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


Kristeleit, Rebecca ORCID: 0000-0003-3825-1326, Plummer, Ruth, Jones, Robert ORCID: 0000-0001-5608-001X, Carter, Louise, Blagden, Sarah ORCID: 0000-0001-8783-3491, Sarker, Debashis ORCID: 0000-0003-4814-8429, Arkenau, Tobias, Evans, Thomas R Jeffry, Danson, Sarah, Symeonides, Stefan N ORCID: 0000-0002-9892-9314 et al (show 4 more authors) (2023) A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer. British journal of cancer, 129 (1). pp. 38-45.

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Abstract

<h4>Background</h4>This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737.<h4>Methods</h4>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.<h4>Results</h4>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 C<sub>min</sub> of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen.<h4>Conclusions</h4>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.<h4>Clinical trial registration</h4>Clinicaltrials.gov NCT02797964.

Item Type: Article
Uncontrolled Keywords: Humans, Neoplasms, Vomiting, Protein Kinase Inhibitors, Maximum Tolerated Dose, Dose-Response Relationship, Drug, Heterocyclic Compounds, 4 or More Rings
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 14 Dec 2023 08:41
Last Modified: 14 Dec 2023 08:43
DOI: 10.1038/s41416-023-02279-x
Open Access URL: https://doi.org/10.1038/s41416-023-02279-x
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3177353
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