RT Journal Article
SR Electronic
T1 Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline <em>BRCA1/2</em> Mutations and Selected Sporadic Cancers
JF Cancer Discovery
JO Cancer Discov
FD American Association for Cancer Research
SP 620
OP 629
DO 10.1158/2159-8290.CD-16-1250
VO 7
IS 6
A1 de Bono, Johann
A1 Ramanathan, Ramesh K.
A1 Mina, Lida
A1 Chugh, Rashmi
A1 Glaspy, John
A1 Rafii, Saeed
A1 Kaye, Stan
A1 Sachdev, Jasgit
A1 Heymach, John
A1 Smith, David C.
A1 Henshaw, Joshua W.
A1 Herriott, Ashleigh
A1 Patterson, Miranda
A1 Curtin, Nicola J.
A1 Byers, Lauren Averett
A1 Wainberg, Zev A.
YR 2017
UL http://cancerdiscovery.aacrjournals.org/content/7/6/620.abstract
AB 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. Treatment-related 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. Cancer Discov; 7(6); 620–9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539