Metastatic Colorectal Cancer (RAS-wildtype) After Response to First-line Treatment With FOLFIR Plus Cetuximab

Prior treatment

• Primarily resectable metastases and the patient wishes for resection
• Myocardial infarction, unstable angina pectoris, balloon angioplasty (PTCA) with or without stenting within the past 12 months before inclusion in the study
• Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study (exclusion criterion solely for part 1)
• Participation in a clinical study or experimental drug treatment within 30 days prior to inclusion or during participation in the study
• Arterial thromboemboli or severe haemorrhage within 6 months prior to inclusion in the study (with the exception of tumour bleeding before tumour resection surgery)
• A significant concomitant disease which, in the investigating physician's opinion, rules out the patient's participation in the study

Other illness

• Grade III or IV heart failure (NYHA classification)
• Additional cancer treatment (chemotherapy, radiation, immune therapy or hormone treatment) during the study treatment in first-line and third-line treatment (treatments that are conducted as part of an anthroposophic or homeopathic treatment approach, e.g. mistletoe therapy do not represent an exclusion criterion)
• Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, cetuximab, oxaliplatin, irinotecan, bevacizumab and chemically related substances
• History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea
• Uncontrolled hypertension
• Marked proteinuria (nephrotic syndrome)
• Haemorrhagic diathesis or tendency towards thrombosis
• Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required)
• History of a second malignancy during the past 5 years before inclusion in the study or during participation in the study, with the exception of a dermal basal cell or squamous cell carcinoma or cervical carcinoma in situ, if these were treated curatively.
• Known history of alcohol or drug abuse

Other

• Proof of a RAS mutation (KRAS or NRAS, exons 2-4 in the tumour (proven in the primary tumour or metastasis) or absence of testing for RAS mutation
• Pregnancy (exclusion to be ascertained by a beta hCG test) or breast feeding
• Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
• Known or clinically suspected brain metastases
• Symptomatic peritoneal carcinosis
• Severe, non-healing wounds, ulcers or bone fractures
• Known DPD deficiency (specific screening not required)
• Absent or restricted legal capacity

• Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum (metastatic colorectal cancer), primarily nonresectable or with surgery refused by the patient
• RAS wild-type tumour status (KRAS and NRAS exon 2-4) (proven in the primary tumour or metastasis) at any timepoint of randomisation
• Age ≥18
• ECOG performance status 0-1
• Patients suitable for chemotherapy administration
• Patient's written declaration of consent obtained
• Estimated life expectancy \> 3 months
• Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria (chest and abdominal CT 4 weeks or less before randomisation)
• Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of blood, plasma and tumour material (patients included directly at Part 2 of the study in whom primary tumour material is no longer available may be included in the study, provided that tumour material from the compulsory biopsy on progression following second-line treatment is available).
• Effective contraceptive measures in men and in women of childbearing age (Pearl index \<1)
• Adequate haematopoietic function:
  • Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
  • Thrombocytes ≥ 100 x 109/L,
  • Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)
• Adequate hepatic function:
  • Serum bilirubin ≤ 1.5 x upper normal limit,
  • ALAT and ASAT ≤ 2.5 x upper normal limit (in the presence of hepatic metastases, ALAT and ASAT ≤ 5 x upper normal limit)
• INR \< 1.5 and aPTT \< 1.5 x upper normal limit (patients without anticoagulation). Therapeutic anticoagulation is allowed if INR and aPTT have remained stable within the therapeutic range for at least 2 weeks.
• Adequate renal function:
  • Serum creatinine ≤ 1.5 x upper normal limit or creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50ml/min.
• adequate cardiac function: ECG and echocardiogram with a LVEF of ≥55%
• Any significant toxicities of previous treatments must have resolved or stabilised
• Last administration of an anti-EGFR substance ≥ 4 months before randomisation 2
  • Inclusion criterion solely for Part 1:
• No previous chemotherapy for metastatic disease
• Time since last administration of a previous adjuvant chemotherapy \>6 months
  • Additional inclusion criteria solely for Part 2:
• Former first-line treatment of the metastatic colorectal cancer with FOLFIRI and cetuximab; data available for the duration of treatment and the response within the context of first-line treatment
• Former second-line treatment of the colorectal cancer without FOLFIRI, irinotecan or an anti-EGFR substance with data available for the substances administered, duration of treatment and response within the context of the second-line treatment
• Proof of a RAS wild-type tumour (KRAS and NRAS exons 2-4) in a tumour biopsy (metastasis) within 4 weeks before randomisation
• CT examinations with evidence of a partial response (PR) or complete response (CR) or stable disease (SD) ≥6 months according to RECIST Version 1.1 criteria as best response within the context of the first-line treatment with FOLFIRI and cetuximab