M. D. de Jonge, C. V. van Herpen, J. Gietema
Sep 1, 2014
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Influential Citations
6
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Quality indicators
Journal
Annals of oncology : official journal of the European Society for Medical Oncology
Abstract
ABSTRACT Background: ABT-767 is a potent oral inhibitor of PARP-1 and -2. Malignancies with defects in homologous repair are more dependent on PARP for DNA repair than normal cells. Objectives of this study are to determine safety and PK of ABT-767 in pts with high grade serous ovarian cancer (OvC), fallopian tube, or primary peritoneal cancer or with BRCA1 or BRCA2 germ line mutation with associated solid tumors. Methods: ABT-767 was administered in escalating doses from 20mg QD to 500 mg BID on days 1 to 28 of a 28 day cycle to determine the RPTD. Treatment emergent adverse events (TEAEs) were reported according to NCI-CTCAE v 4.03; tumor response was measured by RECIST 1.1. PK analysis for single and multiple doses to assess dose proportionality, linear kinetics, and effect of food on bioavailability were performed. Results: A total of 92 pts were treated, 45% had germline BRCA mutations. 86 (93%) had received at least one prior platinum-containing regimen with 57/92 (62%) having a platinum-free interval of 6 months or less. ABT-767 Cmax and AUC were dose-proportional between 20 to 500 mg BID, with a half- life of approx. 3.7 hours. Food had no effect on ABT-767 bioavailability. The most common (≥ 30% of pts) TEAEs were nausea (77%), vomiting (56%), diarrhea (44%), constipation (43%), abdominal pain (42%), dyspepsia (34%) and anemia (30%). Dose limiting toxicities occurring during the first cycle of therapy included angina pectoris (n = 1, 20 mg BID) and anemia (n = 1; 500 mg BID) in the escalation cohorts. In the 400 mg-500 mg BID cohorts, a decrease in hemoglobin leading to grade 3 anemia was observed (nadir at approx. 6 weeks). 500 mg BID was deemed intolerable due to G3 anemia and general malaise, and the RPTD was determined to be 400mg BID. The response rate for pts with measurable disease at baseline (n = 79) was 18%. The 6 month TTP rate was 22% overall, 20% for OvC and 40% for all other cancers. Conclusions: ABT-767 at 400 mg BID has an acceptable safety profile for Phase 2 studies. Preliminary data suggests that ABT-767 has single-agent activity in BRCA-mutated tumors and high-grade serous OvC. Disclosure: S. Shepherd, M. Dunbar, R. Hetman, C. Serpenti, H. Xiong, M. Zhu and V.L. Giranda: The author is employed by AbbVie and may own stock. All other authors have declared no conflicts of interest.