Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study

Abstract

Background: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies.

Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib.

Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily.

Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).

Keywords: PARP inhibitor; Pharmacokinetics; Phase 1; Safety; Talazoparib.

Conflict of interest statement

Yoichi Naito has received lecture fees, honoraria, or other fees from Pfizer, Novartis, and Chugai and research funds from Roche. Yasutoshi Kuboki has received lecture fees, honoraria, or other fees from Taiho Pharmaceutical and research funds from Taiho Pharmaceutical, Takeda Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Daichi-Sankyo, Boehringer Ingelheim, Incyte, Amgen KK, and Chugai Pharmaceutical. Masafumi Ikeda has received lecture fees, honoraria, or other fees from Novartis Pharma, Bayer, Eisai, Taiho Pharmaceutical, Eli Lilly Japan, and Chugai Pharmaceutical and research funds from Bayer, Yakult, ASLAN, Ono Pharmaceutical, Eisai, AstraZeneca, Chugai Pharmaceutical, Bristol Myers Squibb, Merck Serono, Novartis Pharma, Merck Sharp & Dome, and J-Pharma. Nobuaki Matsubara has received research funds from Pfizer Japan Inc. Shigeyuki Toyoizumi, Yuko Mori, Natsuki Hori, and Takashi Nagasawa are employees of Pfizer and report ownership interest in Pfizer.

Kenichi Harano and Takahiro Kogawa have nothing to disclose.

© 2021. The Author(s).

Figures

Fig. 1

Individual laboratory valuesa for hemoglobin (a, b), neutrophils (c, d) and platelets (e, f) during single and multiple dosing with talazoparib 0.75 mg QD (a, c, e) or 1 mg QD (b, d, f), aLaboratory values are shown at scheduled visits only. Decreases in neutrophils and platelets were also observed at unscheduled visits. Patients could not start a next cycle until recovery of neutrophils to ≥1 × 109/L and recovery of platelets to ≥75 × 109/L; bBaseline value is defined as the last value collected on or prior to the first dose date of study drug, QD, once daily