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Author Notes:

Dr. Kari B. Wisinski, UW Carbone Cancer Center, University of Wisconsin, Madison, 1111 Highland Avenue, WIMR 6033, Madison, WI 53705 USA. Email: kbwisinski@medicine.wisc.edu

Ticiana A. Leal: Conceptualization, resources, funding acquisition, investigation, methodology, supervision, writing‐original draft, writing‐review, and editing. Marina N. Sharifi: Data curation, formal analysis, investigation, visualization, methodology, writing‐original draft, writing‐review, and editing. Nancy Chan: Conceptualization, resources, methodology, writing‐review, and editing. Robert Wesolowski: Conceptualization, resources, methodology, writing‐review, and editing. Anita A. Turk: Data curation, formal analysis, visualization, methodology, writing‐review, and editing. Justine Y. Bruce: Resources, writing‐review, and editing. Ruth M. O'Regan: Resources, writing‐review, and editing. Jens Eickhoff: Resources, methodology, writing‐review, and editing. Lisa M. Barroilhet: Resources, writing‐review, and editing. Jyoti Malhotra: Conceptualization, resources, methodology, writing‐review, and editing. Janice Mehnert: Resources, writing‐review, and editing. Eugenia Girda: Resources, writing‐review, and editing. Elizabeth Wiley: Resources and investigation. Natalie Schmitz: Resources, formal analysis, investigation, visualization, methodology, writing‐review, and editing. Shannon Andrews: Resources, formal analysis, investigation, and methodology. Glenn Liu: Conceptualization, resources, methodology, writing‐review, and editing. Kari B. Wisinski: Conceptualization, resources, supervision, funding acquisition, methodology, writing‐original draft, writing‐review, and editing.

The authors thank the UW Carbone Cancer Center Cancer Therapy Discovery and Development Program (CTD2) for essential administrative and logistical support. The authors thank Cameron Scarlett, Ph.D. and Molly Pellitteri Hahn, M.S. (Analytical Instrumentation Center; School of Pharmacy; University of Wisconsin, Madison, WI) for their expertise in analyzing plasma samples for talazoparib concentration on the facility's Sciex 5500. The authors also thank Shannon Andrews, Ph.D. (Cancer Pharmacology Lab, University of Wisconsin Carbone Cancer Center) for the biomarker analysis of PAR, γH2AX, and RAD51. The biomarker analysis was completed under the expertise of Jennifer Schehr, Ph.D., Anupama Singh, Ph.D. (UWCCC Circulating Biomarker Core), and Lauren Nettenstrom, M.S. (UWCCC Flow Lab). We thank Sara Matthiesen, B.S. (Cancer Pharmacology Lab Sample Acquisition Services) for Biospecimen management.

Ticiana A. Leal: Consulting ‐ Boehringer‐Ingelheim, Jazz Pharmaceuticals, Genentech, Lilly; Advisory Boards ‐ AstraZeneca, EMD Serono, Merck, Boehringer‐Ingelheim, Blueprint, Bayer, Janssen, Mirati. Lisa M. Barroilhet: Advisory boards ‐ Clovis, Astrazeneca, Kiayatec. Kari B. Wisinski: Research support ‐ Pfizer, Context, Novartis; Scientific Advisory boards ‐ Eisai, AstraZeneca, Pfizer, Sanofi, Daiichi Sankyo, Novartis. The other authors declare no potential conflict of interest.

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Research Funding:

Supported by UW Comprehensive Cancer Center Support Grant (CCSG) (P30CA014520) and The John Hopkins Translational Science Team and Consortium for ETCTN Studies (UM1CA186691).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • BMN673
  • carboplatin
  • paclitaxel
  • PARP
  • talazoparib
  • METASTATIC BREAST-CANCER
  • RELAPSED OVARIAN-CANCER
  • POLY(ADP-RIBOSE) POLYMERASE
  • DNA-REPAIR
  • OPEN-LABEL
  • MAINTENANCE THERAPY
  • BRCA1/2 MUTATION
  • DOSE-ESCALATION
  • DOUBLE-BLIND
  • OLAPARIB

A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782)

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Journal Title:

CANCER MEDICINE

Volume:

Volume 11, Number 21

Publisher:

, Pages 3969-3981

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. Methods: We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/m2 days 1, 8, 15 of 21-day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4–6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. Results: Forty-three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment-related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13-month median duration of maintenance. Conclusion: We have established the recommended phase II dose of Talazoparib at 250mcg on a 3- or 7-day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21-day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.

Copyright information:

© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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