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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

  1. Author:
    Manzo, Julia
    Puhalla, Shannon
    Pahuja, Shalu
    Ding, Fei
    Lin, Yan
    Appleman, Leonard
    Tawbi, Hussein
    Stoller, Ronald
    Lee, James J
    Diergaarde, Brenda
    Kiesel, Brian F
    Yu, Jing
    Tan, Antoinette R
    Belani, Chandra P
    Chew, Helen
    Garcia, Agustin A
    Morgan, Robert J
    Wahner Hendrickson, Andrea E
    Visscher, Daniel W
    Hurley, Rachel M
    Kaufmann, Scott H
    Swisher, Elizabeth M
    Oesterreich, Steffi
    Katz, Tiffany
    Ji,Jay
    Zhang, Yiping
    Parchment, Ralph E
    Chen, Alice
    Duan, Wenrui
    Giranda, Vincent
    Shepherd, Stacie P
    Ivy, S Percy
    Chu, Edward
    Beumer, Jan H [ORCID]

  2. Author Address

    Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA., Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, PA, USA., Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA., Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA, USA., Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, USA., Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA., Levine Cancer Institute, Charlotte, NC, USA., Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, USA., Division of Hematology/Oncology, Department of Medicine, University of California Davis, Sacramento, CA, USA., Department of Medicine, Louisiana State University, New Orleans, LA, USA., Department of Molecular Pharmacology, City of Hope Beckman Research Institute, Duarte, CA, USA., Department of Oncology, Mayo Clinic, Rochester, MN, USA., Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Department of Obstetrics and Gynecologic, University of Washington, Seattle, WA, USA., Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA., Department of Human and Molecular Genetics, The Florida International University, Miami, FL, USA., AbbVie Laboratories, North Chicago, IL, USA., Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. beumerj@gmail.com., Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. beumerj@gmail.com., Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA, USA. beumerj@gmail.com.,
    1. Year: 2022
    2. Date: Apr 18
    3. Epub Date: 2022 04 18
  2. Journal: Cancer Chemotherapy and Pharmacology
    1. 89
    2. 5
    3. Pages: 721-735
  4. Type of Article: Article
  1. Abstract:

    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 (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. 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. 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. © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

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External Sources

  1. View Full Text
  2. DOI: 10.1007/s00280-022-04430-6
  3. PMID: 35435472
  4. View record in Web of Science®
  5. WOS: 000784028700002
  6. PII : 10.1007/s00280-022-04430-6

Library Notes

  1. Fiscal Year: FY2021-2022
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