Julia Manzo1, Shannon Puhalla1,2, Shalu Pahuja2, Fei Ding3, Yan Lin3,4, Leonard Appleman1,2, Hussein Tawbi1,2, Ronald Stoller1,2, James J Lee1,2, Brenda Diergaarde4, Brian F Kiesel1,5, Jing Yu6, Antoinette R Tan7,8, Chandra P Belani9, Helen Chew10, Agustin A Garcia11, Robert J Morgan12, Andrea E Wahner Hendrickson13, Daniel W Visscher14, Rachel M Hurley15, Scott H Kaufmann13,15, Elizabeth M Swisher16, Steffi Oesterreich17, Tiffany Katz17, Jiuping Ji18, Yiping Zhang18, Ralph E Parchment19, Alice Chen19, Wenrui Duan20, Vincent Giranda21, Stacie P Shepherd21, S Percy Ivy19, Edward Chu1,2, Jan H Beumer22,23,24. 1. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 2. Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 3. Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 4. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 5. Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA, USA. 6. Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, USA. 7. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. 8. Levine Cancer Institute, Charlotte, NC, USA. 9. Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, USA. 10. Division of Hematology/Oncology, Department of Medicine, University of California Davis, Sacramento, CA, USA. 11. Department of Medicine, Louisiana State University, New Orleans, LA, USA. 12. Department of Molecular Pharmacology, City of Hope Beckman Research Institute, Duarte, CA, USA. 13. Department of Oncology, Mayo Clinic, Rochester, MN, USA. 14. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 15. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. 16. Department of Obstetrics and Gynecologic, University of Washington, Seattle, WA, USA. 17. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 18. Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. 19. Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA. 20. Department of Human and Molecular Genetics, The Florida International University, Miami, FL, USA. 21. AbbVie Laboratories, North Chicago, IL, USA. 22. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. beumerj@gmail.com. 23. Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. beumerj@gmail.com. 24. Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA, USA. beumerj@gmail.com.
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.
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.
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