LBA-10 MODUL – A Multicentre Randomised Clinical Trial of Biomarker-Driven Therapy for the 1st-Line Maintenance Treatment of Metastatic Colorectal Cancer (mCRC): A Highly Adaptable Signal-Seeking Approach

Abstract

Background: The old approach of one therapeutic for all patients with mCRC is evolving with a need to target specific molecular aberrations or cell-signalling pathways. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify patients most likely to benefit, and predict treatment response. MODUL is a highly adaptable, randomised, multicentre, active-controlled, open-label, parallel-group trial of biomarker-driven maintenance therapy for the 1stline treatment of mCRC. The 'adaptable' design permits future modification of current cohorts and inclusion of additional treatment cohorts based on novel evidence and corresponding compounds/combinations. Trial design: Eligible patients have measureable, unresectable disease with no prior chemotherapy for mCRC. The study has 3 phases: 1) Induction Treatment (approximately 4 months' of FOLFOX + bevacizumab); 2) Maintenance Treatment; 3) Post-Treatment Follow-up. Eligible patients without progressive disease are assigned to a Maintenance Treatment cohort based on results of biomarker assessments obtained from tumour tissue. Current cohorts are as follows: Cohort 1 - BRAF V600E mutated (BRAFmut); Cohort 2 - 'No Biomarker' cohort. Within each existing cohort, patients are randomized to either experimental treatment or control (2:1 basis): Cohort 1 - experimental (fluoropyrimidine, cetuximab, vemurafenib); Cohort 2 - experimental (fluoropyrimidine, bevacizumab, anti-PD-L1 antibody [MPDL3280A; atezolizumab]). The control arm for all cohorts is fluoropyrimidine + bevacizumab. Co-primary efficacy endpoints are: early efficacy (≥20% reduction in tumour size after 2 months of Maintenance Treatment in first 27 patients of experimental arm); PFS (median and 4- month PFS rate from randomisation). Secondary efficacy objectives are: overall survival; overall response rate; disease control rate; time to treatment response; duration of response. Safety assessment is based on adverse events, treatment modifications, and clinically significant laboratory values. Recruitment of 1680 patients is expected over approximately 3 years (total 6 years' duration of trial) from sites in Europe, Asia, Africa, North America and South America. Current status: Enrolment of patients into the Induction Treatment phase of the MODUL trial is underway as of 17 April 2015. A proposal to include two new cohorts is currently under discussion. The MODUL trial will continue to adapt to include additional treatment cohorts as evidence on potential treatment targets and therapies emerge.