Adaptive Design for a Confirmatory Basket Trial in Multiple Tumor Types Based on a Putative Predictive Biomarker

Abstract

Increasingly, tumors are defined on a molecular basis rather than only on histology, and targeted agents, which address these molecular subtypes, are being approved. This profusion of molecular subtypes creates "rare" diseases as subsets of common cancers, leading to difficulties in enrolling sufficiently large cohorts for confirmatory trials. However, if the molecular subtype is shared across various histologies, these may be pooled into a basket trial. To date, basket trials have been primarily for exploratory early development. In this perspective, we consider qualitative designs for confirmatory basket trials. These confirmatory basket designs will provide patients in niche indications with enhanced access to novel therapies, facilitate development and full approval for niche indications, allow accelerated approval for indications within a basket based on a surrogate endpoint, reduce development cost by combining trials, and enhance the ability of regulatory authorities to evaluate risk and benefit in niche indications.

Multi‐stage enrichment and basket trial designs with population selection

“…Basket designs can be viewed as an extension of the biomarker enrichment design. In contrast to the biomarker enrichment design that follows a prespecified selection (or de‐selection) sequence of its subpopulations based on the biomarker levels, the basket design selects or deselects subpopulations based on their tissue of origin (or other indications for nononcology applications) without any requirement on the ordering sequence of the subpopulations.…”

Quantitation of Targetable Somatic Mutations Among Patients Evaluated by a Personalized Medicine Clinical Service: Considerations for Off‐Label Drug Use

“…Because the interpretation of genomic test results is becoming increasingly complex and time intensive, personalized medicine consultation services are beginning to emerge. These services have the goal of identifying drugs or clinical trials for which the patient is eligible based on reported actionable mutations . Most genomic‐targeted chemotherapeutic agents have on‐label indications listed in the FDA drug insert Indications and Usage section that identifies the somatic mutation and cancer type for which the drug is approved.…”

“…Other examples include off‐label use of olaparib in nonovarian BRCA ‐mutated cancers . Novel clinical trial designs, such as basket trials, are exploring the clinical utility of targeting molecular alternations independent of tumor type …”

“…These services have the goal of identifying drugs or clinical trials for which the patient is eligible based on reported actionable mutations. [6][7][8][9][10] Most genomic-targeted chemotherapeutic agents have on-label indications listed in the FDA drug insert Indications and Usage section that identifies the somatic mutation and cancer type for which the drug is approved. For example, dabrafenib and trametinib are approved for the treatment of BRAF V600E mutated unresectable or metastatic melanoma.…”

“…15,16 Novel clinical trial designs, such as basket trials, are exploring the clinical utility of targeting molecular alternations independent of tumor type. [6][7][8] Moffitt Cancer Center's Personalized Medicine Clinical Service (PMCS) reviews somatic NGS assay results, provides interpretations focusing on actionable mutations, and identifies potential therapeutic options in the context of prior therapies along with other patient-specific characteristics. 9 Clinical interpretation notes are entered into the electronic medical record, communicated to physicians, and when requested, discussed with our patients.…”