A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer

Kristeleit, Rebecca, Plummer, Ruth, Jones, Robert ORCID: https://orcid.org/0000-0003-3576-9496, Carter, Louise, Blagden, Sarah, Sarker, Debashis, Arkenau, Tobias, Evans, Thomas R. Jeffry, Danson, Sarah, Symeonides, Stefan N., Veal, Gareth J., Klencke, Barbara J., Kowalski, Mark M. and Banerji, Udai 2023. A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer. British Journal of Cancer 10.1038/s41416-023-02279-x

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Abstract

Background This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737. Methods Patients with advanced solid tumours enrolled in dose-escalation cohorts and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers. Results In total, 107 patients were treated at dose levels from 20–1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean Cmin of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen. Conclusions SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0007-0920
Date of First Compliant Deposit:	15 May 2023
Date of Acceptance:	13 April 2023
Last Modified:	29 Jun 2023 10:32
URI:	https://orca.cardiff.ac.uk/id/eprint/159492

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