The Cancer Molecular Screening and Therapeutics Program (most): A Molecular Screening Platform with Multiple, Parallel, Signal-Seeking Therapeutic Substudies

Background: Innovative approaches are needed to translate molecular opportunities into clinical care. MoST tests a novel paradigm for evaluation of biomarker-driven treatments (tx) for patients (pts) with advanced cancer, with a particular focus on rare or neglected cancers. Trial design: Tx-refractory pts (N = 1000) undergo molecular screening using archival tumour tissue. Results are reviewed by the Molecular Tumor Board (MTB) to identify actionable variants and eligibility for substudies. A master protocol allows expedited addition of ≥ 12 open-label, phase Ib/IIa, single-arm substudies, with 16 pts per module deemed reasonable for signal-seeking purposes. The primary objectives are to identify potential clinical activity for biomarker-driven tx, biomarkers that predict for response, and to evaluate the MoST study design. Three substudies are active: 1) palbociclib - molecular eligibility includes amplification/activating mutations in cyclin D pathway genes, or loss of function mutations in CDKN2A; 2) olaparib+durvalumab (ola+durva) – molecular eligibility is a homologous recombination repair gene defect; 3) durvalumab+tremelimumab (durva+treme) offers a tx in the absence of actionable findings. Further substudies planned include vismodegib and eribulin for tumours with PTCH1 or SMO mutations, and CD31 positivity respectively. Since September 2016, recruitment to screening has exceeded targets. Of the 571 pts enrolled to April 2018, 474 MTB reports have been issued, 57 are in progress, 31 had insufficient tissue and 43 died prior to issue of a MTB report. Median time to MTB report issue was 44 days over latest quarter (n = 89). Rare cancers comprise at least 44%; an actionable mutation to inform therapy reported in > 40%. Palbociclib (n = 16) and durva+treme (n = 4x16, 64 pts) substudies have completed recruitment; ola+durva (n = 3x16 pts) is currently recruiting. The distribution of actionable mutations across cancers, and in particular rare cancers will be informative, as it comprises the essential first steps to gaining access to novel, personalized treatments for pts. Clinical trial identification: Framework protocol Trial ID ACTRN12616000908437. Registered 08 July 2016. Therapeutic substudy 1 (palbociclib) Trial ID ACTRN12616000931471. Registered 13 July 2016. Therapeutic substudy 2-5 (durvalumab plus tremelimumab) Trial ID ACTRN12616001019493. Registered 02 August 2016. Therapeutic substudy 6-8 (olaparib plus durvalumab) Trial ID ACTRN12617001000392. Registered 11 July 2017. Legal entity responsible for the study: Human Research Ethics Committee, St Vincent's Hospital; approval reference: HREC/16/SVH/23. Coordinating Centre for Molecular Screening: Garvan Institute of Medical Research, Darlinghurst NSW 2010. Coordinating Centre for Therapeutic Substudies: NHMRC Clinical Trials Centre, Camperdown NSW 2050. Funding: The NSW Office for Health and Medical Research, granted 2/3/15: H15/13965 Therapeutic substudies to date have been funded by AstraZeneca Australia and Pfizer, which includes drug supply. Disclosure: All authors have declared no conflicts of interest.