Randomized phase 3 study of intermittent or continuous Panitumumab plus FOLFIRI for first-line treatment of patients with unresectable left sided RAS/B-RAF wild-type metastatic colorectal cancer (IMPROVE-2 trial)

INTERVENTION: Product Name: Vectibi X20 mg/ml concentrate for solution for infusion,Product Code: PRD385467,Pharmaceutical Form: CONCENTRATE FOR SOLUTION FOR INFUSION,Other descriptive name: ,Strength: Panitumumab 20mg CONDITION: MedDRA version: 21.0Level: PTClassification code: 10052358Term: Colorectal cancer metastaticSystem Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Digestive System Diseases [C06]‐Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] ‐ Therapeutics [E02]‐Diseases [C] ‐ Neoplasms [C04] Unresectable left sided RAS/B‐RAF wild‐type metastatic colorectal cancer ; MedDRA version: 21.0Level: PTClassification code: 10052358Term: Colorectal cancer metastaticSystem Organ Class: 100000004864 PRIMARY OUTCOME: Main Objective:To investigate whether experimental intermittent treatment of Panitumumab plus FOLFIRI (given until progression during treatment or inacceptable toxicity) results effective in first line as the same regimen given continuously, in the treatment of metastatic left sided RAS/B‐RAF wild‐type colorectal cancer patients.; To assess whether an improvement in safety, tolerability and quality of life can be achieved in the intermittent arm as compared to the continuous arm.; To explore potential biomarkers of primary and secondary resistance as well as to monitor treatment efficacy and toxicity on both tissue, primary tumors and resected metastases when available, and blood samples. Primary end point(s):Time to Treatment Failure (TTF) between the two arms: TTF is defined as the time from randomization to the objective disease progression by RECIST 1.1 criteria occurred during the treatment (objective disease progression during treatment free intervals are excluded) or death due to any cause, whichever occurs first, or a treatment delay > 28 days for toxicity Secondary Objective: INCLUSION CRITERIA: Written informed consent to study procedures and to correlative studies,Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. Additional analysis of polymorphisms uridine diphosphate‐glycosyltransferase 1 (UGT1A1) enzyme is recommended but not mandatory,Adequate bone marrow hematological function: absolute neutrophil count (ANC) = 1.5 X109 /L AND platelet count = 100 X109 /L AND hemoglobin = 9 g/dL.,Adequate liver function: total bilirubin = 1.5 Xupper limit of normal (ULN) or = 2 in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) = 5 XULN,Adequate renal function: serum creatinine = 1.5 mg/dL OR creatinine clearance = 60 mL/min in males and =50 mL/min in females (calculated according to Cockroft‐Gault formula),Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range,Histologically proven left sided mCRC,RAS/BRAF wild‐type and pMMR and/or MSS status assessed at local centers a SECONDARY OUTCOME: Secondary end point(s):Depth of response (DpR) assessed as the percentage of tumor shrinkage observed at the lowest point (nadir) compared with baseline. Secondary end point(s):Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response. Secondary end point(s):Objective Tumor Response Rate (ORR) assessed according to RECIST criteria 1.1 Secondary end point(s):Overall survival (OS) calculated as the time from the date of randomization until the date of death from any cause. Secondary end point(s):Patient Report Outcome (PRO)‐CTCAE with items dedicated in particular to diarrhea and skin toxicity to evaluate the effect of the treatment on the health‐related QoL Secondary end point(s):Progression‐free survival (PFS) measured as the time from the date of randomization until the date of the first observation of disease progression or death due to any cause, whichever occurs first. Secondary end point(s):Progression‐free survival on treatment (PFSot) measured as the time from the date of randomization to the date of disease progression occurred during treatment or death due to any cause, whichever occurs first. Secondary end point(s):Quality of life (QoL) investigated through the EORTC QLQ‐C30 and CR29 questionnaires‐ Secondary end point(s):Safety evaluated as adverse events graded according NCI CTCAE v 5.0. Secondary end point(s):Time toxicity measured as hospital‐free days Secondary end point(s):Tolerability evaluated as longitudinal toxicity over time and adverse event burden score. Secondary end point(s):We will also explore the prognostic and predictive value of next generation sequencing (NGS), from blood samples (“liquid biopsy”) collected at baseline, at week 16 and thereafter every 8 weeks and serum metabolomic profiling in peripheral blood evaluated by NMR Spectrometer (600 MHz) concomitantly with tumor assessment, and at progression of disease. as well as the potential to monitor treatment activity of at baseline and during treatment.