Intermittent or Continuous Panitumumab Plus FOLFIRI for RAS/B-RAF Wild-type Metastatic Colorectal Cancer (IMPROVE)

This will be a multicenter open label randomized phase II study. The study population will include untreated RAS wild-type metastatic colorectal (mCRC) patients with unresectable disease. A total of 136 patients will be enrolled.

All Patients will receive an induction treatment with panitumumab as 1 hour intravenous infusion at the dosage of 6 mg/kg, given every two weeks, plus FOLFIRI chemotherapy as standard guidelines.

Before start of FOLFIRI plus panitumumab, at the time of enrollment, patients will be immediately randomized electronically 1:1 to one of the two arms. Induction treatment with FOLFIRI plus panitumumab will continue until progressive disease, unacceptable toxicity or informed consent withdrawal, or for up to 8 cycles. At the end of induction treatment, in presence of complete or partial response, or stable disease, non-progressing patients will be allocated to one of the two pre-assigned arms:

A) CONTINOUS: FOLFIRI plus panitumumab until progressive disease, unacceptable toxicity or informed consent withdrawal. Panitumumab will be administered as a 6 mg/kg intravenous infusion over 60 minutes (day 1) every 2 weeks. The dose of Panitumumab should be administered prior to chemotherapy. Irinotecan will be administered as a 180 mg/m2 intravenous infusion over 60 minutes (day 1) every 2 weeks. Folinic acid will be administered as a 200 mg/m2 intravenous infusion over 120 minutes before 5- fluorouracil infusion (day 1) every 2 weeks. 5-fluorouracil will be administered as a 400 mg/m2 intravenous bolus injection (day 1) followed by 2400 mg/m246-hours continuous infusion (day 1), every 2 weeks. Cycle length will be 2 weeks +/- 3 days.

B) INTERMITTENT: treatment free interval until progressive disease; followed by up to 8 cycles of FOLFIRI plus panitumumab; in presence of complete or partial response, or stable disease, non-progressing patients will undergo again to treatment free interval until PD, when they will restart treatment. Treatment cycling will continue till any progressive disease on treatment. Panitumumab will be administered at same dose and infusion with FOLFIRI.

All measurable and non-measurable lesions must be documented at screening (within 21 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks while the patient is on study). Tumor assessment by CT scan of chest, abdomen and pelvis; CEA, CA 19.9; and any other tests having resulted positive during baseline staging, will be performed at week 8 and every 8 weeks thereafter, until disease progression, accordingly with RECIST V 1.1 criteria.

Toxicities will be evaluated throughout the study treatment and graded according to the NCI Common Toxicity Criteria.

The National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTC-AE) Version 4.03 will be used to evaluate the clinical safety of the treatment in this study. Patients will be assessed for AEs at each clinical visit and as necessary throughout the study.

Quality of Life is assessed by the EORTC QLQ-C30, v. 3.0 questionnaire that are completed by patients at baseline, at week 16 and every 8 weeks thereafter.

Biomarkers ancillary study Correlative biological studies will be performed for the evaluation of the biomarkers indicated above on the biological samples available (paraffin-embedded tissue, frozen tissue, blood, serum, etc.). Biomarkers will be evaluated on archival tumor tissues or on newly obtained biopsies at baseline, and during treatment when available. Blood Samples will be collected at baseline, at week 8, 16 and thereafter every 8 weeks concomitantly with tumor assessment.

The sample size is calculated on the basis of median progression-free survival on treatment with intermittent vs continuous Panitumumab plus FOLFIRI, taking into account a median PFS of 11 months observed in the CRYSTAL trial.

The study is designed as a phase II trial with a random assignment to a calibration arm (continous) and to the experimental arm (intermittent). The sample size for intermittent arm is calculated according to the binomial test. The calibration arm has the same sample size, its role is to give a parallel estimation of median PFS to ensure that sample is representative and results are consistent However considering a 5% of drop-outs mainly due to losses to follow-up, the sample size is increased from 130 to 136 patients.

Randomization will be performed with a minimization procedure that will account for center; ECOG (PS 0-1 vs 2); primary site of tumor (Right versus Left); adjuvant treatment (yes vs no); metastatic sites (1 vs>1).