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

Purpose BRCA1 or BRCA2 mutated cancers ( BRCA mut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCA mut and BRCA wt ovarian and basal-like breast cancers. This phase I study determined the recommended...

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Published in:Cancer chemotherapy and pharmacology 2022-05, Vol.89 (5), p.721-735
Main Authors: 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, Jiuping, Zhang, Yiping, Parchment, Ralph E., Chen, Alice, Duan, Wenrui, Giranda, Vincent, Shepherd, Stacie P., Ivy, S. Percy, Chu, Edward, Beumer, Jan H.
Format: Article
Language:English
Subjects:
Antineoplastic Combined Chemotherapy Protocols
Benzimidazoles
BRCA1 protein
BRCA1 Protein - genetics
BRCA2 protein
BRCA2 Protein - genetics
Breast cancer
Cancer Research
DNA repair
Female
Homologous recombination
Homology
Humans
Lymphopenia
Lymphopenia - chemically induced
Lymphopenia - drug therapy
Medicine
Medicine & Public Health
Nausea
Nausea - chemically induced
Oncology
Original Article
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - genetics
Ovaries
Patients
Pharmacodynamics
Pharmacology/Toxicology
Platinum
Platinum - therapeutic use
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerase Inhibitors - adverse effects
Seizures
Seizures - chemically induced
Toxicity
Triple Negative Breast Neoplasms - drug therapy
Vomiting
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Summary:Purpose BRCA1 or BRCA2 mutated cancers ( BRCA mut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCA mut and BRCA wt 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 BRCA mut cohort ( n  = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCA wt 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 BRCA mut carrier, grade 2 seizure at 400 mg BID in a patient with BRCA wt cancer, and grade 2 seizure at 500 mg BID in a BRCA mut 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 BRCA mut overall, and 37% (95% CI 21–55%) at 400 mg BID and above. In BRCA wt, 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 BRCA mut and BRCA wt cancers.
ISSN:0344-5704
1432-0843
1432-0843
DOI:10.1007/s00280-022-04430-6