Kristeleit, R. orcid.org/0000-0003-3825-1326, Plummer, R., Jones, R. et al. (11 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. pp. 38-45. ISSN 0007-0920
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.
Clinical trial registration Clinicaltrials.gov NCT02797964.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Cancer genomics; Drug development |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 05 Jun 2023 13:29 |
Last Modified: | 04 Jul 2023 01:20 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1038/s41416-023-02279-x |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:199677 |