Precision cancer medicine platform trials: Concepts and design of AcSé-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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BG has had an advisory role for AstraZeneca and IDMC roles for trials sponsored by Roche and Novartis. SAG has had an advisory role for EMD Serono/MERCK KGaA and AMGEN and received research funding (institution) from AstraZeneca, GSK and BAYER. LVM has had Advisory Board Honoraria for Bayer, BMS, Day One Biopharmaceuticals, Eli Lilly, Illumina, Novartis and Tesaro. Paediatric Preceptorship/Chair & Speaker's Honoraria - Bayer. IDMC member for clinical trials sponsored by Eisai and Merck. NA has had an advisory role for BAYER and Partners Therapeutics and receives grants (institution) from Bristol Myers Squibb and drugs for a trial from Bristol Myers Squibb, Pierre Fabre, Merck, Pfizer and travel support from Roche; he further has IDMC roles for Accord Healthcare. AR had a consulting role for EusaPharma, Sanofi and SERB. She received honoraria from EusaPharma and Roche for educational events and travel expenses. MC has had advisory roles for Astra Zeneca, Bayer, Pfizer and was invited speaker for Bayer. KN serves on a data monitoring committee for Lilly. All remaining authors have declared no conflict of interest.
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