Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study
| Autor: | Yasutoshi Kuboki, Yuko Mori, Yoichi Naito, Takahiro Kogawa, Nobuaki Matsubara, Shigeyuki Toyoizumi, Takashi Nagasawa, Kenichi Harano, Masafumi Ikeda, Natsuki Hori |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
0301 basic medicine medicine.medical_specialty Maximum Tolerated Dose Anemia Talazoparib Cmax Antineoplastic Agents Phase 1 Poly(ADP-ribose) Polymerase Inhibitors Gastroenterology 03 medical and health sciences 0302 clinical medicine Asian People Japan Pharmacokinetics Phase I Studies Neoplasms Internal medicine medicine Maculopapular rash Clinical endpoint Humans Pharmacology (medical) Neoplasm Metastasis Adverse effect Stomatitis Aged Pharmacology Dose-Response Relationship Drug business.industry Middle Aged medicine.disease PARP inhibitor 030104 developmental biology Oncology 030220 oncology & carcinogenesis Phthalazines Safety Neoplasm Grading medicine.symptom business |
| Zdroj: | Investigational New Drugs |
| ISSN: | 1573-0646 0167-6997 |
| Popis: | SummaryBackground: 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). |
| Databáze: | OpenAIRE |
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