MODUL-a multicenter randomized clinical trial of biomarker-driven maintenance therapy following first-line standard induction treatment of metastatic colorectal cancer: an adaptable signal-seeking approach

Abstract

Purpose: 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.

Methods: MODUL is a signal-seeking trial with a design that is highly adaptable, permitting modification of different treatment cohorts and inclusion of further additional cohorts based on novel evidence on new compounds/combinations that emerge during the study.

Results: MODUL is ongoing and its adaptable nature permits timely and efficient recruitment of patients into the most appropriate cohort. Recruitment will take place over approximately 5 years in Europe, Asia, Africa, and South America. The design of MODUL with ongoing parallel/sequential treatment cohorts means that the overall size and duration of the trial can be modified/prolonged based on accumulation of new data.

Conclusions: The early success of the current trial suggests that the design may provide definitive leads in a patient-friendly and relatively economical trial structure. Along with other biomarker-driven trials that are currently underway, it is hoped that MODUL will contribute to the continuing evolution of clinical trial design and permit a more 'tailored' approach to the treatment of patients with mCRC.

Keywords: Biomarker; FOLFOX + bevacizumab; MODUL; Metastatic colorectal cancer; Signal seeking; Switch maintenance therapy.

Fig. 1

MODUL study design. FP fluoropyrimidine (5-FU/LV or capecitabine), 5-FU/LV 5-fluorouracil/leucovorin; MSI-H high microsatellite instability, MSS microsatellite stable. ^aPatients who progress early and who are not BRAF^mut will enter the post-treatment follow-up phase with initiation of second-line treatment per Investigator discretion. ^bRandomization stratified by: Cohorts 1 and 2: region (EU, Americas, Africa, or Asia), induction treatment response (CR/PR vs. SD); Cohort 3: induction treatment response (CR/PR vs. SD), HER2 IHC (IHC0/ IHC1+/IHC2 + vs. IHC3+); Cohort 4: region (EU vs. rest of world), induction treatment response (CR/PR vs. SD), microsatellite stability (MSI-H vs. MSS), RAS status (wild-type KRAS and NRAS vs. mutant KRAS and/or NRAS). ^cPatients discontinuing study treatment for any reason during the induction or maintenance treatment phases will enter the post-treatment follow-up phase

Fig. 2

Whole blood and plasma biomarker assessments