Once randomisation has been completed, the study treatment should be started preferably immediately; at the latest within one week following randomisation. The patients will be randomised in a ratio of 1:2 to the following two treatment arms. Patients in both treatment arms will receive standard chemotherapy with FOLFOXIRI as background treatment, which can be de-escalated to FOLFIRI in case of toxicity. Standard arm A: The patient will be treated with FOLFOXIRI plus bevacizumab for up to 12 cycles (24 weeks) or until progression (if the latter occurs before completing the 12 cycles). Within the 12 cycles, the FOLFOXIRI plus bevacizumab regimen may be de-escalated, owing to toxicity, to FOLFIRI and bevacizumab at the treating physician's discretion. After 12 cycles of the study treatment, a switch to a maintenance regimen with a fluoropyrimidine (5-FU infusion or capecitabine) plus bevacizumab, administered until progression occurs, is recommended. The recommended maintenance phase of the study is not part of the study treatment. However, maintenance therapy will be counted as first-line therapy. Experimental arm B: The patient will be treated with FOLFOXIRI plus weekly administration of cetuximab for up to 12 cycles (24 weeks) or until progression (if the latter occurs before completing the 12 cycles). Within the 12 cycles, the FOLFOXIRI plus cetuximab regimen may be de-escalated owing to toxicity, to FOLFIRI and cetuximab at the treating physician's discretion. After 12 cycles, a switch to a maintenance regimen with 5-FU and cetuximab or with irinotecan and cetuximab, administered until progression occurs, is recommended. The recommended maintenance phase of the study is not part of the study treatment. However, maintenance therapy will be counted as first-line therapy.
Name: Bevacizumab
Name: Irinotecan
Name: Folinic acid
Name: Oxaliplatin
Name: 5-FU
Name: Cetuximab
Description: (overall response rate) measured in percentage of all treated patients according to RECIST 1.1 criteria
Measure: Overall Response Rate (ORR) Time: up to 48 monthsDescription: Investigation of progression-free survival (PFS) from randomisation
Measure: Progression Free Survival (PFS) Time: up to 60 monthsDescription: Investigation of overall survival (OS) from randomisation
Measure: Overall Survival (OS) Time: up to 60 monthsDescription: Investigation of early tumour shrinkage (ETS)
Measure: Investigation of Early Tumour Shrinkage (ETS) as early-on-Treatment predictor for treatment Time: up to 48 monthsDescription: Investigation of depth of response (DpR)
Measure: Investigation of Depth of Response (DpR) to define nadir for tumour response. Time: up to 48 monthsDescription: Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance of an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples)
Measure: Investigation of Molecular Biomarkers for Prediction of an Anti-EGFR Treatment Time: up to 48 monthsDescription: Investigation of prospective analysis of tumour marker level evolution (CEA and CA 19-9)
Measure: Prospective Analysis of Tumour Marker Level Evolution (CEA and CA 19-9) Time: up to 48 monthsDescription: Recording of the safety and tolerability (NCI-CTCAE version 4.03 criteria) of the treatment
Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] Time: up to 48 monthsAllocation: Randomized
Parallel Assignment
There is one SNP
Inclusion Criteria: - Histologically confirmed UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer [mCRC]); metastases primarily non-resectable or surgery refused by the patient - RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis) - BRAF-mutant (V600E) tumour (proven in the primary tumour or metastasis) - Age ≥18 years - 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 lesion according to the RECIST 1.1 - criteria (chest X-ray in two planes or chest CT and abdominal CT 4 weeks or less before randomisation) - Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of the tumour material. --- V600E ---
- Absent or restricted legal capacity Inclusion Criteria: - Histologically confirmed UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer [mCRC]); metastases primarily non-resectable or surgery refused by the patient - RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis) - BRAF-mutant (V600E) tumour (proven in the primary tumour or metastasis) - Age ≥18 years - 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 lesion according to the RECIST 1.1 - criteria (chest X-ray in two planes or chest CT and abdominal CT 4 weeks or less before randomisation) - Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of the tumour material. --- V600E ---