Precision cancer medicine platform trials: Concepts and design of AcSe-ESMART

Precision cancer medicine brought the promise of improving outcomes for patients with cancer. High-throughput molecular profiling of tumors at treatment failure aims to direct a patient to a treatment matched to the tumor profile. In this way, improved outcome has been achieved in a small number of patients whose tumors exhibit unique targetable oncogenic drivers. Most cancers, however, contain multiple genetic alterations belonging to and of various hallmarks of cancer; for most of these alterations, there is limited knowledge on the level of evidence, their hierarchical roles in oncogenicity, and utility as biomarkers for response to targeted treatment(s). We developed a proof-of-concept trial that explores new treatment strategies in a molecularly-enriched tumor-agnostic, pediatric population. The evaluation of novel agents, including first-in-child molecules, alone or in combination, is guided by the available understanding of or hypotheses for the mechanisms of action of the diverse cancer events. Main objectives are: to determine 1) recommended phase 2 doses, 2) activity signals to provide the basis for disease specific development, and 3) to define new predictive biomarkers. Here we outline concepts, rationales and designs applied in the European AcSé‐ESMART trial and highlight the feasibility but also complexity and challenges of such innovative platform trials.