Regorafenib assessment in refractory advanced colorectal cancer: RegARd-C study protocol

Abstract

IntroductionRegorafenib was recently approved for patients with pretreated advanced colorectal cancer (aCRC), despite a moderate improvement of the patients’ outcome, and significant toxicities. Based on previous studies showing that early fluorodeoxyglucose-positron emission tomography (FDG-PET)-based metabolic response assessment (MRA) might adequately select patients unlikely to benefit from treatment, the RegARd-C trial uses early MRA to identify likely non-responders to regorafenib in a population of patients with aCRC and guide a comprehensive evaluation of genomic and epigenetic determinants of resistance to treatment.Methods and analysisRegARd-C is a multicentric prospective study. Its primary objective is to identify non-benefitters from regorafenib given at 160 mg/day, 3 weeks out of 4 in a population of patients with pretreated aCRC. Baseline PET is repeated at day 14 of the first treatment course. MRA is blinded for the investigators. Overall survival (OS) is the primary end point and will be correlated with metabolic parameters and (epi)genetic alterations assessed from tumour and serial blood samples. A target sample size of 105 evaluable patients (70 as derivation set and 35 as validation set), is considered as sufficient to validate an expected HR for OS of metabolic responders compared to metabolic non-responders significantly <1 (with 80% power and 1-sided 5% α in case of a true HR≤0.59 and a responders rate of 47%).Ethics and disseminationThe study was approved by the Institut Jules Bordet's competent ethics committee and complies with the Helsinki declaration or the Belgian laws and regulations, whichever provides the greatest protection for the patient, and follows the International Conference on Harmonisation E 6 (R1) Guideline for Good Clinical Practice, reference number CPMP/ICH/135/95. The protocol and the trials results, even inconclusive, will be presented at international oncology congresses, and published in peer-reviewed journals. Genomic and epigenetic data will be made available in public open data sets.Trial registration numbersEudraCT number: 2012-005655-16; ClinicalTrials.gov number: NCT01929616.

Combining 18F-FDG PET/CT–Based Metabolically Active Tumor Volume and Circulating Cell-Free DNA Significantly Improves Outcome Prediction in Chemorefractory Metastatic Colorectal Cancer

“…The patients were recruited from 15 Belgian clinical centers. The patient selection criteria and study design are detailed in the RegARd-C study protocol (21). The main enrollment criteria for this study were as follows: histologically proven adenocarcinoma of the colon or rectum; tumor refractory to all standard chemotherapy agents (fluoropyrimidines, irinotecan, and oxaliplatin) and anti-EGFR monoclonal antibodies in the case of RAS wild-type (cetuximab or panitumumab); age greater than 18 y; Eastern Cooperative Oncology Group performance status of 1 or less; life expectancy greater than 12 wk; a baseline 18 F-FDG PET/CT examination with at least 1 measurable target lesion and a plasma sample both acquired within the 7 d before inclusion in the trial; a minimum washout period of 4 wk before inclusion in the trial; ability to undergo the therapy; and provision of signed informed consent (21).…”

Validation of Metabolically Active Tumor Volume and Total Lesion Glycolysis as 18F-FDG PET/CT–derived Prognostic Biomarkers in Chemorefractory Metastatic Colorectal Cancer

“…The SoMore study (EudraCT number 2010-023695-91; NCT number 01290926) investigated a combination of sorafenib (Nexavar, BAY 43-9006; Bayer Pharma AG) and capecitabine (Xeloda; Roche Pharma) (16), whereas the RegARd-C study (EudraCT number 2012-005655-16) investigated regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG) (17). The main enrollment criteria for these 2 studies were tumor refractory to all standard chemotherapy agents (fluoropyrimidines, irinotecan, and oxaliplatin) and anti-EGFR monoclonal antibodies in the case of RAS wild-type (cetuximab or panitumumab); age greater than 18 y; ECOG PS of 1 or less; life expectancy greater than 12 wk; a baseline 18 F-FDG PET/CT examination performed within the 7 d previous to the day of inclusion in the trial with at least 1 measurable target lesion; ability to undergo the therapy; and signed informed consent (17). Both studies were conducted within the same Belgian hospital network and followed a similar study design, testing metabolic response after 1 course of treatment as a predictor of patient's outcome, with OS as the primary endpoint.…”

Study Protocol of Regorafenib Escalation for Colorectal Cancer (RECC): A Phase II Multicenter Clinical Trial of the Efficacy and Safety of Regorafenib Dose Escalation Therapy as the Third or Fourth Line Therapy for Unresectable/Recurrent Colorectal Cancer

“…Re-dose escalation will not be attempted after dose reduction. 8. Patients with multiple primary cancers.…”