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Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers

Lookup NU author(s): Dr Ashleigh Herriott, Dr Miranda Morton, Professor Nicola Curtin

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Abstract

© 2017 AACR. Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatmentrelated adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation- associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day. SIGNIFICANCE: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer.


Publication metadata

Author(s): de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, Kaye S, Sachdev J, Heymach J, Smith DC, Henshaw JW, Herriott A, Patterson M, Curtin NJ, Byers LA, Wainberg ZA

Publication type: Article

Publication status: Published

Journal: Cancer Discovery

Year: 2017

Volume: 7

Issue: 6

Pages: 620-629

Print publication date: 01/06/2017

Online publication date: 27/02/2017

Acceptance date: 21/02/2017

ISSN (print): 2159-8274

ISSN (electronic): 2159-8290

Publisher: American Association for Cancer Research Inc.

URL: https://doi.org/10.1158/2159-8290.CD-16-1250

DOI: 10.1158/2159-8290.CD-16-1250

PubMed id: 28242752


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