A Phase I/II trial of Oral SRA737 (a Chk1 Inhibitor) given in combination with low-dose gemcitabine in patients with advanced cancer

Jones, Robert ORCID: https://orcid.org/0000-0003-3576-9496, Plummer, Ruth, Moreno, Victor, Carter, Louise, Roda, Desamparados, Garralda, Elena, Kristeleit, Rebecca, Sarker, Debashis, Arkenau, Tobias, Roxburgh, Patricia, Walter, Harriet S., Blagden, Sarah, Anthoney, Alan, Klencke, Barbara J., Kowalski, Mark M. and Banerji, Udai 2023. A Phase I/II trial of Oral SRA737 (a Chk1 Inhibitor) given in combination with low-dose gemcitabine in patients with advanced cancer. Clinical Cancer Research 29 (2) , pp. 331-340. 10.1158/1078-0432.CCR-22-2074

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Abstract

Purpose: This was a phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. Patients and Methods: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16 and 17, and intravenous gemcitabine on days 1, 8 and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. Results: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia and thrombocytopenia were grade ≥3 in 8.3% to 11.7% of patients treated at the RP2D. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. Conclusions: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	American Association for Cancer Research
ISSN:	1078-0432
Date of First Compliant Deposit:	17 November 2022
Date of Acceptance:	11 November 2022
Last Modified:	04 Jul 2023 22:40
URI:	https://orca.cardiff.ac.uk/id/eprint/154282

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