Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04).

Autor:	Mohan A; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Griffith KA; Center for Cancer Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan., Wuchu F; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, Michigan., Zhen DB; Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, Washington.; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington., Kumar-Sinha C; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Crysler O; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Hsiehchen D; Division of Hematology and Oncology, Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas., Enzler T; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Dippman D; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Gunchick V; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Achreja A; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, Michigan., Animasahun O; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, Michigan.; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan., Choppara S; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, Michigan., Nenwani M; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, Michigan., Chinnaiyan AM; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Nagrath D; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, Michigan.; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan., Zalupski MM; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Sahai V; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Jul 05; Vol. 29 (13), pp. 2394-2400.
DOI:	10.1158/1078-0432.CCR-23-0036
Abstrakt:	Purpose: Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC). Patients and Methods: Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3-19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1-14.9). Median OS is not yet estimable. Conclusions: Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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