Post-resection/Ablation Chemotherapy in Patients With Metastatic Colorectal Cancer (FIRE-9 - PORT / AIO-KRK-0418)

Inclusion Criteria:

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 randomisationallowed if at least 3 weeks interval between intervention and treatment start isguaranteed) AND resected primary tumor (synchronous or metachronous). In cases ofsynchronous metastases the interval of 3-10 weeks might be calculated following theremoval of the primary tumor if this intervention was the last to address all tumorlesions.

5. Absence of significant active wound healing complications (if applicable) atrandomization. Resolved wound healing complications after resection/ablation areacceptable for inclusion into the trial.

6. No radiographic evidence of active metastatic disease at study entry in a CT and/orMRI scan not older than 10 weeks prior randomization. Pre-surgery/ablation imagesare 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 followinglaboratory test results:

• Absolute neutrophil count >= 1.5 x 109/L (1500/µL)

• Hemoglobin ≥ 80 g/L (8 g/dL)

• Platelet count ≥ 100 x109/L (100000/µL) without transfusion

• Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN)

• Aspartate aminotransferase (AST/GOT) ≤ 3.0 × ULN.

• Calculated glomerular filtration rate (GFR) according to Cockcroft-Gaultformula 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 intothe trial.

10. Proficient fluorouracil metabolism as defined:

11. Prior treatment with 5-FU or capecitabine without unusual toxicity or

12. If tested, normal DPD deficiency test according to the standard of the studysite or

13. 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%

14. For women of childbearing potential (WOCBP): negative pregnancy test within 14 daysbefore randomization and agreement to remain abstinent (refrain from heterosexualintercourse) or use contraceptive methods with a failure rate of < 1% per yearduring the treatment period and for at least 9 months after the last dose ofOxaliplatin or for at least 6 months after the last dose of all other studytreatment.

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.

Exclusion Criteria:

1. Treatment of metastases greater than 3 cm with radio-frequency/microwave ablationwithin 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, ifprevious oxaliplatin-containing chemotherapy at any time for metastatic or localizeddisease was carried out, the inclusion into the trial is permitted under thecondition, that

4. A total duration of oxaliplatin-based therapy of six months (i.e. 12 cycles ofFOLFOX / FOLFOXIRI or 8 cycles CAPOX) is not exceeded - including therapywithin the FIRE-9/PORT trial

5. If already more than three months of oxaliplatin-based therapy (i.e. >6 cyclesof FOLFOX / FOLFOXIRI or >4 cycles CAPOX) was used, the study therapy should bestarted with an irinotecan-based regimen (i.e. FOLFIRI or FOLFOXIRI) However,in the case of FOLFOXIRI therapy in the trial, the above mention regulationconcerning the total dosing of oxaliplatin still applies (i.e. 12 cycles ofFOLFOX / FOLFOXIRI or 8 cycles CAPOX should not be exceeded - including therapywithin the FIRE-9/PORT trial).

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

7. Myocardial infarction within 6 months prior to randomization; percutaneoustransluminal coronary angioplasty (PTCA) with or without stenting within 6 monthsprior to randomization.

8. Unstable angina pectoris.

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

10. Ongoing toxicities > grade 2 NCI CTCAE

11. Active uncontrolled infection by investigator's perspective.

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

13. Known hypersensitivity to 5-FU, folinic acid, irinotecan, oxaliplatin orcapecitabine or to any of the other excipients listed in section 6.1 of thecorresponding SmPC.

14. Recent or concomitant treatment with brivudine.

15. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAEversion 5.0 (see appendix 2)).

16. Inflammatory bowel disease and/or bowel obstruction.

17. Simultaneous application of Johannis herbs preparations.

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

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

20. Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications.

21. Medical history of malignant disease other than mCRC with the following exceptions:

• patients who have been disease-free for at least three years beforerandomization

• patients with adequately treated and completely resected basal cell or squamouscell skin cancer, in situ cervical, breast or prostate cancer, stage I uterinecancer

• patients with any treated or untreated malignant disease that is associatedwith 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 daysprior to potential inclusion in the clinical trial or within a period of 5half-lives of the substances administered in a clinical trial or during anexperimental drug treatment prior to potential inclusion in the clinical trial,depending on which period is longest, or simultaneous participation in anotherclinical 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 tolocal policy in respective center with respect to actual status of pandemic and withreference to the policy that would apply to patients with similar therapy outsidethe trial). This may include assessment of vaccination status, anamnesis, physicalexamination and potentially antigen and/or PCR testing.

25. Patient committed to an institution by virtue of an order issued either by thejudicial 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 withOxaliplatin and/or Irinotecan, and until 6 months after treatment with Irinotecan.