Abstract 4512: Onapristone in patients (pts) with progesterone receptor (PR)-expressing cancers: PK results from part 1 of a randomized, parallel-dose phase 1 study
Authors: Lokiec Francois , Italiano Antoine , Varga Andrea , Bonneterre Jacques , Campone Mario , Leary Alexandra , Rezai Keyvan , Sablin Marie-Paule , Bexon Alice , Proniuk Stefan , Gilles Erard , Bisaha Joseph , Zukiwski Alexander , Cottu Paul 
Published: August 2015

Abstract
Background: Onapristone is a type I PR antagonist, which prevents PR-induced DNA transcription; its anti-cancer activity is well-documented. The reported T1/2 is 2-4h, so an extended-release (ER) tablet was designed to mitigate Cmax spikes, which may be involved in the liver function test (LFT) elevations seen with an immediate-release (IR) onapristone.
Materials and methods: The expansion cohort of this multi-center, open-label, randomized, parallel-group, 2-stage Ph1 study (NCT02052128) is ongoing in endometrioid cancers. Female pts ≥18 years with PR-expressing tumors (including endometrial, ovarian, breast) were eligible. The primary endpoint was to recommend a Ph2 dose of ER onapristone (RP2D), with a 57-day DLT observation period; secondary endpoints include: safety, efficacy, and real-time PK. Pts received onapristone ER 10, 20, 30, 40 or 50 mg BID, or IR tablets 100 mg QD until progressive disease or intolerability in Stage 1.
Results: 52 pts are enrolled (by 2 December 2014). Validated PK data are available for 35 pts. Onapristone AUC and Cmax are dose-proportional across all dose levels including 100mg IR (Table 1), with coefficients of determination (r2) of 0.76 and 0.79, respectively. The bioavailability of onapristone ER vs IR is high. Steady state is consistently attained at approximately 8 days (200 h), with T1/2 at 8-12 h, longer than previously published, with no evidence of onapristone accumulation through day 57.
Table 1.Onapristone PK parameters following first doseOnapristone formERERERERERIRDose (mg)10 bid20 bid30 bid40 bid50 bid100 qdn666566Mean AUC (μg/L*h)51761765015450174403161067980CV%47.7202.722.943.070.555.1Min348029411200038091515033330Median4654860815040207302593062270Max952440000214302667062500125000Mean Cmax (μg/L)226.8676.3767.3641.614594296CV%46.0140.115.693.646.862.8Min922206762914591556Median218403732.547414953726Max4031466988134424927507
Conclusions: This study reveals a longer than anticipated onapristone T1/2, which nevertheless supports using an ER formulation. AUC and Cmax data are dose proportional and allow dosing flexibility. Protracted exposure minimizing Cmax spikes is best achieved with a twice-daily, ER formulation. There were no LFT elevations in the absence of liver metastases in 30 patients exposed to the ER formulation. The RP2D is 50 mg bid based on safety and PK, to be further explored in the endometrioid cohort.
Citation Format: Francois Lokiec, Antoine Italiano, Andrea Varga, Jacques Bonneterre, Mario Campone, Alexandra Leary, Keyvan Rezai, Marie-Paule Sablin, Alice Bexon, Stefan Proniuk, Erard Gilles, Joseph Bisaha, Alexander Zukiwski, Paul Cottu. Onapristone in patients (pts) with progesterone receptor (PR)-expressing cancers: PK results from part 1 of a randomized, parallel-dose phase 1 study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4512. doi:10.1158/1538-7445.AM2015-4512