- The association of FOLFOX (5-fluoruracil, folinic acid, and oxaliplatin) and pan is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients. - The phase III TRIBE trial recently demonstrated that FOLFOXIRI (5-fluoruracil, folinic acid, oxaliplatin and irinotecan) plus bev significantly prolongs PFS and OS and increases RECIST response rate, ETS and DoR, as compared to FOLFIRI (5-fluoruracil folinic acid, and irinotecan) plus bev. The advantage provided by the intensification of the upfront chemotherapy backbone is independent of RAS and BRAF mutational status. - Some phase II trials recently assessed the safety and activity of the combination of three-drugs chemotherapy regimens with an anti-EGFR monoclonal antibody. Promising activity results in terms of RECIST response rate and R0 resection rate have been achieved, with some safety concerns with special regards to gastrointestinal toxicity. - In the phase II randomized MACBETH study the combination of a modified schedule of FOLFOXIRI with cetuximab determined remarkable activity results, with an acceptable and manageable safety profile. - The optimal duration of the upfront treatment with chemotherapy plus anti-EGFRs is not established. The phase II MACRO-2 trial suggested that interrupting FOLFOX after 4 months while continuing cet alone as maintenance, is a reasonable option. - Activity parameters (RECIST response rate, ETS, DoR) are clinically relevant endpoints, associated with longer survival, in particular with anti-EGFR moAb-based treatment. On the basis of these considerations, we designed the present phase III randomized trial of first-line mFOLFOXIRI plus pan versus mFOLFOX6 plus pan in RAS and BRAF wt unresectable mCRC patients.
Name: Panitumumab
Name: Irinotecan
Name: Oxaliplatin
Name: l-leucovorin
Name: 5-fluorouracil
Description: the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria
Measure: Overall response rate Time: 12 monthsDescription: the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 4.0)
Measure: Overall Toxicity Rate Time: 24 monthsDescription: the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 4.0)
Measure: Toxicity Rate Time: 24 monthsDescription: the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first. Documentation of disease progressive disease is defined as per RECIST 1.1 criteria based on investigator assessment
Measure: Progression Free Survival Time: 24 monthsDescription: the time from randomization to the date of death due to any cause
Measure: Overall Survival Time: 48 monthsDescription: the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria based on central re-evaluation of CT scan images.
Measure: Centrally assessed Overall response rate Time: 12 monthsDescription: the percentage of patients, relative to the total of the enrolled subjects, achieving a ≥20% decrease in the sum of diameters of RECIST target lesions at week 8 compared to baseline.
Measure: Early Tumour Shrinkage Rate Time: up to 2 months from randomizationDescription: the relative change in the sum of longest diameters of RECIST target lesions at the nadir, in the absence of new lesions or progression of non-target lesions, when compared with baseline.
Measure: Deepness of Response Time: 12 monthsDescription: the percentage of patients, relative to the total of enrolled subjects, undergoing secondary R0 resection of metastases
Measure: R0 Resection Rate Time: 12 monthsAllocation: Randomized
Parallel Assignment
There is one SNP
- RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of primary colorectal cancer or related metastasis (local or central laboratory assessment). --- V600E ---