A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer

Julia Manzo, UPMC Hillman Cancer Center
Shannon Puhalla, UPMC Hillman Cancer Center
Shalu Pahuja, Department of Medicine, School of Medicine
Fei Ding, UPMC Hillman Cancer Center
Yan Lin, UPMC Hillman Cancer Center
Leonard Appleman, UPMC Hillman Cancer Center
Hussein Tawbi, UPMC Hillman Cancer Center
Ronald Stoller, UPMC Hillman Cancer Center
James J. Lee, UPMC Hillman Cancer Center
Brenda Diergaarde, University of Pittsburgh, Pittsburgh
Brian F. Kiesel, UPMC Hillman Cancer Center
Jing Yu, Magee-Womens Hospital of University of Pittsburgh Medical Center
Antoinette R. Tan, Rutgers Cancer Institute of New Jersey
Chandra P. Belani, Penn State Cancer Institute, Penn State College of Medicine
Helen Chew, University of California Davis
Agustin A. Garcia, Department of Medicine, Louisiana State University, New Orleans, LA, USA.
Robert J. Morgan, Department of Molecular Pharmacology, City of Hope Beckman Research Institute
Andrea E. Wahner Hendrickson, Department of Oncology, Mayo Clinic, Rochester, MN, USA.
Daniel W. Visscher, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Rachel M. Hurley, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
Scott H. Kaufmann, Department of Oncology, Mayo Clinic, Rochester, MN, USA.
Elizabeth M. Swisher, Department of Obstetrics and Gynecologic, University of Washington, Seattle, WA, USA.
Steffi Oesterreich, University of Pittsburgh School of Medicine
Tiffany Katz, University of Pittsburgh School of Medicine, Pittsburgh
Jiuping Ji, Frederick National Laboratory for Cancer Research, Frederick
Yiping Zhang, Frederick National Laboratory for Cancer Research
Ralph E. Parchment, Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
Alice Chen, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis
Wenrui Duan, The Florida International University

Document Type

Article

Publication Date

5-1-2022

Publication Title

Cancer chemotherapy and pharmacology

Abstract

PURPOSE: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients. PATIENTS AND METHODS: Patients (n = 98) were dosed with veliparib 50-500 mg twice daily (BID). The BRCAmut cohort (n = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCAwt cohort (n = 28) consisted primarily of breast cancer (86%). The MTD, DLT, adverse events, PK, PD, and clinical response were assessed. RESULTS: DLTs were grade 3 nausea/vomiting at 400 mg BID in a BRCAmut carrier, grade 2 seizure at 400 mg BID in a patient with BRCAwt cancer, and grade 2 seizure at 500 mg BID in a BRCAmut carrier. Common toxicities included nausea (65%), fatigue (45%), and lymphopenia (38%). Grade 3/4 toxicities were rare (highest lymphopenia at 15%). Overall response rate (ORR) was 23% (95% CI 13-35%) in BRCAmut overall, and 37% (95% CI 21-55%) at 400 mg BID and above. In BRCAwt, ORR was 8% (95% CI 1-26%), and clinical benefit rate was 16% (95% CI 4-36%), reflecting prolonged stable disease in some patients. PK was linear with dose and was correlated with response and nausea. CONCLUSIONS: Continuous veliparib is safe and tolerable. The RP2D was 400 mg BID. There is evidence of clinical activity of veliparib in patients with BRCAmut and BRCAwt cancers.

First Page

721

Last Page

735

DOI

10.1007/s00280-022-04430-6

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