A phase 1 study of PARP-inhibitor ABT-767 in advanced solid tumors with BRCA1/2 mutations and high-grade serous ovarian, fallopian tube, or primary peritoneal cancer

Summary Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Pa...

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Bibliographic Details
Published in:	Investigational new drugs Vol. 36; no. 5; pp. 828 - 835
Main Authors:	van der Biessen, Diane A. J., Gietema, Jourik A., de Jonge, Maja J. A., Desar, Ingrid M. E., den Hollander, Martha W., Dudley, Matthew, Dunbar, Martin, Hetman, Robert, Serpenti, Camille, Xiong, Hao, Mittapalli, Rajendar K., Timms, Kirsten M., Ansell, Peter, Ratajczak, Christine K., Shepherd, Stacie Peacock, van Herpen, Carla M. L.
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-10-2018 Springer Nature B.V
Subjects:	Adenosine diphosphate Anemia Appetite loss Bioavailability Biomarkers BRCA1 protein BRCA2 protein Breast cancer Cancer Dosage Fallopian tube Fallopian tubes Fatigue Gastric cancer Homologous recombination Homology Inhibitors Medicine Medicine & Public Health Mutation Nausea Oncology Ovarian cancer Patients Peritoneal cancer Peritoneum Pharmacokinetics Pharmacology Pharmacology/Toxicology Phase I Studies Platinum Poly(ADP-ribose) Poly(ADP-ribose) polymerase Response rates Ribose Safety Sensitivity Solid tumors Studies Toxic diseases Toxicity Tumors BRCA Solid tumor Homologous recombination deficiency PARP inhibitor Ovarian cancer
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Summary:	Summary Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500 mg BID and half-life of ~2 h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400 mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2 , homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7 months) versus HRD negative patients (1.8 months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400 mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767.
ISSN:	0167-6997 1573-0646
DOI:	10.1007/s10637-017-0551-z