20INHOW TO DESIGN THE TRIALS TO MEET THE PERSPECTIVES OF PERSONALISED CANCER MEDICINE

Abstract In the current era of stratified medicine and biomarker driven therapies, the focus has shifted from predictions based on the traditional anatomic staging systems to guide the choice of treatment for an individual patient to an integrated approach using the genetic makeup of the tumor and the genotype of the patient. Starting from early phase trials for initial marker validation to larger definitive trials, clinical trial designs utilized in the developmental pathway for biomarkers and biomarker-directed therapies are rapidly evolving. Two critical issues that need careful consideration are the choice of the clinical trial design (based on the strength of the preliminary evidence, marker prevalence etc.), and biomarker assay related issues surrounding the marker assessment methods such as the reliability and reproducibility of the assay. While assessing the safety profile and establishing the maximum tolerated dose remains the primary focus of Phase I trials for all agents, establishing a preliminary efficacy signal and/or identification of subsets of patients most likely to benefit from the new treatment are increasingly assessed as part of Phase I trials of targeted therapeutics. The choice of endpoints, patient selection, model-based versus rule-based design algorithms and inclusion of expansion cohorts need careful consideration in this setting. Phase II trials have at least 3 main purposes: assess the regimen / drug under investigation for evidence of efficacy; evaluate the patient population for a phase III study (i.e., identify genomic-defined patient subsets) and finally, to more fully assess the toxicity profile in a larger number of patients than that of a phase I study. While most of the prospective designs for biomarker-directed therapy were primarily developed for marker validation in phase III setting, they have evolved since then to be applicable in an initial marker validation phase II setting. Designs for biomarker validation (initial and definitive) are broadly classified into enrichment, all-comers, hybrid or adaptive (with various adaptation strategies). This talk will provide numerous examples of cancer clinical trials that utilize a design strategy aiming at personalized medicine. Disclosure: The author has declared no conflicts of interest.