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

Bo Gao; Mark Voskoboynik; Adam Cooper; Kate Wilkinson; Siao Hoon; Chih-Yi Hsieh; Suixiong Cai; Ye Edward Tian; Jun Bao; Ning Ma; Chen Wang; Ming Zhang; Baoyue Li; Mingchuan Guo; Ruiyu Zhou; Xiaozhu Wang; Cong Xu; Paul de Souza

doi:10.1002/cncr.34662

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

Cancer. 2023 Apr 1;129(7):1041-1050. doi: 10.1002/cncr.34662. Epub 2023 Jan 31.

Authors

Bo Gao¹, Mark Voskoboynik^{2

3}, Adam Cooper⁴, Kate Wilkinson⁴, Siao Hoon¹, Chih-Yi Hsieh⁵, Suixiong Cai⁵, Ye Edward Tian⁵, Jun Bao⁵, Ning Ma⁵, Chen Wang⁵, Ming Zhang⁵, Baoyue Li⁵, Mingchuan Guo⁵, Ruiyu Zhou⁵, Xiaozhu Wang⁵, Cong Xu⁵, Paul de Souza⁴

Affiliations

¹ Department of Medical Oncology, Blacktown Hospital and University of Sydney, Sydney, New South Wales, Australia.
² Medical Oncology, Nucleus Network, Melbourne, Victoria, Australia.
³ Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁴ Western Sydney University Medical School, Campbelltown, New South Wales, Australia.
⁵ IMPACT Therapeutics Inc., Shanghai, China.

PMID: 36718624
DOI: 10.1002/cncr.34662

Abstract

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.

Keywords: Australia; BRCA mutation; PARP inhibitor; recommended phase 2 dose; senaparib; solid tumors.

Publication types

Clinical Trial, Phase I
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / adverse effects
Antineoplastic Agents* / therapeutic use
Australia
Humans
Maximum Tolerated Dose
Neoplasms* / pathology
Poly(ADP-ribose) Polymerase Inhibitors* / adverse effects
Poly(ADP-ribose) Polymerase Inhibitors* / therapeutic use

Substances

Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors

Associated data

ClinicalTrials.gov/NCT03507543