Abstract A218: Pharmacokinetics of orally administered rucaparib in patients with advanced solid tumors.
Authors: Shapiro Geoffrey , Kristeleit Rebecca , Middleton Mark , Burris Howard , Molife L. Rhoda , Evans Jeff , Wilson Richard , LoRusso Patricia , Spicer James , Dieras Veronique , Patel Manish , Dominy Erin , Simpson Dayna , Giordano Heidi , Allen Andrew R. , Jaw-Tsai Sarah S. , Plummer Ruth 
Published: August 2014

Abstract
Background: Oral cancer therapies are often complicated by variable absorption leading to highly variable plasma pharmacokinetics (PK) and thus unpredictable toxicity and efficacy. Rucaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), is being developed for treatment of tumors associated with homologous recombination repair deficiency with a pre-specified target plasma trough level. While efficacy has been shown for PARPis, dose interruptions/reductions due to adverse events (AEs) are common for PARPis. Here, we report the PK results for oral rucaparib in patients and assess exposure predictability.
Methods: Rucaparib PK was studied in two Phase I studies. CO-338-010 (N=39) is an ongoing Phase I/II monotherapy study examining safety, PK, and preliminary efficacy of oral rucaparib administered continuously 40-500 mg once (qd) or 240-600 mg twice daily (bid) (NCT01482715). The effect of a high-fat meal on rucaparib PK was examined at 40 mg (N=3) and 300 mg (N=6). A4991014 (N=53) is an ongoing Phase I study currently assessing rucaparib in combination with carboplatin (CBDCA) (NCT01009190). Patients received lead-in oral rucaparib on Day -5 followed by CBDCA on Day 1 and oral rucaparib qd on Days 1-14 of every 21-day treatment cycle. Patients in earlier cohorts also had a single lead-in dose of intravenous rucaparib for calculating oral bioavailability. Plasma rucaparib levels were determined using a validated LC-MS/MS method.
Results: Rucaparib exhibited good oral absorption with a dose-independent oral bioavailability of 36% and median Tmax ranging from 1 to 6 hours. Exposure generally exhibited dose proportional kinetics up to 1200 mg daily dose (600 mg bid). The target trough level of 2 μM was achieved in 100% of patients (n=14) at ≥240 mg bid with low inter-patient variability (&lt;4-fold) within each dose group. Steady state trough levels also exhibited low intra-patient variability (24% CV). No sporadically high exposures were observed. In the combination study, rucaparib PK at doses of 80 to 360 mg qd was not meaningfully altered by concomitant AUC3 to AUC5 CBDCA. Rucaparib half-life of ∼17 hours was independent of dose. There was no food effect; patients may take rucaparib on an empty stomach or with food. Overall variability of exposure was low, both intra- and inter- patient.
Conclusions: Rucaparib showed desirable dose- and time- independent PK with low inter- and intra- patient variability in exposure compared to published olaparib data. Predictable PK following oral dosing may lead to low rates of over- and under- dosing, potentially minimizing AEs associated with high unpredictable exposures, an important attribute for maintenance therapy. Rucaparib's low inter-patient variability is beneficial for uniform flat dosing strategies. This will be explored in the two upcoming studies, ARIEL2 and ARIEL3.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A218.
Citation Format: Geoffrey Shapiro, Rebecca Kristeleit, Mark Middleton, Howard Burris, L. Rhoda Molife, Jeff Evans, Richard Wilson, Patricia LoRusso, James Spicer, Veronique Dieras, Manish Patel, Erin Dominy, Dayna Simpson, Heidi Giordano, Andrew R. Allen, Sarah S. Jaw-Tsai, Ruth Plummer. Pharmacokinetics of orally administered rucaparib in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A218.