STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer

This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.

• Progression free survival (PFS) [Time frame: up to 1 year last patients randomized]
• Overall survival (OS) [Time frame: up to 1 year last patients randomized]
• Objective Tumor Response Rate (ORR) [Time frame: up to 1 year last patients randomized]
• Disease Control Rate (DCR) [Time frame: up to 1 year last patients randomized]
• Progression free survival 2 (PFS2) [Time frame: up to 1 year last patients randomized]
• Overall Toxicity rate [Time frame: up to 1 year last patients randomized]
• Quality of life (QoL) [Time frame: questionnaires must be completed before any study procedure but within 2 weeks prior to randomization (baseline) and thereafter every 8 weeks from randomization until disease progression, treatment failure or death, assessed up to 18 months]
• Quality of life (QoL) [Time frame: questionnaires must be completed before any study procedure but within 2 weeks prior to randomization (baseline) and thereafter every 8 weeks from randomization until disease progression, treatment failure or death, assessed up to 18 months.]
• PRO-CTCAE [Time frame: questionnaires must be completed before any study procedure but within 2 weeks prior to randomization (baseline) and thereafter every 8 weeks from randomization until disease progression, treatment failure or death, assessed up to 18 months.]
• Financial toxicity assessed through the PROFFIT questionnaire [Time frame: at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks from randomization until disease progression, treatment failure or death, assessed up to 18 months.]