452P - A study of ABT-767 in advanced solid tumors with BRCA 1 and BRCA 2 mutations and high grade serous ovarian, fallopian tube, or primary peritoneal c...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Drug Development
Gynaecologic Malignancies
Translational Research
Presenter Maja J.A. De Jonge
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors M.J.A. De Jonge1, C. van Herpen2, J.A. Gietema3, S. Shepherd4, R. Koornstra2, A. Jager5, M. Den Hollander6, M. Dunbar7, R. Hetman8, C. Serpenti9, H. Xiong10, M. Zhu11, V.L. Giranda4
  • 1Department Of Medical Oncology, Erasmus University Medical Center, NL-3075 EA - Rotterdam/NL
  • 2Department Of Medical Oncology/452, Radboud University Medical Centre Nijmegen, 6500 HB - Nijmegen/NL
  • 3Medical Oncology, University Medical Center Groningen, Groningen/NL
  • 4Oncology, AbbVie Oncology, North Chicago/US
  • 5Medical Oncology, Erasmus MCDaniel den Hoed Cancer Center, NL-3075 EA - Rotterdam/NL
  • 6Medical Oncology, University Medical Center Groningen, 9700 RB - Groningen/NL
  • 7R43v, AbbVie, 60064 - North Chicago/US
  • 8R477, AbbVie, 60064 - North Chicago/US
  • 9R&d, Clinical Operations, AbbVie B.V., Hoofddorp/NL
  • 10R4pk, AbbVie, North Chicago/US
  • 11R436, AbbVie, 60064 - North Chicago/US

Abstract

Aim

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.