahlung besteht (z.B. bei einer Lage im oberen Rektumdrittel), sodass die Behandlung der des Kolonkarzinoms entspricht.

2) Bekannter MSI- oder MMR- Status

3) Bestätigung, dass das ctDNA Ergebnis verfügbar ist

4) Unterzeichnete zweite Einwilligungserklärung (für die randomisierte Phase)

Ausschlusskriterien für das Screening
Patienten, die eines der folgenden Kriterien erfüllen, werden vom Screening ausgeschlossen:

1) Patienten mit bekannter Mikrosatelliteninstabilität (MSI-H) oder Mismatch-repair-Defizienz (dMMR)

2) Bekannte klinische Hochrisikosituation, wenn diese als sichere Indikation für eine adjuvante Therapie betrachtet wird

3) Patienten, die eine offensichtliche Kontraindikation für eine adjuvante Chemotherapie haben (z.B. auf Grundlage des Allgemeinzustands, der Komorbidität, eines aktiven Zweittumors, des hohen Alters)
Es soll dabei in Betracht gezogen werden, dass Patienten über 75 Jahre häufig nicht die Einschlusskriterien für eine adjuvante Chemotherapie erfüllen.

4) R1- oder R2- Status.
(Patienten mit [noch] unbekanntem R-Status können in das Screening)

5) Patienten, bei denen die Randomisation oder Chemotherapie aus logistischen Gründen nicht möglich ist (Anreiseweg, Compliance)

6) Alter < 18 Jahre

7) Schwangere oder stillende Patienten


Ausschlusskriterien für die randomisierte Phase
Patienten, die eines der folgenden Kriterien erfüllen, werden von der randomisierten Phase ausgeschlossen:

1) Patienten mit Mikrosatelliteninstabilität (MSI-H) oder Mismatch-repair-Defizienz (dMMR)

2) Bekannte klinische Hochrisikosituation, wenn diese als sichere Indikation für eine adjuvante Therapie betrachtet wird

3) R1- oder R2- Status oder mit unbekanntem R-Status (Rx)

4) Anzahl der untersuchten Lymphknoten < 10

5) Allgemeinzustand nach WHO >= 2

6) Kolon- oder Rektumkarzinom im Stadium III oder IV

7) Zweitkarzinom, außer
a. simultanes oder metachrones Kolon- oder Rektumkarzinom im UICC Stadium = I,
b. kurativ behandeltes Basalzellkarzinom oder Plattenepithelkarzinom der Haut oder in-situ Zervixkarzinom
c. Tumor mit einem krankheitsfreien Überleben von mehr als fünf Jahren

8) Kontraindikationen für eine Chemotherapie, insbesondere:
a. Leukozyten < 3,0 Gpt/l
b. Neutrophile Granulozyten < 1,5 Gpt/l
c. Thrombozyten < 100 Gpt/l
d. ALAT oder ASAT > 3 x obere Norm
e. Kreatininclearance (berechnet nach Cockcroft-Gault) < 30 ml/min

9) Begleiterkrankungen mit einem relevanten Einfluss auf die Prognose des Patienten, z.B.:
a. Herzinsuffizienz NYHA III/IV
b. relevante koronare Herzerkrankung,
c. Diabetes mellitus mit Spätschäden

10) Organ-, Stammzell- oder Knochenmarktransplantation

11) Bekannte Überempfindlichkeit gegenüber Capecitabin
Bei einer bekannten Überempfindlichkeit gegen Oxaliplatin, können Patienten an der Studie teilnehmen, aber kein Oxaliplatin erhalten

12) Medikation mit Brivudin, Sorivudin oder Analoga in den letzten vier Wochen vor geplantem Behandlungsstart

13) Bekannter biallelischer oder homozygoter Dihydropyrimidindehydrogenase (DPD)-Mangel

14) Akute Infektionen

15) Bekannte HIV- Infektionen, bekannte, aktive Hepatitis B oder C-Infektion

16) Teilnahme an einer anderen interventionellen Studie mit medikamentöser Therapie in den letzten vier Wochen vor Randomisation

17) Neoadjuvante Therapie vor Resektion

18) Patienten, bei denen die Randomisation oder Chemotherapie aus logistischen Gründen nicht möglich ist (Anreiseweg, Compliance)

19) Alter < 18 Jahre

20) Schwangere oder stillende Patientinnen

21) Gebärfähige Frauen und Männer mit gebärfähiger Partnerin, die nicht zu hoch effektiven Verhütungsmaßnahmen bereit sind, wenn sie in den Arm “Chemotherapie randomisiert werden.

Study Population
Investigators will be expected to maintain a screening log of all potential study candidates that includes limited information about the potential candidate (eg, date of screening).
Eligibility criteria will be evaluated during screening.
Before any study-specific activities/procedures, the appropriate written informed consent must be obtained (see Section 11.3).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, will not be provided.

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

101 Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures. The informed consent (including the additional separate performance study informed consent, if required per local regulations) must be obtained prior to provision of tumor samples to test for KRAS p.G12C mutation.

102 Age >= 18 years (or >= legal age within the country if it is more than 18 years).

103 Pathologically documented metastatic colorectal adenocarcinoma with KRAS p.G12C mutation by a locally validated assay.

104 Central confirmation of KRAS p.G12C mutation using an investigational in vitro diagnostic test, therascreen KRAS RGQ PCR Kit, developed by Qiagen (QIAGEN Manchester Limited, Citylabs 2.0, 200 Hathersage Road, Manchester, M13 0BH, UK).

105 Subjects must provide archived tumor tissue samples (formalin-fixed, paraffin embedded [FFPE] sample collected within 5 years from the date of screening) or undergo a pre-treatment tumor biopsy during screening and prior to enrollment.

106 Measurable metastatic disease per RECIST v1.1 criteria. Lesions previously radiated are not considered measurable unless they have progressed after radiation.

107 Eastern Cooperative Oncology Group (ECOG) Performance Status of <= 1.

108 Life expectancy of > 6 months, in the opinion of the investigator.

109 If prior adjuvant therapy was given for non metastatic disease, or neoadjuvant therapy for non metastatic disease, it must have been completed at least 6 months before the identification of metastatic disease. Subject must not have received any systemic therapy in the setting of metastatic disease except for a maximum of 1 dose of SOC FOLFIRI (chemotherapy backbone) administered only during the study screening period, if initiation of treatment is deemed necessary by the investigator. This 1 dose is not a requirement of the study and is not part of this clinical study.

110 Adequate hematologic and end organ function, defined as the following as assessed within 14 days prior to cycle 1 day 1 and must be collected after the SOC FOLFIRI dose, if administered during the screening period:
- Absolute neutrophil count >= 1.5 x 10^9 cells/L (without granulocyte colony stimulating factor support within 2 weeks of laboratory test used to determine eligibility).
- Hemoglobin >= 9.0 g/dL (without transfusion within 2 weeks of laboratory test used to determine eligibility).
- Platelet count >= 100 x 10^9/L (without transfusion within 2 weeks of laboratory test used to determine eligibility).
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 times the upper limit of normal (ULN), and up to 5 x ULN for subjects with liver metastases.
- Serum bilirubin <= 1.0 x ULN.
- International normalized ratio (INR) <= 1.5 x ULN. Prothrombin time (PT) <= 1.5 x ULN may be used instead of INR for sites whose labs do not report INR.
- Estimated creatinine clearance based on Cockcroft Gault equation >= 30 mL/min/1.73 m^2.

111 If a subject randomized to the control arm is considered by the investigator as appropriate for treatment with bevacizumab-awwb, then the urine analysis should have <= 1+ protein.
Subjects discovered to have <= 2+ protein at baseline must undergo a 24 hour urine collection that must demonstrate < 1 g of protein/24 hour or have a urine protein to creatinine ratio (UPC) < 1.0 to allow participation in the study with use of bevacizumab -awwb.

112 Corrected QT interval (QTcF) <= 470 msec.

113 Ability to take oral medications and willing to record daily adherence to investigational product.

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

Disease Related

201 Active, untreated brain metastases. Subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 are eligible if they meet all of the following criteria:
- Residual neurological symptoms grade <= 2.
- On stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable.
- Follow-up MRI performed within 28 days of day 1 shows no progression or new lesions.

202 Leptomeningeal disease.

203 Tumor is known to be MSI-H.

204 Tumor is known to have BRAF V600E mutation.

205 Subject that is a candidate for complete surgical resection of all metastatic disease at the time of entry into study.

206 Subjects where there is predetermined intent to resect metastatic disease after induction chemotherapy are not eligible for participation in the study.

Other Medical Conditions

207 Prior history of PRES.

208 History of other malignancy within the past 5 years, with the following exceptions:
- Adequately treated non-melanoma skin cancer or lentigo maligna (non-invasive counterpart to melanoma) without evidence of disease.
- Adequately treated cervical carcinoma in situ without evidence of disease.
- Adequately treated breast ductal carcinoma in situ without evidence of disease.
- Prostatic intraepithelial neoplasia without evidence of prostate cancer.

209 Known human immunodeficiency virus (HIV) with cluster of differentiation 4 (CD4)+ T-cell count < 350 cells/µL. Subjects with a CD4+ T-cell count = 350 cells/µL while on nonexcluded
antiretroviral therapy for HIV are eligible to enroll provided all other eligibility criteria are met (Section 5.1 and Section 5.2).

210 History of acquired immunodeficiency syndrome-defining opportunistic infections within the past 12 months.

211 Known hepatitis B with a detectable viral load, or hepatitis C with a detectable viral load.
Subjects with hepatitis B or hepatitis C that achieved a sustained virologic response with a non detectable viral load, following antiviral therapy are not excluded if otherwise eligible.

212 Known dihydropyrimidine dehydrogenase (DPD) deficiency.

213 Known UDP-glucuronosyltransferase 1A1 (UGTA1)*28 homozygosity or diagnosis of Gilbert’s disease.

214 Known sensitivity to any of the products or components to be administered during dosing.

215 Significant uncontrolled concomitant disease that could affect compliance with protocol
procedures or interpretation of results or that pose a risk to subject safety, in the opinion of
the investigator or Amgen medical monitor.

216 Gastrointestinal disorder that results in significant malabsorption, requirement for IV
alimentation, or inability to take oral medication.

217 History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline CT scan.

218 Subject with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection within 14 days prior to cycle 1 day 1.

219 Significant cardiovascular disease, such as New York Heart Association Heart Failure Class 2 or greater or myocardial infarction within 6 months prior to randomization, unstable arrhythmias or unstable angina.

220 If a site intends to use bevacizumab-awwb (if randomized to the control arm) in the subject then they should refer to the current regional label to confirm that there are no contraindications. In countries without regional prescribing information, the IB may be utilized

221 Subject has received a live attenuated virus vaccination within 4 weeks of the first dose of study treatment or intends to receive a live vaccine at any time during the study until 90 days after the last dose of study treatment; vaccines that do not contain live virus are permitted.

Patienten, die sich in den Behandlungskontext des teilnehmenden Zentrums begeben haben und die folgende Kriterien erfüllen:
Prospektiver Patienteneinschluss:
- männliche und weibliche Patienten mit der Diagnose eines Kolonkarzinoms im Stadium I, II oder III
- Bereitschaft der mit dem Studienzentrum kooperierenden Pathologie, Gewebeblöcke gemäß der Protokollanforderungen für die wissenschaftlichen Analysen zur Verfügung zu stellen
- Alter >= 18 Jahre und fähig, die Anforderungen des Registers und die Aufklärung dazu zu verstehen, zu hinterfragen und zu bemessen
- gemäß ICH-GCP unterschriebene Einwilligungserklärung zur Teilnahme an dem Register
- unterschriebene Schweigepflichtentbindung der behandelnden Ärzte für die Zwecke der Studienerhebungen

Retrospektiver Patienteneinschluss:
- Erstdiagnose gestellt ab dem 1.1.2006
- übrige Einschlusskriterien siehe Protokoll 5.1.1

Patienten, die
- die Einschlusskriterien nicht erfüllen
- ihr Einverständnis zur Studienteilnahme zurückziehen

- Kolonobstruktion bei Patienten mit linksseitigem Kolon oder oberem Rektumtumor (Milzflexur bis zum intraperitonealen Rektum (Tumor > 12 cm von der Analgrenze)), die in kurativer Absicht behandelt werden
- der Tumor muss im CT oder in der Endoskopie hochgradig verdächtig auf Darmkrebs sein
- Nachweis der Dickdarmdilatation durch Computertomographie
- der Tumor einschließlich möglicher Metastasen muss als kurativ resezierbar gelten
- = 18 Jahre alt, männlich und weiblich
- Fähigkeit des Patienten zur Einwilligung

- Rechtsseitiger Dickdarm
- Extraperitonealer Rektumkarzinom des unteren und mittleren Drittels (Tumor < 12 cm vom Analrand)
- Lebenserwartung < 120 Tage aufgrund einer fortgeschrittenen Tumorerkrankung
- lokal fortgeschrittene Tumorerkrankung mit lokaler Infiltration anderer Strukturen, die eine R0-Resektion ausschließt oder eine neoadjuvante Behandlung erfordert
- Patienten, die in palliativer Absicht behandelt werden
- Anzeichen einer Darmperforation im CT (freie Luft)
- Patienten, die für eine Operation nicht in Frage kommen (ASA-Score = IV)
- mangelnde Einhaltung
- Suchterkrankungen oder andere Erkrankungen, die es der betroffenen Person nicht erlauben, Art und Umfang der klinischen Prüfung und deren mögliche Folgen zu beurteilen

Inclusion criteria

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

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

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

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

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

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

Exclusion criteria

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

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

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

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

Alle erwachsenen Patienten (im Alter von 18 Jahren und älter), die sich einer rechten Kolonresektion mit oder ohne primäre Anastomose unterziehen. Die rechte Kolonresektion wird definiert als lleozökalresektion oder rechtsseitige Hemikolektomie (jede kolonische Durchtrennung mit dem distalen Resektionsrand proximal zur Flexura lienalis).
Alle Patienten, die sich einer rechten Kolonresektion unterziehen, sind berechtigt, einschließlich solcher, die keine Anastomose haben und durch ein proximales Stoma entlastet werden.
Prozeduren für jede Pathologie, über jeden operativen Zugang (offen, laparoskopisch, robotergestützt oder konvertiert), sind berechtigt.
Elektive (Operation bei geplanter Aufnahme), beschleunigte (innerhalb von 48 Stunden) und
Notfall- (Operation bei ungeplanter Aufnahme) Prozeduren sind berechtigt.

Patienten, die während derselben Operation mehr als eine gastrointestinale Anastomose haben.
Bei Morbus Crohn zusätzliche Strikturenplastik oder Resektion/Anastomose zur Behandlung von Erkrankungen oder Strikturen während derselben Operation.
Gleichzeitige rechte Kolonresektion und hypertherme intraperitoneale Chemotherapie (HIPEC) und/oder zytoreduktive Chirurgie.
Jeder einzelne Patient sollte nur einmal in EAGLE aufgenommen werden. Nach dem Indexverfahren, das in EAGLE 2 aufgenommen ist, sollten Patienten, die zusätzliche Verfahren innerhalb des Studienzeitraums durchlaufen, nicht ein zweites Mal aufgenommen werden.

1. Patient’s signed informed consent

2. Patients >= 18 years at the time of signing the informed consent

3. Histologically confirmed adenocarcinoma of the colon or rectum (appendix carcinoma is excluded)

4. Metastatic colorectal cancer (mCRC) with at least one measurable lesion according to RECIST 1.1 in a computed tomography (CT) or magnetic resonance imaging (MRI) scan performed within 5 weeks prior to randomisation

5. Metastases are primarily unresectable or patient is unable/unwilling to undergo surgery

6. RAS wild-type (KRAS, exons 2, 3, 4 and NRAS, exons 2, 3, 4) mCRC, proven in the primary tumor or metastasis. The RAS mutational status must be determined by means of a validated test method.

7. Patient is not eligible to undergo combination chemotherapy according to investigator’s assessment or unwilling to undergo combination chemotherapy.

8. ECOG performance status 0-2

9. Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results:
- Absolute neutrophil count >= 1.5 x 10^9/L (1500/MikroL)
- Hemoglobin >= 80 g/L (8 g/dL)
- Platelet count >= 75 x 10^9/L (75,000/MikroL) without transfusion
- Total serum bilirubin of <= 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) <= 2.5 x ULN; if liver function abnormalities are due to underlying liver metastasis, AST and ALT <= 5 x ULN
- Calculated glomerular filtration rate (GFR) according to Cockcroft –Gault formula or according to MDRD >= 30 mL/min or serum creatinine <= 1.5 x ULN
- Urine dipstick for proteinuria < 2+ (within 14 days prior to randomisation), unless a subsequent 24-hour urine collection demonstrates < 1 g of protein in 24 hours.

10. Patients without anticoagulation need to present with an INR < 1.5 x ULN and PTT < 1.5 x ULN. Patients with anticoagulation may be enrolled if the patient receives the medication at a stable dose for at least 2 weeks before randomisation and provided that INR and PTT are < 1.5 x ULN.

11. For females of childbearing potential (FCBP): negative pregnancy test within 14 days before randomisation and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1 % per year during the treatment period and for at least 6 months after the last dose of study treatment.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1 % per year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives that inhibit ovulation supplemented with a barrier method, hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

12. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, 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 6 months after the last dose of study treatment. In this regard, double barrier methods are not considered to have a failure rate of < 1 %. Men must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication 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 acceptable methods of contraception.

1. Prior systemic therapy of metastatic disease.
NOTE: Prior adjuvant chemotherapy is permitted, if completed > 3 months prior to randomisation. Multimodal treatment of rectal cancer is not considered antimetastatic therapy and does not preclude study participation

2. Known brain metastasis. In case of symptoms that are suggestive of brain metastasis, brain metastasis has to be ruled out by means of cranial CT/MRI.

3. Significant cardiovascular disease such as: New York Heart Association Class III or greater heart failure; myocardial infarction within 6 months prior to randomisation; balloon angioplasty (PTCA) with or without stenting within 6 months prior to randomisation; despite anti-arrhythmic therapy unstable cardiac arrhythmia > grade 2 NCI CTCAE; unstable angina pectoris

4. Transient ischaemic attack or cerebrovascular accident within 6 months prior to randomization, history of cerebral or aortic aneurysm or dissection

5. Medical history of deep vein thrombosis or pulmonary embolism within 6 months prior to randomisation or medical history of recurrent thromboembolic events (> 1 episode of deep vein thrombosis, pulmonary embolism, peripheral embolism) within the last 2 years.

6. Severe bleeding event within the last 6 months before randomisation (except tumor bleeding surgically treated by tumor resection)

7. Evidence of bleeding diathesis or significant coagulopathy

8. Uncontrolled hypertension defined as systolic blood pressure >= 160 mm Hg and/or diastolic >= 100 mm Hg under antihypertensive medication

9. Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.

10. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intra-abdominal abscess -unrelated to surgery- within 6 months prior to randomisation.

11. Acute or subacute bowel obstruction, active chronic inflammatory bowel disease or chronic diarrhea

12. History of keratitis, ulcerative keratitis or severe dry eye.

13. Hypersensitivity to trifluridine/tipiracil or panitumumab or bevacizumab or any of the excipients, known hypersensitivity to Chinese hamster ovary cell products, known hypersensitivity to human or humanized antibodies

14. Current or recent (within 10 days of randomisation) use of or anticipated need for continuous treatment during study treatment with acetylsalicylic acid > 325 mg/day or treatment with dipyramidole, ticlopidine > 2 x 250 mg/day,
clopidogrel > 75 mg/day, and cilostazol.
Combination of these drugs are not allowed.

15. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation, or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 28 days prior to randomisation or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure

16. Core biopsy or other minor surgical procedure, excluding placement of a vascular access devices, within 3 days prior to the first dose of bevacizumab

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

18. 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.

19. Medical history of other malignant disease than mCRC with the following exceptions:
- patients who have been disease-free for at least three years before randomisation
- patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer
- patients with any treated or untreated malignant disease that is associated with a 5 year survival prognosis of >= 90 % and does not require active therapy

20. Known alcohol or drug abuse

21. Pregnant or breastfeeding females

22. Participation in a clinical trial or experimental drug treatment within 28 days prior to inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.

23. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities

24. Patient possibly dependent from the investigator including the spouse, children and close relatives of any investigator

25. Limited legal capacity

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

1. Patient’s signed informed consent.

2. Patient’s age >=18 years at the time of signing the informed consent.

3. Histologically confirmed adenocarcinoma of the colon or rectum.

4. Resected (R0 or R1) and/or effectively treated metastases (all techniques allowed) of colorectal cancer within 3-10 weeks before randomization (earlier randomisation allowed if at least 3 weeks interval between intervention and treatment start is guaranteed) AND resected primary tumor (synchronous or metachronous). In cases of synchronous metastases the interval of 3-10 weeks might be calculated following the removal of the primary tumor if this intervention was the last to address all tumor lesions.

5. Absence of significant active wound healing complications (if applicable) at randomization. Resolved wound healing complications after resection/ablation are acceptable for
inclusion into the trial.

6. No radiographic evidence of active metastatic disease at study entry in a CT and/or MRI scan not older than 10 weeks prior randomization. Pre-surgery/ablation images are eligible for the study if all lesions have been addressed in the interval.

7. ECOG performance status 0-2.

8. Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results:
- Absolute neutrophil count >= 1.5 x 10^9/L (1500/µL)
- Hemoglobin >==80 g/L (8 g/dL)
- Platelet count >= 100 x10^9/L (100000/µL) without transfusion
- Total serum bilirubin of <= 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST/GOT) <= 3.0 x ULN
- Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or according to MDRD >= 50 mL/min or serum creatinine <= 1.5 x ULN

9. Patients without anticoagulation need to present with an INR < 1.5 x ULN and PTT < 1.5 x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial.

10. Proficient fluorouracil metabolism as defined:
a) Prior treatment with 5-FU or capecitabine without unusual toxicity
or
b) If tested, normal DPD deficiency test according to the standard of the study site
or
c) If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine/capecitabine dosage should be reduced by 50%

11. For women of childbearing potential (WOCBP): negative pregnancy test within 14 days before randomization and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 9 months after the last dose of Oxaliplatin or for at least
6 months after the last dose of all other study treatment.

A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified
cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per
year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

For men: With female partners of childbearing potential, 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 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period

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

1. Treatment of metastases greater than 3 cm with radio-frequency/microwave ablation within 24 months prior to study entry if applicable.

2. Treatment of metastases greater than 5 cm with radiation (stereotactic/ brachytherapy) within 24 months prior to study entry if applicable.

3. Any previous systemic therapy is allowed for inclusion into the trial. However, if previous oxaliplatin-containing chemotherapy at any time for metastatic or localized disease was carried out, the inclusion into the trial is permitted under the condition, that
a) A total duration of oxaliplatin-based therapy of six months (i.e. 12 cycles of FOLFOX /FOLFOXIRI or 8 cycles CAPOX) is not exceeded - including therapy within the FIRE9/PORT trial
b) If already more than three months of oxaliplatin-based therapy (i.e. >6 cycles of FOLFOX / FOLFOXIRI or >4 cycles CAPOX) was used, the study therapy should be started with an irinotecan-based regimen (i.e. FOLFIRI or FOLFOXIRI) However, in the case of FOLFOXIRI therapy in the trial, the above mention regulation concerning the total dosing of oxaliplatin still applies (i.e. 12 cycles of FOLFOX / FOLFOXIRI or 8 cycles CAPOX should not be exceeded - including therapy within the FIRE-9/PORT trial).

4. New York Heart Association Class III or greater heart failure by clinical judgement.

5. Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.

6. Unstable angina pectoris.

7. Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic therapy.

8. Ongoing toxicities > grade 2 NCI CTCAE

9. Active uncontrolled infection by investigator’s perspective.

10. Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.

11. Known hypersensitivity to 5-FU, folinic acid, irinotecan, oxaliplatin or capecitabine or to anyof the other excipients listed in section 6.1 of the corresponding SmPC.

12. Recent or concomitant treatment with brivudine.

13. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE version 5.0 (see appendix 2)).

14. Inflammatory bowel disease and/or bowel obstruction.

15. Simultaneous application of Johannis herbs preparations.

16. Pernicious or other megaloblastic anemia caused by vitamin B12 deficiency.

17. Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization or at least to intended treatment start, or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure.

18. 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.

19. Medical history of malignant disease other than mCRC with the following exceptions:
- patients who have been disease-free for at least three years before randomization
- patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer
- patients with any treated or untreated malignant disease that is associated with a 5-year survival prognosis of >= 90% and does not require active therapy

20. Known alcohol or drug abuse.

21. Pregnant or breastfeeding females.

22. Participation in a clinical trial or experimental drug treatment within 28 days prior to potential inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to potential inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.

23. Patients depending on Sponsor, investigator or study site.

24. Suspected SARS-CoV-2 infection with or without symptoms (evaluation according to local policy in respective center with respect to actual status of pandemic and with reference to the policy that would apply to patients with similar therapy outside the trial). This may include assessment of vaccination status, anamnesis, physical examination and potentially antigen and/or PCR testing.

25. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.

26. Limited legal capacity.

27. Concomitant administration of strong CYP3A4 and/or UGT1A1 inducers (e.g. Rifampicin, Carbamazepin, Phenobarbital, Phenytoin or Apalutamid).

28. Planned inoculation/vaccination with a live vaccine during treatment with Oxaliplatin and/or Irinotecan, and until 6 months after treatment with Irinotecan.

Cohort-specific criteria

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

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

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

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

C5: See Section 5.2 of the Cohort 5 Appendix


Patients must:

1. Provide written informed consent prior to study participation.

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

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

4. Have measurable lesions per RECIST v1.1

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

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

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

Patients must not have:

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

2. Received previous treatment with immune checkpoint inhibitors.

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

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

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

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

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

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

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

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

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

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

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

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

13. A seizure disorder that requires pharmacotherapy.

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

15. A medical contraindication to undergoing biopsies.

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

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

18. Women who are pregnant or breastfeeding.

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

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

21. Legal incapacity or limited legal capacity.

22. Life expectancy less than 3 months

To qualify for enrollment, patients must meet the following inclusion criteria to enroll in any cohort and must meet the specific eligibility criteria for at least one cohort currently open for enrollment.

INCLUSION CRITERIA FOR BIOMARKER ELIGIBILITY TESTING

Patients must meet all of the following criteria for biomarker eligibility testing:

- Signed NGS Biomarker Eligibility Informed Consent Form

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

INCLUSION CRITERIA FOR SCREENING

Patients must meet all of the following criteria for entry in the study:

- Signed cohort-specific Informed Consent Form
Note: For patients undergoing central biomarker status evaluation, a signed NGS Biomarker Eligibility Informed Consent Form and signed cohort-specific Informed Consent Form

- Biomarker eligibility (per cohort-specific definition; see Table 2) as determined at a College of American Pathologists/Clinical Laboratory Improvement Amendments-certified or equivalently accredited diagnostic laboratory using a validated test based on:
Prior test results completed before signing cohort-specific Informed Consent Form and availability of a full report of the testing results: Refer to each respective appendix and Table 4, as criteria for type of assay and/or timepoint of assay for determining biomarker eligibility may differ.

OR

- Blood-based FoundationOne Liquid CDx biomarker eligibility test result generated prior to or during screening or, in case of re-enrollment after treatment discontinuation, prior to starting a new anti-cancer therapy. The clinical performance of the FoundationOne Liquid CDx test being used as a clinical trial assay for the treatment of patients with CRC with the different drug combinations being investigated in the present study is being evaluated under the clinical performance study referenced in Section 3.1.2.

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

- ECOG Performance Status <= 1

- Life expectancy >= 3 months, as determined by the investigator

- Histologically confirmed adenocarcinoma originating from the colon or rectum

- Metastatic disease (Stage IV American Joint Committee on Cancer, Version 7)

- Prior therapies for metastatic disease: Refer to each respective appendix, as criteria for prior therapies may vary.

- Ability to comply with the study protocol, in the investigator's judgment

- Measurable disease (at least one target lesion) according to RECIST v1.1
Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.

- Baseline tumor tissue samples will be collected from all patients, preferably by means of an archival tissue block or a biopsy performed at study entry, for exploratory biomarker research (see Section 4.5.6 for information on tumor specimens)

If an archival tumor tissue sample is not available and a biopsy is not deemed feasible, the eligibility decision will be made by the investigator. The Medical Monitor is available to advise as needed.

- Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following:
- ANC >= 1500/µL without granulocyte colony-stimulating factor
. WBC count >= 2.5 x 10^9/L (2500/µL)
- Lymphocyte count >= 0.5 x 10^9/L (500/µL)
- Platelet count >= 100,000/µL
- Hemoglobin >= 9 g/dL
Patients must not have been transfused within 2 weeks prior to screening to meet this criterion.

- Total bilirubin <= 1.5 x upper limit of normal (ULN) (<= 3 x ULN if Gilbert syndrome)

- Serum albumin >= 2.8 g/dL or 28 g/L

- AST and ALT <= 2.5 x ULN with the following exception:
Patients with documented liver metastases may have AST and/or ALT 5.0 ULN.

- ALP <= 2.5 x ULN with the following exception:
Patients with documented liver or bone metastases: ALP <= 5.0 x ULN

- Creatinine clearance >= 50 mL/min (calculated through use of the Cockcroft-Gault formula) or creatinine <= 1.5 x ULN

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

- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures as outlined in each respective appendix

- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined in each respective appendix

In addition to the inclusion criteria above, to be enrolled in a cohort of the study, patients must meet all of the cohort-specific inclusion criteria, which may be more stringent, as detailed in each respective appendix:

COHORT SPECIFIC INCLUSION CRITERIA

Biomarker-Based Cohort Treatment Arm Appendix

PIK3CA mutation: Inavo + Cetux Appendix A, Section A.4.1.1
No RAS (KRAS, NRAS) mutation
or BRAFV600E mutation detected

PIK3CA mutation: Inavo + Bev Appendix B, Section B.4.1.1
RAS (KRAS, NRAS) mutation

MSI-H Atezo + Tira + Bev Appendix C, Section C.4.1.1

MSI-H Atezo + Tira Appendix C, Section C.4.1.1

BRAFV600E mutation Atezo + SY-5609 Appendix D, Section D.4.1.1

KRAS G12C mutation GDC-6036 + Cetux + FOLFOX Appendix E, Section E.4.1.1

KRAS G12C mutation GDC-6036 + Cetux Appendix F, Section F.4.1.1

Atezo = atezolizumab; Bev = bevacizumab; Cetux = cetuximab; FOLFOX = 5-fluorouracil, leucovorin, oxaliplatin; Inavo = inavolisib; MSI-H = microsatellite instability-high; Tira = tiragolumab.

Note: In the event of overlapping eligibility criteria, the cohort-specific eligibility criteria supersede the general criteria.

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

- Current participation or enrollment in another interventional clinical trial
Patients who are participating in the follow-up period of an interventional clinical trial are eligible for the study.

- Any systemic anti-cancer treatment within 2 weeks or 5 half-lives (whichever is shorter) prior to start of study treatment

- Treatment with investigational therapy within 28 days prior to initiation of study treatment
Note: For re-enrollment in a different cohort after study treatment discontinuation, the timepoint for initiation of the new study treatment (i.e., Day 1 of Cycle 1) may be sooner than 28 days since the final dose of the prior study treatment.

- Pregnant or breastfeeding, or intending to become pregnant during the study and as outlined in each respective appendix
Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

- History of or concurrent 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 or confounds the ability to interpret data from the study

- 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, in the opinion of the investigator, could impact patient safety

- Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of study treatment

- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
Use of an in-dwelling catheter (e.g., PleurX ) is allowed.

- Uncontrolled tumor-related pain

Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period.

Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be evaluated for loco-regional therapy, if appropriate, prior to enrollment.

- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected serum calcium > ULN), or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab

- Clinically significant and active liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis

- Negative HIV test at screening, with the following exception:

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

Sites should include an HIV test during screening, as allowed per local regulations.

- Symptomatic, untreated, or actively progressing CNS metastases

Patients with a history of treated CNS metastases are eligible provided that all of the following criteria are met:
- Measurable disease, per RECIST v1.1, must be present outside the CNS.
- The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
- Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
- There is no evidence of interim progression between completion of CNS-directed therapy and the screening brain scan.
- The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment or whole-brain radiotherapy within 14 days prior to initiation of study treatment.
- The patient has no ongoing requirement for corticosteroids as therapy for CNS disease with corticosteroids discontinued for > 2 weeks prior to enrollment and no ongoing symptoms attributed to CNS metastases.
- If the patient is receiving anti-convulsant therapy, the dose is considered stable.
- Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan.

- History of leptomeningeal disease or carcinomatous meningitis

- History of malignancy other than CRC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer

- Any other disease, unresolved toxicity from prior therapy, 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

- Requirement for treatment with any medicinal product that contraindicates the use of any of the study treatments, may interfere with the planned treatment, affects patient compliance, or puts the patient at higher risk for treatment-related complications

In addition to the exclusion criteria above, to be enrolled in a cohort of the study, patients must not meet any of the cohort-specific exclusion criteria, which may be more stringent, as detailed in each respective appendix:

Cohort-Specific Exclusion Criteria

Biomarker-Based Cohort Treatment Arm Appendix

PIK3CA mutation: Inavo + Cetux Appendix A, Section A.4.1.2
No RAS (KRAS, NRAS) mutation
or BRAFV600E mutation detected

PIK3CA mutation: Inavo + Bev Appendix B, Section B.4.1.2
RAS (KRAS, NRAS) mutation

MSI-H Atezo + Tira + Bev Appendix C, Section C.4.1.2

MSI-H Atezo + Tira Appendix C, Section C.4.1.2

BRAFV600E mutation Atezo + SY-5609 Appendix D, Section D.4.1.2

KRAS G12C mutation GDC-6036 + Cetux + FOLFOX Appendix E, Section E.4.1.2

KRAS G12C mutation GDC-6036 + Cetux Appendix F, Section F.4.1.2

Atezo = atezolizumab; Bev = bevacizumab; Cetux = cetuximab; FOLFOX = 5-fluorouracil, leucovorin, oxaliplatin; Inavo = inavolisib; MSI-H = microsatellite instability-high; Tira = tiragolumab.
Note: In the event of overlapping eligibility criteria, the cohort-specific eligibility criteria supersede the general criteria.

Participants must meet the following key inclusion criteria to be eligible for the study:

- Have histologically and/or cytologically documented adenocarcinoma of the colon or rectum, which is locally advanced unresectable or metastatic

- Participants must be willing and able to provide the most recently available formalin-fixed paraffin-embedded tumor tissue blocks (or freshly sectioned slides, see laboratory manual for details), obtained prior to treatment initiation, to a sponsor-designated central laboratory for biomarker analysis. If archival tissue is not available, then a newly-obtained baseline biopsy of an accessible tumor lesion is required within 35 days prior to the Cycle 1 Day 1 timeframe. Biopsy must provide adequate tissue for analysis; the following biopsy types are acceptable: resection, excision, punch (skin lesions only) and core needle biopsies.

- Have HER2+ disease as determined by tissue-based investigational HER2 IHC and ISH assays performed at a sponsor-defined central laboratory. HER2 amplification will be determined using ASCO/CAP guidelines for gastric and gastroesophageal cancer with IHC 3+ or IHC 2+/ISH+ result.

- Have RAS WT disease as determined by local or central testing. Central testing may only be used with Medical Monitor approval if local testing is not available or when otherwise deemed necessary. For central RAS testing, tissue must be submitted prior to study enrollment and analyzed within 1 year of biopsy date.

- Have radiographically measurable disease per RECIST v1.1 according to INV assessment, with at least one site of disease that is measurable and that has not been previously irradiated; or, if the participant has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation

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

- CNS Inclusion Based on screening contrast brain magnetic resonance imaging (or CT with contrast if MRI is contraindicated), participants may have any of the following:

a. No evidence of brain metastases

b. Previously treated brain metastases which are asymptomatic

- Brain metastases previously treated with local therapy must not have progressed since treatment

- Time since whole brain radiation therapy (WBRT) is >= 14 days prior to enrollment, time since stereotactic radiosurgery (SRS) is >= 7 days prior to enrollment, or time since surgical resection is = 28 days prior to enrollment

- Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions

Participants will be excluded from the study for any of the following key exclusion criteria reasons:

- Have previously received any systemic anticancer therapy for CRC in the locally advanced unresectable or metastatic setting or have participated in any interventional clinical trial for CRC in the locally advanced unresectable or metastatic setting; note that participants may have received a maximum of 2 doses of mFOLFOX6 in the locally advanced unresectable or metastatic setting prior to randomization.

Note: participants may have received prior chemotherapy for CRC in the adjuvant setting provided that it was completed >6 months prior to enrollment.

- Have previously received radiation therapy within 14 days prior to enrollment (or within 7 days in the setting of SRS). Participants who have received prior radiation therapy must have recovered to baseline from any treatment-related adverse events (AEs). Participants who have received palliative radiotherapy for symptomatic metastases may enter the study without a washout period provided that the participant has recovered from any treatment-related AEs.

- Have previously been treated with anti-HER2 therapy

- Have ongoing >= Grade 2 diarrhea of any etiology

- Inability to swallow pills or any significant GI disease which would preclude the adequate oral absorption of medications

- Participants with active CNS metastases (irradiated or resected lesions are permitted, See Inclusion Criteria for details). Participants with carcinomatous meningitis are excluded without exception.

Each potential participant must satisfy all of the following criteria to be enrolled in the study:

Age

1. Be =18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.

Disease Characteristics

2. Have histologically or cytologically confirmed adenocarcinoma of the left-sided colorectal cancer. Participants must have unresectable or metastatic disease.

Notes:
- Left-sided CRC is defined as a primary tumor that involves the splenic flexure, descending colon, sigmoid colon, rectosigmoid, or rectum.
- Carcinoma of the anal canal is excluded.

3. Be diagnosed to have KRAS, NRAS, and BRAF WT tumor as determined by local testing.
Both tissue- and blood-based testing is an acceptable method for the eligibility determination.

The local test must at least include and participants must be WT for KRAS/NRAS G12 and G13 and BRAF V600 codons. Other KRAS/NRAS codons, as well as MSI-H/dMMR status and ERBB2/HER2 amplification status, should be determined per the local guidelines and standard practice. A participant is excluded from the study if the participant is known to have a mutation (with the exception of a silent mutation) in any of the following codons based on local testing: KRAS/NRAS A59, Q61, K117, or A146 or BRAF V600. A copy of the test report documenting the WT status for KRAS/NRAS and BRAF must be included in the participant records, and a de-identified copy must be submitted to the sponsor during the
screening period.

The local test must be performed in accordance with local guidelines using an FDA-approved test or laboratory-developed test that is validated in a CLIA-certified laboratory (sites in the United States) or an accredited local laboratory (sites outside of the United States). In the European Union, the local test must be CE-marked or an in-house laboratory-developed test from health institutions in the European Union in accordance with Article 5(5) of the IVDR 2071/746, as amended.

4. Must agree to the submission of fresh tumor tissue.

Notes:

- The most recent sample should be submitted if multiple samples exist.
- Fresh tumor biopsy is required, if clinically feasible, for participants who have received neoadjuvant therapy, adjuvant therapy, or both.
- When fresh tissue biopsy collection is not clinically feasible, then archival tissues collected at diagnosis (for participants without prior adjuvant or neoadjuvant therapy) or post-adjuvant or neoadjuvant treatments can be used.

5. Have measurable disease according to RECIST v1.1. If only 1 measurable lesion exists, it may be used for the screening biopsy as long as baseline tumor assessment scans are
performed = 7 days after the biopsy.

Prior Therapy Restrictions or Requirements

6. Has not received any prior systemic therapy for unresectable or metastatic CRC.

Following prior adjuvant/neoadjuvant therapy in the non-metastatic disease is permitted.
However, the last course of adjuvant or neoadjuvant chemotherapy must have concluded >12 months prior to CRC recurrence/metastases.

- Adjuvant chemotherapy that included fluoropyrimidine alone or in combination with oxaliplatin or irinotecan (no more than 6 months of treatment); or radiation with radiosensitizing chemotherapy.
- Neoadjuvant chemotherapy with fluoropyrimidine monotherapy.

Performance Status

7. Have an ECOG PS of 0 or 1 (Appendix 8).

Renal Function

8. Have at least 1 of the following:
a. Serum creatinine = 1.5 x ULN
b. eGFR based on the MDRD 4-variable formula (see Appendix 10) or directly measured creatinine clearance = 50 mL/min

Hepatic Function

9. Participants are eligible if they have the following laboratory values:

Hepatic metastases
No known / Yes
AST: = 3 x ULN / = 5 x ULN
ALT: = 3 x ULN / = 5 x ULN
Total bilirubin: = 1.5 x ULN
Bilirubin in case of known congenital / isolated total bilirubin =1.5xULN with
nonhemolytic hyperbilirubinemias such / conjugated (direct) bilirubin =1.5xULN
as Gilbert syndrome

Hematologic Values

10. Participants should have (without transfusion or growth factors within 1 week of randomization):
- Hemoglobin = 9.0 g/dL
- Neutrophils = 1.5 x 10^3/µL or = 1.0x10^3/µL for participants with benign ethnic neutropenia

Participants with benign ethnic neutropenia must have a source document describing the (1) persistent low neutrophil count (eg, neutrophil count < 1.5 x 10^3/µL in 2 consecutive laboratory tests performed at least 2 weeks apart); (2) absence of other cytopenias, splenomegaly, or lymphadenopathy; and (3) other possible etiology of neutropenia have been ruled out.
- Platelets = 100 x 10^3/µL

Sex and Contraceptive/Barrier Requirements

11. While on study treatment and for 9 months after the last dose of study treatment, a participant must:
- Not breastfeed or be pregnant
- Not donate gametes (ie, eggs or sperm) or freeze for future use for the purposes of assisted reproduction
- Wear an external condom
- If of childbearing potential,
- Have a negative highly sensitive (eg, beta-human chorionic gonadotropin [beta-hCG]) pregnancy test at screening and within 24 hours before randomization and agree to further pregnancy tests per the SoA
- Practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used
- If a participant’s partner is of childbearing potential,
- The partner must practice a highly effective method of contraception unless the participant is vasectomized

See Appendix 4 for details.

Informed Consent

12. Must sign an ICF (or their legally designated representative must sign) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.

13. Be willing and able to adhere to the lifestyle restrictions specified in this protocol.

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

Medical Conditions

1. Has uncontrolled illness including, but not limited to, the following:

a. Diabetes mellitus

b. Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics/antimicrobials 1 week prior to starting study treatment]) or diagnosed or suspected viral infection except as allowed by Exclusion Criterion 14 for HIV

c. Active bleeding diathesis. Bleeding from the primary tumor is not an exclusion.

d. Impaired oxygenation requiring continuous oxygen supplementation

e. Psychiatric illness/social situation that would limit compliance with study requirements

f. Significant history of bleeding events (eg, hemoptysis, upper or lower gastrointestinal bleeding) within 6 months of randomization unless the source of bleeding has been resected or controlled

g. History of gastrointestinal perforation within 6 months of randomization. However, if the perforation was from the primary tumor that has been surgically resected and controlled, the individual may be enrolled.

2. Has medical history of (noninfectious) ILD/pneumonitis/pulmonary fibrosis or has current ILD/pneumonitis/pulmonary fibrosis, or where suspected ILD/pneumonitis/pulmonary fibrosis cannot be ruled out by imaging at screening.

3. Has known allergies, hypersensitivity, or intolerance to excipients of any of the following:
a. amivantamab (refer to the IB) or cetuximab (refer to the product label) (all participants)
b. any component of mFOLFOX6 (refer to the product labels) (participants receiving mFOLFOX6)
c. any component of FOLFIRI (refer to the product labels) (participants receiving FOLFIRI)

4. Participant has a history of clinically significant cardiovascular disease including, but not limited to, the following:

a. Diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior to randomization or any of the following within 6 months prior to randomization: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically nonsignificant thrombosis, such as nonobstructive catheter-associated clots, are not exclusionary.

b. Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate). Note: Participants with cardiac pacemakers who are clinically stable are eligible.

c. Uncontrolled (persistent) hypertension: systolic BP >180 mm Hg; diastolic BP >100 mm Hg

d. Congestive heart failure defined as NYHA class III or IV or hospitalization for congestive heart failure (any NYHA class) within 6 months of randomization (Appendix 9)

e. Pericarditis/clinically significant pericardial effusion

f. Myocarditis

5. Has or will have any of the following:
a. An invasive operative procedure with entry into a body cavity within 4 weeks or without complete recovery before the first administration of study treatment.
Thoracentesis or paracentesis, if needed, and percutaneous biopsy for baseline tumor tissue sample may be done less than 4 weeks prior to the first administration of study treatment as long as the participant has adequately recovered from the procedure prior to the first dose of study treatment in the clinical judgement of the investigator.
b. Significant traumatic injury within 3 weeks before the start of the first administration of study treatment (all wounds must be fully healed prior to Day 1).
c. Expected major surgery while the investigational agent is being administered or within 6 months after the last dose of study treatment.

Note: Port placement for chemotherapy administration is allowed.

6. Has a prior or concurrent second malignancy other than the disease under study or one whose natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s) (see Appendix 7 for details). Prior or concurrent second malignancies must be reviewed and agreed to with the medical monitor.

Disease Characteristics

7. Participant with known dMMR/MSI-H status.

8. Participant with known HER2-positive/amplified tumor.

9. Has prior exposure to any agents that target EGFR or MET (including but not limited to protein products, monoclonal antibodies, tyrosine kinase inhibitors, or antisense oligonucleotide therapy).

10. Participant with known complete absence of DPD activity.

11. For a participant who is to receive FOLFIRI: known to be homozygous for the UGT1A1*28 or *6 alleles or is compound or double heterozygous for the UGT1A1*28 and *6 alleles per local guidelines. Participants with Gilbert syndrome must be tested for UGT1A1 per local guidelines.

Brain and Central Nervous System Metastases

12. Has symptomatic or untreated brain metastasis.

Note: Participants with definitively, locally treated metastases that are clinically stable and asymptomatic for a least 2 weeks and who are off or receiving low-dose corticosteroid
treatment (= 10 mg prednisone or equivalent) for at least 6 weeks prior to randomization are eligible.

13. Has medical history or known presence of leptomeningeal disease or spinal cord compression.

HIV Status

14. HIV-positive participants are not eligible if they meet any of the following criteria:
a. Detectable viral load (ie, > 50 copies/mL) at screening
b. CD4+ count < 300 cells/mm^3 at screening
c. AIDS-defining opportunistic infection within 6 months of screening
d. Not receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.
Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to randomization).

Viral Hepatitis Assessments

15. Has active hepatitis of infectious origin at screening:

a. Seropositive for hepatitis B: defined by a positive test for HBsAg. Participants with resolved infection (ie, participants who are HBsAg-negative with positive antibodies to total anti-HBc) must be screened using RT-PCR measurement of HBV DNA levels.
Those who are RT-PCR-positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by RT-PCR (see Appendix 11).

b. Known hepatitis C infection or positive serologic testing for HCV (anti-HCV) antibody.

c. Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative HCV RNA test is obtained at screening or within 3 months prior to first dose of study treatment.

d. Other clinically active liver disease of infectious origin.

Prior/Concomitant Therapy or Clinical Study Experience

16. Had radiation therapy within 28 days before randomization.

Note: Localized radiotherapy for palliative purposes must be completed at least 21 days prior to randomization.

17. Requires a prohibited medication that cannot be discontinued, substituted, or temporarily interrupted during the study (see Section 6.9.3 for prohibited therapies).

18. Received an investigational treatment (including investigational vaccines but not including anticancer therapy) or used an invasive investigational medical device within 8 weeks of
randomization.

Other Exclusions
19. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could revent,
limit, or confound the protocol-specified assessments.

NOTE: Investigators must ensure that all study enrollment criteria have been met at screening. If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study treatment is given such that the participant no longer meets all eligibility criteria, then the participant must be excluded from participation in the study. Section 5.4 describes options for retesting. The required source documentation to support meeting the enrollment criteria is noted in Appendix 2.

To obtain a homogenous but still representative patient population for analysis and high external validity, all patients with primary loop ileostomy closure and without further interventions or conditions to the abdominal wall, which might interfere with the primary outcome measure and reduce the reproducibility and interpretability of the data, are eligible for inclusion and will be informed about the P.E.L.I.O.N trial:

1. Planned elective loop ileostomy closure

2. Adult Patients (>= 18 years of age)

3. Life expectancy > 2 years

4. Written informed consent

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

1. American Society of Anesthesiologist (ASA) physical status class >= 4

2. Infected/septic surgical site (Risk for Surgical Site Occurrences (SSO) of Grade 4 according to Ventral Hernia Working Group (VHWG)-classification) (see appendix 1)

3. Presence of parastomal hernia in loop ileostomy site with fascia defect > 8cm* (Table 3)

4. Presence of a concomitant incisional hernia that impedes loop ileostomy reversal or placement of the mesh at the ileostomy site* (Table 3)

5. Patients with prior mesh placement on site of ileostomy

6. Chronic renal failure under haemodialysis/ peritoneal dialysis

7. Patients under strong immunosuppression or other medications likely to impede wound healing as judged by the operating surgeon**

8. Congenital haemorrhagic diathesis with need of perioperative treatment

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

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

1. Patient* provide signed informed consent form.

2. Patient is = 18 years at the time of given informed consent.

3. Patient has been diagnosed with histologically or cytologically proven microsatellite stable (MSS)/proficient mismatch repair (pMMR) metastatic adenocarcinoma of the colon or rectum, which is not amenable to potentially curative resection.

4. Known RAS (KRAS or NRAS) and BRAF V600E mutational status.
Note: These mutations are mutually exclusive. Therefore, if one of the factors is mutated, it is not required to determine the mutation status of the others, as they are then assumed to be wildtype.

5. Patient is without liver metastases (NLM), defined as subjects without active liver metastases at screening as determined on baseline imaging of the liver as performed by CT scan with contrast or MRI. Definitively treated liver metastases (which includes surgical resection, microwave or radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) that were treated at least 3 months prior to enrollment with no evidence of radiologic progression on subsequent imaging are considered to be non-active liver metastases.

6. Patient received at least one line of previous treatment with a fluoropyrimidine, oxaliplatin, irinotecan, VEGF(R) and if indicated EGFR and/or BRAF inhibitors in the advanced setting, or the patient has been intolerable or ineligible to those treatments.

7. Patient has an ECOG performance status = 1.

8. Patient has a life expectancy > 16 weeks.

9. Patient has adequate hematological, hepatic, and renal function.

a. Absolute number of neutrophils (ANC) = 1.5 x 10^9/L.

b. Platelets = 100 x 10^9/L.

c. Hemoglobin = 9 g/dL (5.58 mmol/L).

d. Total bilirubin = 1.5 times the upper limit of normal (ULN) (or < 2 x ULN in case of prior liver involvement or Gilbert’s disease).

e. AST (SGOT) and ALT (SGPT) = 2.5 x ULN, AP = 5 x ULN.

f. Serum creatinine = 1.5 x ULN or creatinine clearance (measured by 24 h urine) = 30 mL/min (i.e., if serum creatinine level is > 1.5 x ULN, then a 24-hour urine test must be performed to check the creatinine clearance to be determined).

g. Urinary protein = 2+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is = 3+, a 24-hour urine collection for protein must demonstrate < 2000 mg of protein in 24 hours to allow participation in this protocol).

10. Adequate coagulation function as defined by International Normalized Ratio (INR) = 1.5, and a partial thromboplastin time (PTT) = 5 seconds above the ULN (unless receiving anticoagulation therapy).

11. Patients of childbearing potential must agree to remain abstinent (abstain from heterosexual intercourse) or use a very reliable method of contraception (methods with a failure rate of less than 1%) during treatment and for up to 6 months after treatment ends. Patients using hormonal contraception must be willing to use an additional barrier method (actual adherence only required if randomized to arm B). Non-sterilized male patients with a partner of childbearing potential must be willing to remain abstinent or use reliable methods of contraception during treatment and for up to 6 months after treatment ends (actual adherence only required if randomized to arm B). Male patients with a pregnant partner must be willing to remain abstinent or use condoms for the duration of the pregnancy (actual adherence only required if randomized to arm B). Patients of child-bearing potential must have a negative pregnancy test within the last 7 days prior to the start of trial therapy.

12. Patient is willing and able to comply with the protocol (including contraceptive measures) for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

* There is no data that indicates a specific gender distribution. Therefore, patients are included regardless of their gender.

1. Patient hasknown allergic / hypersensitive reactions to at least one of the treatment components.

2. Patient had previous malignancy other than that under study within 3 years or concomitant malignancy, except: those with a 5-year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer.

3. Patient received previous treatment with Fruquintinib, trifluridine/tipiracil, regorafenib or an anti-PD-1/anti-PD-L1 antibodies.

4. Patient receives current treatment with any anti-cancer therapy, such as systemic immunotherapy, chemotherapy, or hormone therapy within = 2 weeks prior to study treatment start.

5. Patient receives simultaneous treatment with a different anti-cancer therapy other than that provided for in the trial (excluding palliative radiotherapy for symptom control).

6. Patient has known untreated or symptomatic CNS or leptomeningeal metastases.

7. Patient has impaired cardiac function or clinically significant cardiac disease including unstable angina within 6 months before the first dose of study treatment, acute myocardial infarction < 6 months prior to the first dose of study treatment, New York Heart Association (NYHA) class II–IV congestive heart failure, uncontrolled hypertension (defined as an
average systolic blood pressure > 160 mmHg or diastolic > 100 mmHg despite optimal treatment, uncontrolled cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin, active coronary artery disease or corrected QT interval (QTc) = 470.

8. Patient has history of uncontrolled infection with human deficiency virus (HIV) or chronic infection with hepatitis B or C virus (HBV, HCV).

9. Patient has evidence of bleeding diathesis.

10.Patient has history of gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation.

11.Patient has grade 3-4 gastrointestinal bleeding within 3 months prior to first dose of trial therapy.

12.Patient received strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of trial drug (see Appendix 4 for examples).

13.Patient had a major surgery within 2 weeks prior to first dose of trial therapy.

14.Patient experienced severe, life-threatening, or recurrent (Grade 2 or higher) immune-mediated adverse events (AEs) or infusion-related reactions including those that led to permanent discontinuation while on treatment with immune-oncology agents.

15.Patient received prior immunosuppressive therapy: immunosuppressive doses of systemic medications of > 10 mg/day of prednisone or equivalent must be discontinued = 2 weeks before the first dose of study treatment. Short courses of high dose corticosteroids and/or continuous low dose of prednisone (< 10 mg/day) are permitted. In addition, inhaled, intranasal, intraocular, and/or joint injections of corticosteroids are allowed.

16.Patient has active autoimmune disease that has required systemic treatment (except replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy while on study.

17.Patient has history of solid organ transplantation.

18.Patient has history of thromboembolic events (including deep vein thrombosis and pulmonary embolism) within the past 6 months or history of stroke and/or transient ischemic attack within the last 12 months.

19.Patient has a history of or current interstitial pneumonitis.

20.Patients has evidence of any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect.

21. Female patient is pregnant or breast feeding or planning to become pregnant within and up to 6 months after end of treatment.

- Alter >= 18 Jahre
- Indikation zur elektiven, tiefen anterioren Rektumresektion bei malignen und benignen Erkrankungen des Rektums
- minimalinvasiv oder offene operative Entfernung (Resektion)
- ASA I-III
- Mündliche und schriftliche Einwilligung
- Fähigkeit, den Studieninhalt und -umfang zu verstehen und diesen umsetzen zu können

- Rektumresektion als sekundärer Eingriff
- Koloanale Anastomose
- Teilnahme an einer anderen Studie, die das Studienergebnis beeinträchtigt
- > ASA III