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.

Patients with histologically or cytologically confirmed unresectable, locally advanced or metastatic, HER2+ overexpressing or amplified BC, GEAC, or CRC who are previously treated with the standard of care first line and/or second line treatment (depending on the cohort)

MAIN INCLUSION CRITERIA:

- 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 informed consent form (ICF)

- Cohorts A to K and Cohort O: Documented HER2+ mBC or mGEAC according to ASCO-CAP guidelines [R23-3591, R23-3707], for the respective cancer indication according to the
result of local testing from the latest available biopsy.

- Cohorts L (L-ext), M, and N (mCRC): Documented HER2 overexpression/amplification according to ASCO/CAP gastric cancer guidelines [R23-3591] and according to the result of local testing:
testing:
- HER2 IHC 3+ by gastric algorithm, or
- HER2 IHC 2+ and HER2 amplification by ISH, or
- HER2 amplification in archival tissue by next generation sequencing (NGS) assay (copy number = 6), or
- HER2 amplification in ctDNA by blood based NGS assay and investigator confirmation by IHC/ISH or tissue NGS prior to or in parallel with the screening process

- For dose optimization and justification (Phase II): Patient must provide tumor tissue from locations not radiated prior to biopsy, if possible, collected through archival tissue

- History of prior treatment lines in palliative setting:

- For cohorts A, B, C, D, E, F, G, H, I, I-ext, J, J-ext, K and O documented investigator assessed progression after HER2-directed treatment for unresectable locally advanced or metastatic disease (For Cohorts D, H, I (I-ext), J (J-ext) - patients must have been pretreated with T-DXd and have progressed or have been intolerant to previous T-DXd).

- For cohorts L, L-ext, M and N documented progression or recurrence of disease during or following their latest line of therapy. Patients must have had at least one prior line of
therapy for locally advanced unresectable disease or metastatic disease (adjuvant and neoadjuvant therapy excluded) and documented disease progression or recurrence of disease during or following their latest line of therapy. In the opinion of the Investigator, patients must be unlikely to tolerate or derive clinically meaningful benefit from further standard of care therapy known to prolong survival.

- Presence of at least one measurable lesion according to RECIST 1.1

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

- Adequate organ function based on laboratory values


INCLUSION CRITERIA

1. Signed and dated written ICF in accordance with ICH-GCP and local legislation prior to admission to the trial.

2. 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.

3. HER2 status:

i. For mBC and mGEAC (Cohorts A to K and Cohort O): Documented HER2+ mBC or mGEAC according to ASCO-CAP guidelines [R23-3591, R23-3707], for the respective cancer indication according to the result of local testing from the latest available biopsy. For specific requirements in Phase II, see Section 6.2.1.

ii. For mCRC (Cohorts L,L-ext, M, and N): Documented HER2 overexpression/amplification according to ASCO/CAP gastric cancer guidelines [R23-3591] according to the result of local testing:
- HER2 IHC 3+ by gastric algorithm, or
- HER2 IHC 2+ and HER2 amplification by ISH, or
- HER2 amplification in archival tissue by next generation sequencing (NGS) assay (copy number =6), or
- HER2 amplification in ctDNA by blood based NGS assay and investigator confirmation by IHC/ISH or tissue NGS prior to or in parallel with the screening process.
For specific requirements in Phase II, see Sections 5.4 and 6.2.1.

4. For dose optimization (Phase II): Patient must provide tumor tissue from locations not radiated prior to biopsy, if possible, collected through archival tissue, see Sections 5.4.3 and 6.2.1 for details regarding acceptable tissue

5. History of prior treatment lines in palliative setting – Cohorts A, B, C, D, E, F, G, H, I, I-ext, J, J-ext, K and O:
Documented investigator assessed progression after HER2-directed treatment for unresectable, locally advanced, or metastatic disease:

i. For Cohorts A, B, C, G, K, and O, (dose escalation), one line of prior therapy is required, and additional lines of therapy are allowed.

ii. For Cohort D (dose optimization, combination with T-DM1 in mBC), one line of prior therapy is required, and two prior lines of therapy are allowed.
However, previous treatment with small molecule HER2 inhibitors, including, but not limited to, tucatinib, pyrotinib, lapatinib, and neratinib in the palliative setting and/or treatment with capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil]) for metastatic disease for more than 21 days is allowed in up to 15 patients in each dose level (see
exclusion criterion 1.i and 1. iv). For these patients, up to three prior lines of therapy are allowed.
All patients must have been pretreated with T-DXd and have progressed or have been intolerant to previous T-DXd.

iii. For Cohort E (dose optimization, combination with T-DXd in mBC), one line of prior therapy is allowed, which must be trastuzumab with or without pertuzumab and taxane. Additional prior lines of therapy are not allowed. However, previous treatment with T-DXd in the palliative setting is allowed for up to 15 patients in each dose level. For these patients, up to three prior lines of therapy are allowed, including also treatment with small molecule HER2 inhibitors, including, but not limited to, tucatinib, pyrotinib, lapatinib and neratinib, capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil]) and/or T-DM1 in the palliative setting. For Cohort F (dose optimization, combination with T-DXd in mGEAC), one line of prior therapy is required, and 2 or 3 prior lines of therapy are allowed, which can be trastuzumab or other anti-HER2 antibody containing the same epitope as trastuzumab in combination with chemotherapy and with or without a checkpoint inhibitor.

iv. For Cohort H (dose optimization, combination with capecitabine and trastuzumab in mBC) one line of prior therapy is required, and two prior lines of therapy are allowed. However, previous treatment with T-DM1 in the palliative setting is allowed for up to 15 patients in each dose level. For these patients, up to three prior lines of therapy are allowed.
All patients must be pretreated with T-DXd and progressed on or are intolerant to previous T-DXd.

v. For Cohort I (dose optimization, zongertinib monotherapy in mBC, and I-ext, respectively) and Cohort J (dose optimization, zongertinib combination with trastuzumab in mBC, and J-ext, respectively) a maximum of 5 lines of prior therapy are allowed. All patients must have previously received taxane-trastuzumab and been pretreated with T-DXd, having either progressed on it or been unable to tolerate it.

vi. For Cohorts D, E, H, I (I-ext), and J (J-ext) at least 7 patients in each zongertinib dose level should have brain metastases at baseline, defined as patients with a history of brain metastases, current brain metastases, or equivocal brain lesions at baseline, using RECIST 1.1 and RANO based on investigator assessment.

History of prior treatment lines in palliative setting – Cohorts L, L-ext, M, and N:
Documented progression or recurrence of disease during or following their latest line of therapy. In the opinion of the Investigator, patients must be unlikely to tolerate or derive clinically meaningful benefit from further standard of care therapy known to prolong survival. HER2-targeted mAB and prior HER2-targeted antibody-drug conjugates (ADCs) are allowed.

6. Recovered from any previous therapy-related toxicity to = CTCAE Grade 1 at start of treatment with the exception of the following, which are permitted if = CTCAE Grade 2 and stable: alopecia, stable sensory neuropathy, and hypothyroidism (on stable thyroid hormone replacement). Stable, irreversible endocrine immune-related adverse events (e.g., adrenal insufficiency, insulin-dependent diabetes mellitus) that are well-controlled with appropriate hormone replacement therapy are permitted.
For Cohort O, recovered from prior therapy-related congestive heart failure to Grade 0.

7. Presence of at least one measurable lesion according to RECIST 1.1, as determined by the local site investigator/radiology assessment.

8. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 [R01-0787].

9. Adequate organ function defined as all the following:

i. Absolute neutrophil count =.5 x 10^9/L (= 1.5 x 10^3/MikroL) (= 1500/mm^3); platelets = 100 x 10^9/L (100 x 10^3/MikroL) (100 x 10^3/mm^3) without the use of hematopoietic growth factors within 3 weeks of start of trial drugs.
Cohorts M and N: Absolute neutrophil count = 2.0 x 10^9/L (= 2.0 x 10^3/MikroL) (= 2000/mm^3) without the use of hematopoietic growth factors within 3 weeks of start of trial drugs;

ii. Hemoglobin = 9.0 g/dL (= 90 g/L) (= 5.6 mmol/L) without the use of hematopoietic growth factors or transfusion within 1 week prior to start of trial drugs. If a transfusion is needed because of bone marrow depletion, a washout period of 3 weeks is required prior to starting the trial drugs.

iii. Total bilirubin = 1.5 times the upper limit of normal (ULN), except for patients with Gilbert’s syndrome: total bilirubin = 3 times ULN or direct bilirubin = 1.5 times ULN.

iv.Estimated glomerular filtration rate =30 mL/min - calculated using Chronic Kidney Disease Epidemiology (CKD-EPI) formula.

v. Aspartate transaminase and alanine transaminase = 2.5 times ULN or = 5.0 times ULN for patients with liver metastases.

vi. Alkaline phosphatase < 5 times ULN

vii. PTT/aPTT < 1.5 times ULN unless on a stable dose of an anticoagulant and no unexplained elevation of INR.

10. Life expectancy of at least 12 weeks at the start of treatment in the opinion of the investigator.

11. Male or female participants. Women of childbearing potential (WOCB)1 and men able to father a child must be ready 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 in combination with a barrier method. A list of contraception methods meeting these criteria and instructions on the duration of their use will be provided in the patient information and in Section 4.2.2.3.

MAIN EXCLUSION CRITERIA:

- Previous treatment with:
- Any small molecule HER2 inhibitor in the palliative setting in Cohorts D, E, F, H, L, L-ext, M, and N. In Cohort D allowed in up to 15 patients in each DL.
- T-DXd in Cohorts E and F. In Cohort E allowed in up to 15 patients in each DL.
- T-DM1 in the palliative setting in Cohort D and H. In Cohort H allowed in up to 15 patients in each DL.
- Capecitabine in Cohort D and H. In Cohort D allowed in up to 15 patients in each DL

- Presence of uncontrolled and/or symptomatic brain metastases, or leptomeningeal disease

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

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

- Ejection fraction < 50% or the lower limit of normal of the institutional standard within 28 days prior to randomization

- History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening


EXCLUSION CRITERIA

1. Previous treatment with:

i. Any small molecule HER2 inhibitors (including, but not limited to, tucatinib, pyrotinib, lapatinib, and neratinib) in the palliative setting in Cohorts D, E, F, H, L, L-ext, M and N. Twelve months must have passed after use in the curative setting. For Cohorts L and L-ext, previous use of any small molecule HER2 inhibitor is not allowed, regardless of palliative or curative setting. Note: In Cohort D, previous treatment with small molecule HER2 inhibitors in the palliative setting and/or treatment with capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil] for metastatic disease for more than 21 days is allowed in up to 15 patients in each dose level.

ii. T-DXd in Cohorts E and F. Note: In Cohort E, previous treatment with T-DXd in the palliative setting is allowed for up to 15 patients in each dose level in Cohort E. For these patients, up to three prior lines of therapy are allowed, including also treatment with small molecule HER2 inhibitors, including, but not limited to, tucatinib, pyrotinib, lapatinib and neratinib, capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil]) and/or T-DM1 in the palliative setting.

iii. T-DM1 in the palliative setting in Cohort D and H (but allowed in Cohort H in up to 15 patients in each dose level, for these patients, up to three prior lines of therapy are allowed)

iv. For Cohort D and H: Have previously been treated with capecitabine (or other fluoropyrimidine [e.g., 5-fluorouracil]) for metastatic disease (except in cases where capecitabine was given for = 21 days and was discontinued for reasons other than disease progression or severe toxicity).
Note: In Cohort D, pretreatment with small molecule HER2 inhibitors in the palliative setting and/or treatment with capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil] for metastatic disease for more than 21 days is allowed in up to 15 patients in each dose level.
Note: Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.

v. For Cohort O: See exclusion criterion 33.

2. Previous or concomitant malignancies other than the one treated in this trial within the previous 2 years, which require current systemic therapy except:

i. effectively treated non-melanoma skin cancers
ii. effectively treated carcinoma in situ of the cervix
iii. effectively treated ductal carcinoma in situ
iv. other effectively treated malignancy that is considered cured by local treatment

3. Uncontrolled and/or symptomatic brain metastases. Patients with known central nervous system (CNS) lesions must not have any of the following:

- Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor and approval for enrolment is given

- Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent).

- However, patients on a chronic stable dose of = 2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical monitor

- Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g. brain stem lesions).

- Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study if treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study if all of the following criteria are met:
- Time since WBRT is =21 days prior to first dose of treatment, time since SRS is = 7 days prior to first dose of treatment, or time since surgical resection is = 28 days
- Other sites of disease assessable by RECIST 1.1 are present

- Known or suspected leptomeningeal disease as documented by the investigator

- Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy

4. Patients who must or wish to continue the intake of restricted medications (see Section 4.2) or any drug considered likely to interfere with the safe conduct of the trial.

5. Radiotherapy within 4 weeks prior to randomization except for palliative radiotherapy for symptomatic metastasis within 2 weeks prior to randomization, but this must be discussed with the sponsor.

6. Not completely recovered from major surgery (major according to the investigator’s assessment) performed prior to randomization or planned within 6 months after screening, e.g. hip replacement.

7. Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the trial or interfere with the evaluation of the safety and efficacy of the test drug.

8. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of = III or IV, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction, stroke, or pulmonary embolism within 6 months prior to randomization.

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

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

11. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, personal or family history of long QT syndrome or unexplained sudden death under 40 years-of-age.

12. Ejection fraction < 50% or the lower limit of normal of the institutional standard within 28 days prior to randomization.

13. Women who are pregnant or nursing or who plan to become pregnant or nurse during the trial or within 9 months after last dose of mFOLFOX6 with or without trastuzumab, within 7 months after the last dose of trial treatment with T-DXd, T-DM1, trastuzumab or capecitabine and trastuzumab, within 4 months after last dose of zanidatamab or within 10 days after last dose of zongertinib monotherapy.

14. Patients with chronic HBV infection with active disease who meet the criteria for anti-HBV therapy (according to local or institutional standard) who have not been treated with suppressive antiviral therapy prior to initiation of study treatment OR patients with a history of HCV infection who meet one or both of the following criteria:
criteria:
i. Currently receiving curative antiviral treatment
ii, HCV viral load is above the limit of quantification (HCV RNA positive)

15. Known history of allergy to the trial drugs or any excipients of the trial drugs.

16. History of severe hypersensitivity reactions and infusion-related reactions to mAbs.

17. 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 other condition that, in the investigator’s opinion, makes the patient an unreliable patient).

18. History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

19. Patients with history of human immunodeficiency virus (HIV) infection who meet one or more of the following criteria:
i. CD4+ count < 350 cells/MikroL
ii. Viral load > 400 copies/mL (local lab assessment)
iii. Not receiving antiretroviral therapy
iv. Receiving established antiretroviral therapy for less than 4 weeks prior to the start of trial treatment
v. History of AIDS-defining opportunistic infections within 12 months prior to start of trial treatment

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

21. Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the trial drug (e.g. nausea, vomiting, Crohn’s disease, ulcerative colitis, chronic diarrhea, malabsorption) in the opinion of the investigator.

22. Previous enrolment in this trial.

23. Previous enrolment in this trial.
Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s) or receiving other investigational treatment(s). Patients may enroll in this trial if they are in follow-up and have completed study treatment for another trial.

24. Have known complete dihydropyrimidine dehydrogenase (DPD) deficiency (only for Cohorts G, H, M, and N)

25. History of severe and unexpected reactions to fluoropyrimidine therapy (only for Cohort G, H, M, and N)

26. Hypersensitivity to capecitabine or to any of the excipients or to fluorouracil or to any of the excipients (only for Cohorts G, H, M, and N).

27. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy (Cohorts G, H, J, K, N, L, J-ext, and L-ext).

28. Need for concomitant treatment with Brivudine and/or treatment with Brivudine within 4 weeks prior to start of study medication for Cohorts G, H, M, and N.

29. Serious infection (e.g. Herpes zoster, chickenpox) (only for Cohorts M and N).

30. Peripheral sensitive neuropathy with functional impairment (only for Cohorts M and N)

31. Pernicious anemia or other anemias due to vitamin B12 deficiency (only for Cohorts M and N)

32. Hypersensitivity reactions to platinum-based drugs (only for Cohorts M and N)

33. Patients who have previously participated in another trial of zanidatamab (only for Cohort O)

34. Patients with prior treatment-related congestive heart failure CTC AE Grade = 2 (only for Cohort O)

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

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

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

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

4 Are = 18 years of age.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Part-specific criteria

Parts A, B, and C

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

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

Part D

20 Have a histologically confirmed diagnosis of PDAC.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

11 Have a history of leptomeningeal carcinomatosis.

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

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

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

15 Have a diagnosis of Gilbert’s syndrome.

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

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

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

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

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

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

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

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

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

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

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

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

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

1. Be 18 years or older.

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

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

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

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

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

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

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

- Refer to Appendix 8 updated information on Arm VI.

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

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

Refer to Appendix 9 for updated information on Arm VII

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

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

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

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

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

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

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

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

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

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

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

1. Neuropathy > grade 2

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

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

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

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

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

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

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

9. Active gastrointestinal tract disease with malabsorption syndrome.

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

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

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

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

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

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

16. Any condition potentially decreasing compliance to study procedures.

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

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

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

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

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

22. Currently breastfeeding

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

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

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

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

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

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

4. Patients with one of the following indications:

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

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

Phase I:

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

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

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

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

Phase II:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Highly effective contraception methods include:

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

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

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

19. Pregnant or nursing (breast feeding) women.

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

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 x10^9/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 anti-metastatic 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 > 2x250 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/MikroL)
- Hemoglobin = 80 g/L (8 g/dL)
- Platelet count = 100 x 10^9/L (100000/MikroL) 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 FIRE-9/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 any of 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.

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.

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

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

3. Life expectancy minimum of = 12 weeks.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

e. Phase 1b adagrasib combination dose expansion in NSCLC

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

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

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

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

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

- Hepatic:

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

- Renal:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cabozantinib combination:

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

Adagrasib combination:

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

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

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

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

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

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

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

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

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

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

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

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

11. Any active infection including but not limited to:

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

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

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

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

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

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

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

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

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

15. Cardiac and vascular criteria:

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

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

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

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

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

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

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

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

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

Um in die KP aufgenommen zu werden, müssen folgende Einschlusskriterien erfüllt sein:

1. Eine vom Patienten und vom Hauptprüfer/Prüfer eigenhändig datierte und vollständig unterschriebene Einwilligungserklärung liegt vor

2. Patienten mit einem Mindestalter von 18 Jahren

3. Patienten mit einem Karnofsky Index = 70 %

4. Patienten mit einer angenommenen Lebenserwartung von mindestens 12 Monaten

5. Patienten mit soliden Tumoren

6. Patienten, bei denen eine unmodifizierte und in Deutschland zugelassene Chemotherapie mit Taxanen oder Platinderivaten oder deren Kombination mit einer geplanten Therapiedauer von mind. 3 Monaten (Lunarmonate/ 12 Wochen) geplant ist

7. Bei Patientinnen im gebärfähigen Alter liegt ein negativer Schwangerschaftstest vor

Um in die KP aufgenommen zu werden, dürfen folgende Ausschlusskriterien nicht zutreffen:

1. Teilnahme an einer interventionellen Studie (mit einem Prüfpräparat), die zeitgleich er folgt oder innerhalb von 4 Wochen vor Einschluss in diese Studie erfolgt ist

2. Schwangere und stillende Patientinnen oder Patientinnen ohne effektive Kontrazeption (Pearl-Index < 1)

3. Patienten, die innerhalb von 4 Wochen vor Einschluss in diese Studie mit topischen und/oder innerlich verabreichten Arzneimitteln oder Kosmetika, die Blauen Eisenhut (Aconitum napellus), Kampfer (Camphora), ätherisches Lavendelöl (Lavandulae aetheroleum) und/oder Quarz enthalten, behandelt wurden

4. Patienten mit einer bekannten Überempfindlichkeit gegen Kampfer und/oder einen der anderen Inhaltsstoffe von Aconit Schmerzöl sowie Erdnuss oder Soja

5. Patienten, bei denen davon auszugehen ist, dass sie aus sprachlichen, kognitiven bzw. anderen Gründen nicht in der Lage sind, die Bedeutung der klinischen Studie zu erfassen, die dafür notwendige Compliance aufzubringen und/oder die deutschsprachigen Patientenfragebogen und das Patiententagebuch auszufüllen

6. Patienten mit einer geplanten Applikation der Chemotherapie in =4-wöchigen Abständen

7. Patienten mit einer Alkohol-/Drogen-/Medikamentenabhängigkeit

8. Patienten mit bekannten genetischen Dispositionen für Polyneuropathien

9. Patienten mit vorangegangener oder bestehender Polyneuropathie unabhängig von der Ursache

10. Patienten mit vorangegangener oder aktueller neurotoxischer Medikation außerhalb des geplanten Chemotherapie-Protokolls, die einen Einfluss auf den primären Endpunkt hat (nach Ermessen des Prüfers) und vorangegangener Taxan- und/oder Platinderivat-Gabe

11. Patienten mit folgenden bekannten Begleiterkrankungen, die eine Prädisposition für eine CIPN haben: unzureichend substituierte Hypothyreose, Niereninsuffizienz ab Grad 4, Vaskulitis/Kollagenose, unzureichend behandelter Diabetes mellitus

12. Patienten mit aktuell bestehenden und/oder klinisch relevanten Infektionskrankheiten:
HIV, Borreliose, Hepatitis B/C, Herpes-Infektionen

13. Bekanntes Vorliegen eines multiplen Myeloms oder Non-Hodgkin-Lymphoms

14. Bestehende neurologische Erkrankungen Morbus Alzheimer, Multiple Sklerose, Morbus Parkinson und sonstige neurologische Erkrankungen, die nach Ermessen des Prüfarztes eine Beurteilung des primären Endpunkts erschweren oder unmöglich machen

15. Patienten mit Metastasen im zentralen Nervensystem

16. Vorangegangene Amputation von Extremitäten

17. Patienten mit distaler Muskelschwäche und/oder Atrophie

18. Hautläsionen oder andere Befunde im Bereich der Extremitäten, die eine Anwendung des Prüfpräparats unmöglich machen (z. B. Hand-Fuß-Syndrom)

19. Vorliegen einer anderen schwerwiegenden akuten oder chronischen organischen oder psychischen Erkrankung mit starker Beeinträchtigung des Allgemeinbefindens, die eine regelmäßige Studienteilnahme beeinträchtigt oder ausschließt

20. Einnahme von Co-Analgetika wie Gabapentin, Pregabalin, Amitriptylin, Nortriptylin, Clomipramin, Imipramin, Duloxetin 1 Woche vor Studienbeginn (Baseline) und Einnahme während der Studie vor Erreichen von CIPN Grad III

21. Geplante Akupunktur zur Behandlung einer CIPN während der Studie

22. Topische Anwendung von Substanzen wie Lidocain, Capsaicin, Botulinumtoxin, Amitriptylin, Menthol an Händen und/oder Füßen bis 1 Woche vor Studienbeginn (Baseline) und Anwendung während der Studie

23. Elektrotherapie an den Extremitäten bis 1 Woche vor Studienbeginn (Baseline) und während der Studie

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 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, and if indicated, VEGF(R), 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. 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)
d. AST (SGOT) and ALT (SGPT) = 2.5 x ULN, AP = 5 x ULN
e. 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).
f. 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 childbearing 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 are no data that indicate special gender distribution. Therefore, patients will be enrolled in the trial gender-independently.

1. Patient has known 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. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study 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

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

Signed Written Informed Consent

1) Participants must have signed and dated an IRB/IEC-approved written ICF in accordance with regulatory, local, and institutional guidelines. The study-specific ICF and any optional ICFs (if
applicable) must be obtained before performing any protocol-related procedures that are not part of normal patient care.

Note: Participants must agree to comply with the requirements and restrictions listed in the IC and in this protocol.

Type of Participant and Target Disease Characteristics

2) Previously untreated, histologically confirmed recurrent or metastatic colorectal adenocarcinoma, not amenable to curative surgery.

Note: If participant has received adjuvant or neoadjuvant chemotherapy, there must be more than a 6-month gap (> 6 months) between the completion of that therapy and diagnosis of recurrent or metastatic disease.

3) Noknownpresence of dMMR or MSI-H CRC per historical results (a validated test should be used).

4) No known presence of BRAF V600E mutation. Tumor BRAF mutation status must have been documented based on available historical local testing results prior to randomization.

5) KRASand NRAS mutation status must have been documented based on available historical or local testing results prior to randomization in Phase 2.

6) Measurable disease as defined by RECIST v1.1 (see APPENDIX 6).

Note: Lesions that have been treated with external beam radiotherapy or loco-regional therapies such as radiofrequency ablation must show evidence of disease progression based on RECIST v1.1 to be deemed a target lesion.

7) Tumortissue requirements:
Fresh (strongly preferred) or archived tumor tissue samples are acceptable. Tumor biopsy having significant risk to the safety and/or well-being of the participant should not be performed. If a recent biopsy is not available, archival tissue blocks obtained within 3 years prior to the date of enrollment are acceptable for patients without intervening anti-cancer therapy, including radiotherapy, between tissue sampling and study enrollment. FFPE block specimens are preferred over slides. FFPE tissue blocks must contain sufficient tissue to support the minimum number of slides. If blocks cannot be provided, freshly cut sections (= 4 months old) must be submitted. A minimum of 15 unstained slides are required and must be cut sequentially from the same block; submission of 20 unstained slides is strongly recommended to enable important exploratory biomarker work. If despite best efforts, a minimum of 15 slides is not obtainable, submission of fewer slides may be acceptable upon discussion with the Medical Monitor (or designee). Tissue must be submitted prior to randomization. In exceptional cases, tissue can be submitted after randomization upon discussion with the Medical Monitor (or designee).

Core needle biopsy, punch biopsy, excisional biopsy, or surgical specimens are acceptable.

Note: Fine needle aspirates, pleural effusion drainage, other cytology samples, and biopsies of bone lesions are not acceptable.

For country-specific requirements, see APPENDIX 7.

8) ECOG Performance Status of 0- 1. See APPENDIX 5 for ECOG Performance Status scale.

Age of Participant

9) Aged = 18 years at the time of signing the ICF. For country-specific requirements, see APPENDIX 7.

Reproductive Status

Note: The investigator or designee shall counsel IOCBP participants (as defined in APPENDIX 3) and male (as assigned at birth) participants who are sexually active with IOCBP on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention present in seminal fluid to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.

Note: The investigator or designee shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.

Note: Local laws and regulations may require the use of alternative and/or additional contraceptive methods.

Note: Study participants receiving study intervention have the potential risk of infertility, either temporary or permanent. The investigator or designee shall counsel participants on further information about locally available fertility preservation options including cryopreservation of gametes, prior to treatment as clinically appropriate.

10) Female (as assigned at birth) participants:

Note: Female (as assigned at birth) participants who are not of childbearing potential (as defined in APPENDIX 3) must have documented proof of reproductive status.

Note: Documentation can be obtained from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview.

Note: Individuals who are not of childbearing potential are exempt from contraceptive requirements.

a) IOCBP must have a negative highly sensitive urine or serum, as required by local regulations, pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 (up to 72) hours prior to the start of study intervention.

Note: If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

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

b) IOCBP and male (as assigned at birth) participants who are sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.
i) IOCBP are permitted to use hormonal contraceptive methods (as described in APPENDIX 3).

c) A female (as assigned at birth) is eligible to participate if they are not pregnant or breastfeeding and at least 1 of the following conditions applies:
i) Is not an IOCBP
OR
ii) Is an IOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with user independent methods, as described in APPENDIX 3, during the intervention period and for at least 9 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period. For country-specific requirements, see APPENDIX 7.

11) Male (as assigned at birth) participants:

Note: A male (as assigned at birth) who is sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.

Note: Azoospermic males are not exempt from contraceptive requirements and will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant.

a) Male (as assigned at birth) participants are required to use a condom during the intervention period and for at least 6 months after the last dose of study intervention. For country specific requirements, see APPENDIX 7.

b) IOCBP partners of male (as assigned at birth) participants should be advised to use a highly effective method of contraception during the study intervention period and for at least 6 months after the last dose of study intervention for the male participant. Male (as assigned at birth) participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral) during the intervention period and for at least 6 months after the last dose of study intervention. For country-specific requirements, see APPENDIX 7.

c) Male (as assigned at birth) participants must refrain from donating sperm during the intervention period and for at least 6 months after the last dose of study intervention.

d) Breastfeeding partners of male (as assigned at birth) participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms.

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

Medical Conditions

1) Untreated known CNS metastases including brain, leptomeningeal and/or spinal cord compression

Note: Participants are eligible if CNS metastases are adequately treated, and participants are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization, and have been treated andare clinically stable or have returned to baseline (except residual effects from treatment).

Note: Participants must have either discontinued corticosteroids or be on a stable or decreasing dose of = 10 mg prednisone (or equivalent) daily for at least 2 weeks prior to randomization.

Note: Baseline imaging required at screening must be performed 28 days after definitive treatment for CNS metastases is completed. CNS metastases must be radiographically stable.

2) Active, known, or suspected autoimmune disease. Participants with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For country-specific requirements, see APPENDIX 7.

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

4) Prior malignancy active within the previous 2 years, except for locally curable cancers that have been apparently cured (ie, basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast) and considered to be of low risk of recurrence

5) Significant cardiovascular disease such as myocardial infarction, unstable angina, arterial thrombosis or cerebrovascular accident within 6 months prior to randomization, or uncontrolled hypertension (= 160 systolic and/or = 100 diastolic mmHg) despite optimal medical management. Congenital long QT syndrome or QTc prolongation > 480 msec (the ECG can be repeated at the discretion of the investigator prior to randomization to confirm eligibility).

6) Major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study intervention

7) Serious or non-healing wound, or (incompletely healed) bone fracture

8) Evidence of major coagulation disorders (eg, hemophilia)

9) Clinically significant hematemesis or clinically significant GI hemorrhage within 28 days of randomization

10) Tumor lesions invading large vessels with significant risk of bleeding by investigator’s assessment

11) History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism within 3 months prior to enrollment, unless patient has been fully treated (eg, inferior vena cava filter placed) and/or adequately anticoagulated on stable dose of anticoagulants

Note: Participants receiving anticoagulation therapy at a stable dose may be eligible if their PT and aPTT values are stable and within the intended therapeutic range, and if hemorrhagic risk is assessed as low per investigator’s clinical judgment.

12) History of abdominal fistula or gastrointestinal perforation within 6 months prior to enrollment

13) Persistence of toxicities related to prior neo/adjuvant chemotherapy grade > 1 (CTCAE v5.0) (except alopecia, fatigue, Grade 2 peripheral neuropathy may be permitted for patients enrolling in the FOLFIRI-containing arm)

14) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results

15) Any other medical, psychiatric and/or social reason as determined by the investigator

16) Known DPD deficiency

Note: Systematic screening for DPD deficiency testing must be conducted where locally mandated. For country-specific requirements, see APPENDIX 7.

17) Known UGTIAI deficiency, if participant is planned to receive FOLFIRI

Note: UGT1A1 testing should be conducted in accordance with local guidelines if a participant is planned to receive FOLFIRI

Prior/Concomitant Therapy

18) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7: Prior and Concomitant Therapy

19) Prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, CD137 agonists, or anti CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways or chemotherapy

20) Received cancer-related IPs and/or biologic therapy within 28 days or 5 half-lives, whichever is longer, prior to randomization

21) Prior focal palliative radiotherapy must have been completed at least 14 days prior to randomization

22) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese
medicines) with an anti-tumor indication intended to treat the disease under study within 2
weeks prior to randomization

23) Participants who have received a live/attenuated vaccine within 30 days of first treatment

24) Current treatment with non-topical medications known to be strong inducers or inhibitors of CYP3A4, or strong inhibitors of UGT1A1 (if planned chemotherapy includes irinotecan).
Participants who discontinue strong CYP3A4 inducers or switch to another medication at least 14 days or 5 half-lives, whichever is longer, prior to starting study treatment are eligible.
Participants receiving strong CYP3A4 inhibitors to be eligible should discontinue strong CYP3A4 inhibitors or switch to another medication at least 1 week prior to starting study treatment.

25) Current or recent (within 10 days prior to first dose of study treatment) ongoing treatment with therapeutic-dose anticoagulants

Note: Prophylactic anticoagulation (eg, for DVT prophylaxis) is permitted if medically indicated and approved by the investigator.

Note: Participants receiving anticoagulation therapy at a stable dose may be eligible if their PT and aPTT values are stable and within the intended therapeutic range, and if hemorrhagic risk is assessed as low per investigator’s clinical judgement.

Reproductive Status

26) Participant is an IOCBP who is pregnant or breastfeeding, or who intends to become pregnant during participation in the study. For country-specific requirements, see APPENDIX 7.

Physical and Laboratory Test Finding

27) Inadequate organ function; screening laboratory values must meet the following criteria:
a) Neutrophils < 1500/MikroL; participants must not have received treatment with G-CSF agents or GM-CSF agents within 28 days prior to randomization
b) Platelets < 100 x 10^3/MikroL
c) Hemoglobin < 9.0 g/dL
d) Serum albumin < 3.0 g/dL
e) Creatinine clearance < 40 mL/min (measured or calculated using the Cockcroft-Gault formula)
f) AST or ALT > 3.0 x ULN (or > 5.0 x ULN if liver metastases are present)
g) Total bilirubin > 1.5 x ULN (except participants with the history of Gilbert Syndrome who must have a total bilirubin level of = 3.0 x ULN)
h) INR or PT/aPTT > 1.5 x ULN
i) Proteinuria = 2+ by urine dipstick or urinalysis at baseline

Note: For participants with proteinuria = 2+ by urine dipstick or urinalysis at baseline, 24 hour urine must be collected. Proteinuria > 1 g/24 hours is exclusionary. It is acceptable to estimate UPCR instead of 24-hour urine collection. UPCR > 1000 mg/g is exclusionary.

28) Active viral hepatitis, defined as follows:

a) Any positive test result for HBV indicating presence of virus (eg, HBsAg or HBV DNA positive) would be excluded.

Note: Participants with anti-hepatitis B antibodies attributed to prior vaccination or resolved infection are eligible to enroll.

Note: See APPENDIX 7 for country-specific requirements.

b) Any positive test for 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.

29) Known HIV infection or known AIDS, with the following exceptions:
a) Participants with CD4+ T cell counts = 350 cells/mL, per local laboratory, should generally be eligible for the trial
b) Participants who have not had an opportunistic infection within the past 12 months are eligible

Note: Eligible participants should have adequate virological control and be on ART for at least 4 weeks prior to first dose and continue on ART therapy (as clinically indicated) while enrolled on-study.

Note: HIV testing must be conducted where locally mandated. HIV-positive participants must be excluded where mandated locally.

Allergies and Adverse Drug Reactions

30) Any contraindications to any of the study drugs or of the chemotherapy regimen. Investigators should refer to local package insert of the chemotherapy drugs and bevacizumab.

31) History of allergy or hypersensitivity to study drug components

Other Exclusion Criteria

32) Prisoners or participants who are involuntarily incarcerated

Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned while on study may be permitted to continue as a participant. Strict conditions apply, and Sponsor approval is required.

1. Subjects with histologically confirmed primary (non-recurrent) LARC (tumor =12 cm from the anal verge, as assessed by rigid proctoscopy), stage II (T3-4 N0 M0) or stage III (TX N1-2 M0) according to base-line pelvic MRI and PET-CT or CT of the chest abdomen and pelvis.

2. Patients who are planned for TNT and are surgical candidates as determined by the treating physician.

3. No prior chemotherapy, immunotherapy, radiotherapy or surgery for rectal cancer.

4. No prior radiotherapy to the pelvis, for any reason.

5. Able to provide the FFPE block or 10 unstained slides from the colonoscopy for confirmation of the diagnosis, CPS status and for investigational purposes.

6. Age = 18 years.

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2.

8. Screening laboratory values must meet the following criteria (using CTCAEv5.0):
a. WBC = 2000/MikroL
b. Neutrophils = 1500/MikroL
c. Platelets > 100 x 10^3/MikroL
d. Hemoglobin > 9.0 g/dL
e. Serum creatinine < 1.5 x ULN and actual or calculated (using the Cockcroft Gault formula) creatinine clearance > 60 mL/min
f. AST and ALT < 2.5 x ULN.
g. Total bilirubin < 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome).

9. Ability to swallow tablets.

10. Adequate contraception in fertile patients; using a highly effective method of birth control for the duration of the study, and for at least 9 months after the last dose of chemotherapy and 120 days after the last dose of immunotherapy.

11. Women of childbearing potential must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to the start of treatment.

12. Women must not be breastfeeding.

13. Signed written IRB approved informed consent. This must be obtained before the performance of any protocol related procedure that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatments, and laboratory testing.

1. Active or background history of an autoimmune disease except for type I diabetes mellitus, hypothyroidism requiring hormone replacement only and skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment.

2. Any evidence of interstitial lung disease or active, noninfectious pneumonitis

3. Medical history of vasculitis.

4. Prior organ transplant, including allogenic bone marrow transplantation.

5. Current or prior use of immunosuppressive medication within 14 days before the first dose of study treatment.

6. Grade > 1 peripheral sensory neuropathy.

7. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways.

8. Patients with mismatch repair deficient (MMRd) / microsatellite instability-high (MSI-H) tumors.

9. Any prior active malignancy = 2 years before trial entry except for any locally recurring cancer that has been treated curatively (e.g. resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).

10. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy.

11. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

12. Known acute hepatitis B, known chronic hepatitis B infection with active untreated disease, or known active hepatitis C infection. In participants with a history of HBV or HCV, participants with detectable viral loads will be excluded.