Abstract B152: Clinical pharmacokinetics of an improved tablet formulation of ONT-380 in HER2+ metastatic breast cancer patients
Authors: Vo Alex C. , Walker Luke , Hausman Diana , Peterson Scott 
Published: May 2016

Abstract
Background: ONT-380 is an orally active, reversible small molecule HER2 kinase inhibitor with nanomolar potency and 500-fold selectivity compared to EGFR. In a Phase 1 single agent study using a powder-in-capsule formulation, ONT 380 was well tolerated and provided clinical benefit to patients with HER2+ disease with minimal EGFR-related toxicities. ONT-380 is currently being evaluated in two phase 1b combination studies in patients with HER2+ advanced metastatic breast cancer using an improved tablet formulation.
Methods: The pharmacokinetics of an amorphous dispersion tablet formulation of ONT-380 were evaluated in two open-label phase Ib dose range finding combination studies. In the first study, ONT-380 pharmacokinetics were determined on cycle 1 day 1 and cycle 2 day 1 (steady state) in patients co-administered ado-trastuzumab emtansine (T-DM1). The pharmacokinetics of DM1 were also evaluated at these same time intervals. In the second study, ONT-380 pharmacokinetics were studied in patients co-administered capecitabine. For this study, drug pharmacokinetics of ONT-380 were measured at cycle 1 day 14 to measure ONT-380 levels when co-administered with capecitabine, and at cycle 1 day 21 to measure ONT-380 pharmacokinetics after cessation of capecitabine administration. In addition, the pharmacokineitics of capecitabine and its catabolites/metabolites DFCR, DFUR, 5FU, and FBAL were also evaluated for potential drug-drug interactions with ONT-380.
Results: Pharmacokinetics of ONT-380 were determined for patients treated at 300 mg BID and 350 mg BID tablets. Drug levels at both doses were well above the level corresponding to &gt;90% inhibition of HER2 based on cellular potency assays. At steady state, ONT-380 half-life was 4-7 h and time to Cmax was approximately 2 h. The tablet formulation displayed reduced AUC variability (CV ∼ 30%). In the T-DM1 combination study, ONT-380 dosed at 300 mg BID yielded a steady state mean Cmax of 802 ng/ml, and a mean AUC_daily of 10207 h*ng/ml. In the capecitabine combination study, ONT-380 dosed at 300 mg BID yielded a steady state mean Cmax of 781 ng/ml and a mean AUC_daily of 9998 h*ng/ml. At 350 mg BID, the mean Cmax remained relatively unchanged while the mean AUC_daily increased proportionally compared to the 300 mg BID dose. The pharmacokinetics of ONT-380 alone or in combination with T-DM1 or capecitabine were very similar suggesting that there was no drug drug interactions between ONT-380 and these therapeutics. The pharmacokinetics of DM1 and capecitabine and its catabolites/metabolites were also similar to published literature values.
Conclusion: At steady state, the drug exposure for ONT-380 at the MTD dose of 300 mg BID indicated the newly improved tablet formulation resulted in approximately two-times greater drug bioavailability compared to the old powder-in-capsule (PIC) formulation.
Citation Format: Alex C. Vo, Luke Walker, Diana Hausman, Scott Peterson. Clinical pharmacokinetics of an improved tablet formulation of ONT-380 in HER2+ metastatic breast cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B152.