Evaluating Many Treatments and Biomarkers in Oncology: A New Design

Richard Kaplan, Timothy Maughan, Angela Crook, David Fisher, Richard Wilson, Louise Brown, Mahesh Parmar

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)

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 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 population-enriched 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.
Original languageEnglish
Pages (from-to)4562-4568ii
Number of pages9
JournalJournal of Clinical Oncology
Volume31
Issue number36
DOIs
Publication statusPublished - 20 Dec 2013

ASJC Scopus subject areas

  • Medicine(all)

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