title: 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 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.
authors.affiliation: Richard Kaplan, Angela Crook, David Fisher, Louise Brown, and Mahesh Parmar, Medical Research Council Clinical Trials Unit, London; Timothy Maughan, University of Oxford, Oxford; and Richard Wilson, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.forename: Timothy
authors.initials: T
authors.lastname: Maughan
authors.forename: Angela
authors.initials: A
authors.lastname: Crook
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.forename: Louise
authors.initials: L
authors.lastname: Brown
authors.forename: Mahesh
authors.initials: M
authors.lastname: Parmar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002986:Clinical Trials as Topic / Q000379:methods* / Q000592:standards / Q000639:trends; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019317:Evidence-Based Medicine; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D012107:Research Design / Q000639:trends*; D018401:Sample Size; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor