Study design
toxicity
EVENT, ADVERSE EVENT
The objectives of this first-in-human, Phase 1/2, open-label, dose-escalation study of SRA737 as a single agent were to establish the safety profile, define the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) and schedule, and to evaluate preliminary efficacy in prospectively selected genetically defined patients enrolled in indication-specific expansion cohorts. Secondary objectives included defining the pharmacokinetic (PK) profile of SRA737.The study used an accelerated titration design in dose escalation beginning with single subject dose-level cohorts. Doubling of the SRA737 dose was permitted in the subsequent cohort if a dose level was determined to be safe by the cohort review committee consisting of the lead investigator, study investigators representing the site(s) currently enrolling patients, and representatives of the study sponsor. In the event of any SRA737-related adverse event Grade 2 or greater toxicity during Cycle 1, the cohort was to be expanded to 3 to 6 subjects. Thereafter the study followed a rolling 6 design wherein once the first subject completed the 7-day observation period following the first dose of SRA737, subsequent subjects in that cohort started treatment. In the absence of a dose-limiting toxicity (DLT), the dose of SRA737 was escalated in less than 100% (typically 25–75%) increments. Enrolment of expansion cohorts at the highest dose level determined to be safe and tolerable was initiated prior to the completion of dose escalation and determination of MTD or RP2D.The trial (ClinicalTrials.gov identifier NCT02797964) was carried out in 15 centres in the United Kingdom between July 18, 2016 and October 28, 2019.Research ethics committees approved the study protocol before initiation of patient enrolment, and all patients provided written informed consent prior to study enrolment in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Guidelines for Good Clinical Practice, and applicable local regulations.