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

• Published in: Cancer chemotherapy and pharmacology Vol. 89; no. 5; pp. 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: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-05-2022; Springer Nature B.V
• 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; Pharmacodynamics; Phase I; DNA damage; Veliparib; PARP inhibitor; Solid tumors; BRCA1; Pharmacokinetics; BRCA2; Ovarian cancer; Triple-negative breast cancer
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-022-04430-6

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.