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Demographic and Disease Characteristics from A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer

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posted on 2023-09-28, 21:20 authored by Robert Jones, Ruth Plummer, Victor Moreno, Louise Carter, Desamparados Roda, Elena Garralda, Rebecca Kristeleit, Debashis Sarker, Tobias Arkenau, Patricia Roxburgh, Harriet S. Walter, Sarah Blagden, Alan Anthoney, Barbara J. Klencke, Mark M. Kowalski, Udai Banerji

Patients are displayed in cohorts defined by tumor type, including indication-specific expansion cohorts (anogenital, cervical, HGSOC, SCLC and STS), a grouping of patients with rectal cancer who were enrolled under dose escalation, and four patients with urothelial cancer enrolled under previous protocol versions. A total of 18 patients were “double counted” in that they appear under both “All dose escalation” and in their specific tumor-type cohorts. These 18 patients consisted of 15 dose-escalation patients with rectal cancer, one dose-escalation patient with anogenital cancer, one concurrently enrolled dose-escalation/expansion patient with cervical cancer, and one concurrently enrolled dose-escalation/expansion patient with STS.

Funding

Imperial College London/Hammersmith hospital NHS Trusts (ECMC)

Cancer Research UK

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National Institute for Health and Care Research (NIHR)

Cancer Research UK (CRUK)

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ARTICLE ABSTRACT

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 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. 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 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. 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. 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.

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    Clinical Cancer Research

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    cancer

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