A first-in-human phase I/II trial of SRA737 (a Chk1 Inhibitor) in subjects with advanced cancer.

Elizabeth Ruth Plummer, Rebecca Sophie Kristeleit, Elena Cojocaru, Noor Md Haris, Louise Carter, Robert Hugh Jones, Sarah Patricia Blagden, T.R. Jeffry Evans, Hendrik-Tobias Arkenau, Debashis Sarker, Sarah Danson, Stefan N. Symeonides, Harriet Walter, Joanita Ocen, Manreet Randhawa, Mark Marion Kowalski, Ines Verdon, Andrew Dye, Udai Banerji

Research output: Contribution to conferenceAbstractpeer-review

Abstract

3094 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The C max and AUC 0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the C min (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.
Original languageEnglish
Pages3094-3094
Number of pages1
DOIs
Publication statusPublished - 2019

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