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.
Original language | English (US) |
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Pages (from-to) | 721-735 |
Number of pages | 15 |
Journal | Cancer chemotherapy and pharmacology |
Volume | 89 |
Issue number | 5 |
DOIs | |
State | Published - May 2022 |
Keywords
- BRCA1
- BRCA2
- DNA damage
- Ovarian cancer
- PARP inhibitor
- Pharmacodynamics
- Pharmacokinetics
- Phase I
- Solid tumors
- Triple-negative breast cancer
- Veliparib
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)