Evaluating Many Treatments and Biomarkers in Oncology: A New Design

Abstract

There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined populationenriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.

Toward Personalized Targeted Therapeutics: An Overview

“…Umbrella trials evaluate the impact of different drugs on different mutations in a single type of cancer. Examples of umbrella trials include BATTLE [43,44], Lung-MAP [42], and FOCUS4 [45]. In contrast, basket trials test the effect of 1 or more drugs on 1 or more single mutation in a variety of cancer types.…”

Immunotherapy in glioblastoma: emerging options in precision medicine

“…However, innovative clinical trial designs (basket trials, adaptive Bayesian clinical trials, etc.) such as those seen in NCI-MATCH [99], FOCUS4 [100], I-SPY 2 [101] and the forthcoming GBM AGILE [102], represent the progress of biomarker, multiagent collaborative trials. The GBM AGILE trial, for example, will include multiple research arms and allocate patients based on Bayesian probability of treatment efficacy, thereby dropping treatments that are ineffective and accruing treatment arms that are successful.…”

Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples

“…One ongoing umbrella trial is FOCUS4, which enrolls previously untreated metastatic colorectal cancer patients and assigns them to one of four biomarker-enriched cohorts following 16 weeks of standard front-line chemotherapy. Within each cohort, patients are randomized to an experimental targeted agent versus placebo [55,56]. FOCUS4 further contains a cohort for all-wild-type patients where patients may be randomized to treatments showing promise in the marker-positive cohorts, thereby enhancing participation as potential access to experimental treatment is ensured for all eligible patients.…”