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.
In this prospective, randomized phase III study, first of all we aim 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. Patients RAS mut at first liquid biopsy will be randomized with a 1:1 ratio, to receive FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. Patients with RAS wt at first biopsy will be treated with FOLFIRI plus cetuximab up to 8 cycles outside the protocol. Patients not progressed after 4 months (8 cycles of treatment) will undergo to a second liquid biopsy. In case of mutation of RAS, the patients will be randomized with a 1:1 ratio to continue cetuximab or to switch to bevacizumab. The treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, other conditions compromise subject safety or patient refusal. Plasma samples will be analyzed for mutations of KRAS, NRAS and in BRAF V600 using the Idylla system (Biocartis). Samples will be retrospectively analysed by next generation sequencing using the Oncomine Pan-Cancer Cell-free Assay, which assesses genetic alterations in 52 driver genes, in order to evaluate the possible correlation of tumor heterogeneity with patients' outcome. With this study we could identify the best monoclonal antibody treatment in mCRC RAS/BRAF wild type on tumor tissue and RAS mutated on liquid biopsy and if liquid biopsy can be used in clinical practice as an integrated analysis to mutational tissue evaluation, to identify RAS mutations not detected on tissue.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
280
This is the treatment assigned to experimental arm: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.
This is the treatment assigned to control arm: All treatments will continue until disease progression, death, unacceptable toxicity, clinical decision or consent withdrawn.
FOLFIRI 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.
FOLFIRI 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.
FOLFIRI 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.
Ospedale San Salvatore
Coppito, L'Aquila, Italy
RECRUITINGOspedale Civile di Guastalla
Guastalla, Reggio Emilia, Italy
RECRUITINGAUSL/IRCCS di Reggio Emilia
Reggio Emilia, Reggio Emilia, Italy
RECRUITINGAzienda ULSS 3 Serenissima
Mirano, VE, Italy
RECRUITINGProgression 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.
Time frame: From the date of randomization to the date of first progression or death for any cause, whichever occurs first, assessed up to 36 months
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.
Time frame: up to 36 months
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.
Time frame: up to 36 months
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.
Time frame: up to 36 months
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.
Time frame: up to 36 months
Compliance
The compliance to treatment will be described presenting number of administered cycles; frequency and reasons for drug discontinuation and treatment modifications.
Time frame: up to 36 months
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