A phase 1 dose-escalation study of the poly(ADP-ribose) polymerase inhibitor senaparib in Australian patients with advanced solid tumors.

Autor: Gao B; Department of Medical Oncology, Blacktown Hospital and University of Sydney, Sydney, New South Wales, Australia., Voskoboynik M; Medical Oncology, Nucleus Network, Melbourne, Victoria, Australia.; Central Clinical School, Monash University, Melbourne, Victoria, Australia., Cooper A; Western Sydney University Medical School, Campbelltown, New South Wales, Australia., Wilkinson K; Western Sydney University Medical School, Campbelltown, New South Wales, Australia., Hoon S; Department of Medical Oncology, Blacktown Hospital and University of Sydney, Sydney, New South Wales, Australia., Hsieh CY; IMPACT Therapeutics Inc., Shanghai, China., Cai S; IMPACT Therapeutics Inc., Shanghai, China., Tian YE; IMPACT Therapeutics Inc., Shanghai, China., Bao J; IMPACT Therapeutics Inc., Shanghai, China., Ma N; IMPACT Therapeutics Inc., Shanghai, China., Wang C; IMPACT Therapeutics Inc., Shanghai, China., Zhang M; IMPACT Therapeutics Inc., Shanghai, China., Li B; IMPACT Therapeutics Inc., Shanghai, China., Guo M; IMPACT Therapeutics Inc., Shanghai, China., Zhou R; IMPACT Therapeutics Inc., Shanghai, China., Wang X; IMPACT Therapeutics Inc., Shanghai, China., Xu C; IMPACT Therapeutics Inc., Shanghai, China., de Souza P; Western Sydney University Medical School, Campbelltown, New South Wales, Australia.
Jazyk: angličtina
Zdroj: Cancer [Cancer] 2023 Apr 01; Vol. 129 (7), pp. 1041-1050. Date of Electronic Publication: 2023 Jan 31.
DOI: 10.1002/cncr.34662
Abstrakt: Background: Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. This first-in-human, phase 1, dose-escalation study examined the safety and preliminary efficacy of senaparib in patients with advanced solid tumors.
Methods: Patients with advanced solid tumors were enrolled from three centers in Australia, using a conventional 3 + 3 design. Dose-escalation cohorts continued until the maximum tolerated dose or a recommended phase 2 dose was determined. Patients received one dose of oral senaparib and, if no dose-limiting toxicity occurred within 7 days, they received senaparib once daily in 3-week cycles. The primary end points were safety and tolerability.
Results: Thirty-nine patients were enrolled at 10 dose levels ranging from 2 to 150 mg. No dose-limiting toxicities were observed in any cohort. Most treatment-emergent adverse events were grade 1-2 (91%). Seven patients (17.9%) reported hematologic treatment-emergent adverse events. Treatment-related adverse events occurred in eight patients (20.5%), and the most frequent was nausea (7.7%). Two deaths were reported after the end of study treatment, one of which was considered a complication from senaparib-related bone marrow failure. Pharmacokinetic analysis indicated that senaparib the accumulation index was 1.06-1.67, and absorption saturation was 80-150 mg daily. In 22 patients with evaluable disease, the overall response rate was 13.6%, and the disease control rate was 81.8%. The overall response rate was 33.3% for the BRCA mutation-positive subgroup and 6.3% for the nonmutated subgroup.
Conclusions: Senaparib was well tolerated in Australian patients with advanced solid tumors, with encouraging signals of antitumor activity. The recommended phase 2 dose for senaparib was determined to be 100 mg daily.
Gov Id: NCT03507543.
(© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
Databáze: MEDLINE
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