Abstract 1301: Investigation of a potential pharmacokinetic interaction between ABT-888 and topotecan in a phase I trial
Authors: Kayode Olumide , Reid Joel M. , Satele Danel V. , Tang Hui , Haluska Paul , Peethambaram Prema P. , Ames Matthew M. , Chen Alice , Kaufmann Scott H. , Northfelt Donald W. , Erlichman Charles , Menefee Michael E. 
Published: June 2012

Background: ABT-888 is an inhibitor of poly(ADP-ribose) polymerase1 (PARP1) and PARP2, two highly conserved enzymes implicated in DNA repair, maintenance of genomic stability, and regulation of transcription. Topotecan (TPT) is a water soluble camptothecin derivative with antitumor activity against ovarian tumors. The combination of ABT-888 with TPT is under investigation in phase I trials because PARP inhibition sensitizes tumors cells to TPT in vitro and in vivo. In those trials, the pharmacokinetics of TPT and ABT-888 are being studied to determine if ABT-888 levels are sufficient to modulate PARP activity and to investigate the potential interaction between TPT and ABT-888.

Methods: Advanced cancer patients with ECOG performance scores 0-2, adequate hematological, renal and hepatic function were treated with ABT-888 on days 1-3, 8-10, and 15-17 every 28 days. Topotecan was administered on days 2, 9 and 16 every 28 days. DLTs were defined as grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 anemia or ≥ grade 3 non-hematologic toxicities despite maximal supportive care. ABT-888 and Toptoecan pharmacokinetics were characterized in all patients. Analysis of urinary recovery is ongoing.

Results: In this ongoing Phase I trial, 13 female patients with ovarian (n=12) or breast (n=1) cancer have been enrolled to date and pharmacokinetic data is available for 12 of those patients. ABT-888/TPT dose levels are: Level 1- 10 mg/ 2 mg/m2, Level 2- 20 mg/2 mg/m2, Level 3- 10 mg/3 mg/m2, and Level 4- 20 mg/3 mg/m2. The combination of ABT-888 with topotecan has been tolerable, with no dose limiting toxicity, and dose escalation continues at dose level 5. Topotecan t1/2 and clearance values were 3.0 ± 0.5 hrs and 9.50 ± 1.51 L/hr/m2 when administered alone, and were not affected by administration with ABT-888. When administered alone, ABT-888 t1/2, Cmax, AUC0-∞ values after the 10 mg dose were 8.2 ± 2.4 hrs, 432 ± 217 nM, and 2568 ± 1300 nM*hr, respectively. ABT-888 t1/2, Cmax, AUC values after the 20 mg dose were 5.7 ± 3.1 hrs, 600 ± 165 nM, and 3870± 934 respectively. When administered with TPT, ABT-888 t1/2, Cmax, AUC values after the 10 mg dose were 7.2 ± 2.1 hrs, 412 ± 283 nM, and 2705± 1089 nM*hr are: nM*hr respectively. ABT-888 t1/2, Cmax and AUC values after the 20 mg dose combined with TPT were 5.8 ± 2.2 hrs, 664 ± 97.6 nM, and 4283± 936 nM*hr respectively.

Conclusions: Plasma clearance of TPT and ABT-888 does not appear to be altered when they are administered together. The effect of co-administration of these agents on renal clearance is presently under investigation and those results will be presented. This work was supported by NIH grants R25 GM75148-04, U01CA069912-16S and MM01-RR00585.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1301. doi:10.1158/1538-7445.AM2011-1301