Abstract

Background:Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years.Methods:FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials.Results:Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014–March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016–July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017–October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised.Conclusion:Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.

Highlights

  • FOCUS4 is the first molecularly stratified platform trial to be undertaken in colorectal cancer and it remains one of the first umbrella trial designs to be launched globally.[1]

  • We have already published a series of papers on the practical aspects of running these sorts of complex platform trials,[8,9,10,11] but systematically eliciting learning experiences from all stakeholders within one large stratified medicine platform trial have not been reported previously and this is the primary objective of this article

  • FOCUS4 was co-funded by the Medical Research Council (MRC)/NIHR Efficacy and Mechanism Evaluation (EME) Programme and Cancer Research UK (CRUK) with funding commencing in April 2013

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Summary

Introduction

FOCUS4 is the first molecularly stratified platform trial to be undertaken in colorectal cancer and it remains one of the first umbrella trial designs to be launched globally.[1]. Recent high profile trials, such as the RECOVERY and PRINCIPLE trials,[2,3] tested multiple treatments in the midst of the Covid-19 pandemic and generated practice-changing results swiftly and efficiently They raised the visibility of these adaptive trial designs which have previously been implemented successfully over a number of years, for example, the STAMPEDE4 trial in prostate cancer. These trial designs offer great potential for testing treatments efficiently and improving outcomes for patients in a faster time frame[5,6] and there is a desire for increased use but they come with multiple challenges in terms of delivery and in some cases a lack of regulatory acceptance. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014–March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4B (February 2016–July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C

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