The Molecular Screening and Therapeutics (MoST) Program: A precision medicine framework for biomarker-driven signal-seeking clinical studies for rare cancers.

Abstract

TPS2621 Background: Precision medicine aims to link molecular targets in tumors to cognate therapies and has the potential to yield new treatments for cancer patients with unmet clinical need. With the accelerating pace of discovery and genomic capacity, innovative approaches are needed to translate molecular opportunities into clinical care. The MoST program tests a novel paradigm for evaluation of biomarker-driven treatment of patients with advanced cancer. The key elements of the design are a molecular screening platform to identify ‘actionable’ variants and an overarching protocol for multiple, parallel, signal-seeking clinical substudies. Methods: 1000 patients with advanced solid cancer of any histologic type, having failed all standard therapies will undergo tumor molecular profiling on archival tissue with a 393-gene panel and other molecular assays. Eligibility for biomarker-driven substudies of targeted treatments is based on tumor variants assessed by a Molecular Tumor Board. A novel framework design allows expedited addition of substudies, with ≥12 open-label, single-arm, signal-seeking substudies planned. The primary objective is to identify signals of clinical activity, as measured by objective tumor response or the ratio of time-to-progression on study treatment over the preceding period. Cohorts of 16 patients will be recruited to each substudy. Substudies with ≥3/16 responding patients will be considered sufficiently interesting to investigate further.As of Feb 2017, 65 patients have been screened, and 8 recruited to 2 open sub-studies: CDK4/6 inhibitor (palbociclib) for Rb pathway defects; CTLA-4 plus PD-L1 checkpoint inhibitors (durvalumab + tremelimumab) for patients with no actionable mutations. Additional substudies under development include: PARP plus PD-L1 inhibitors (olaparib + durvalumab) for HR DNA repair defects; SMO inhibitor (vismodegib) for Hh pathway defects. The modular signal-seeking trial design will be evaluated and is intended to expedite testing of biomarker-based therapies for rare cancers. Clinical trial information: ACTRN12616000908437; ACTRN12616000931471; ACTRN12616001019493.