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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Date
2023-01-17ICR Author
Author
Jones, R
Plummer, R
Moreno, V
Carter, L
Roda, D
Garralda, E
Kristeleit, R
Sarker, D
Arkenau, T
Roxburgh, P
Walter, HS
Blagden, S
Anthoney, A
Klencke, BJ
Kowalski, MM
Banerji, U
Type
Journal Article
Metadata
Show full item recordAbstract
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 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. 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.
Collections
Subject
Humans
Gemcitabine
Deoxycytidine
Neoplasms
Small Cell Lung Carcinoma
Antineoplastic Combined Chemotherapy Protocols
Lung Neoplasms
Research team
Clinical Pharmacology
Language
eng
Date accepted
2022-11-11
License start date
2023-01-17
Citation
Clinical Cancer Research, 2023, 29 (2), pp. 331 - 340
Publisher
AMER ASSOC CANCER RESEARCH