This study is a prospective, randomized phase III, to evaluate if in patients with mCRC RAS/BRAF wild type on tumor tissue and RAS mutations on liquid biopsy, treating in first line with antibody anti-VEGF (bevacizumab) plus chemotherapy (FOLFIRI) is superior in terms of PFS compared to standard treatment with antibody anti-EGFR (cetuximab) plus FOLFIRI, and then in patients RAS/BRAF wild type on tumor tissue who develop RAS mutations on liquid biopsy after the beginning of the first line treatment with cetuximab plus FOLFIRI, in the absence of a clinical or radiological progression disease, to anticipate a change of treatment with bevacizumab plus FOLFIRI further impacts on the PFS.
Provision of written informed consent;
Male or female > 18 years of age;
Histologically confirmed diagnosis of colorectal adenocarcinoma RAS/BRAF wild type (analysed either on primary and/or related metastasis);
Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease;
Previous chemotherapy treatment, with the exception of patient treated in adjuvant setting completed at least 6 months before the randomization;
Any contraindication to the use of Cetuximab, Bevacizumab, Irinotecan, 5FU or folinic acid;
Radiotherapy to any site within 4 weeks before the randomization;
Serious, non-healing wound, ulcer, or bone fracture;
Parallel
Bevacizumab
DrugThis is the treatment assigned to experimental arm: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.
Cetuximab
DrugThis is the treatment assigned to control arm: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.
5-FU
DrugFOLFIRI regimen: This is the treatment assigned to control and to experimental arms: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.
Irinotecan
DrugFOLFIRI regimen: This is the treatment assigned to control and to experimental arms: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.
Calcium levofolinate
DrugFOLFIRI regimen: This is the treatment assigned to control and to experimental arms: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.
Progression free survival (PFS) in patients with RASmut at liquid biopsy and RASwt on tissue.
The primary objective of the study is to assess whether the combination of bevacizumab plus chemotherapy is superior to cetuximab plus chemotherapy in terms of progression free survival (PFS) in patients with RASmut at liquid biopsy and RASwt on tissue.
Overall survival (OS)
Overall survival (OS) defined as the time from start of treatment to the date of death for any cause or, for living patients, the date of last contact.
Objective response rate (ORR)
Objective Response Rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR) as best response during treatment as determined by RECIST 1.1.
Prevalence of RAS mutation
Percentage of RAS mut patients on the total of patients who undergone to liquid biopsy at the first and second evaluations.
Patients Safety
The maximum toxicity grade experienced by each patient, for each toxicity, according to NCI-CTCAE v. 5.0; the number of patients experiencing grade 3-4 toxicity for each toxicity; type, frequency and nature of SAEs; patients with at least a SAE; patients with at least a SADR; patients with at least a SUSAR.
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Azienda USL Reggio Emilia - IRCCS
Lead sponsor
Istituto Di Ricerche Farmacologiche Mario Negri
Collaborator
Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
Collaborator
