Abstract 1169: Rational dose and schedule selection for the combination of paclitaxel and the investigational agent alisertib in recurrent ovarian cancer: optimization of therapeutic index based on translational hematological toxicity and exposure-efficacy modeling.
Authors: Ecsedy Jeffrey , Zhou Xiaofei , Mettetal Jay , Zhang Mengkun , Chakravarty Arijit , Manfredi Mark , Benaim Ely , Kleinfield Rob , Shyu Wen Chyi 
Published: August 2014

Alisertib (MLN8237), an investigational selective small molecule Aurora A kinase inhibitor, combined with taxanes (docetaxel or paclitaxel), demonstrated durable antitumor activity in multiple in vivo xenograft models. Based on these findings, a Phase I/II study was initiated to evaluate the safety and antitumor activity of alisertib administered BID on Days 1-3, 8-10 and 15-17 of 28-day cycles with weekly paclitaxel in recurrent ovarian cancer patients (study C14008).

As neutropenia is a common dose-limiting toxicity for taxanes and alisertib, a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to predict the time course of plasma PK versus absolute neutrophil count (ANC), to aid in dose and schedule selection for this combination. These models account for the time delay between drug exposure and decrease in ANC since the drugs affect the progenitor cells rather than the neutrophils directly. The model was fitted to PK and ANC data from Sprague-Dawley rats dosed over multiple days with alisertib and/or docetaxel. Differences in plasma protein binding and CFU-GM IC50s were used to correct for human-rat interspecies variation. This model of neutropenia predicted that decreasing the weekly paclitaxel dose from 80 to 60 mg/m2 would allow achievement of higher alisertib doses, a finding which was corroborated by the clinical experience. In addition, the model predicted that skipping alisertib dosing in the second week would further mitigate neutropenia, thereby providing an alternative dosing schedule for continued dose escalation of alisertib in the setting of dose-limiting neutropenia.

As multiple maximum tolerated doses (MTDs) were achieved in the C14008 study (e.g. alisertib with 80 or 60 mg/m2 weekly paclitaxel), an exposure-efficacy model was developed to interpret the achieved MTDs in the context of preclinical antitumor efficacy. Isobolograms relating alisertib and paclitaxel exposures to tumor growth inhibition were generated from in vivo efficacy studies in tumor-bearing mice. The clinically achieved exposures of alisertib and paclitaxel from the C14008 study were mapped onto the isobologram by correcting for mouse-human variation in plasma protein binding and maximum tolerated exposures for both agents. These isobolograms provided support for the choice of 60 mg/m2 weekly paclitaxel over 80 mg/m2, for the phase 2 portion of the C14008 study.

Taken together, the simultaneous application of predictive hematological toxicity modeling and exposure efficacy modeling using isobolograms provides a powerful basis for therapeutic index optimization and rationalizing dose selection for development of combination regimens.

Citation Format: Jeffrey Ecsedy, Xiaofei Zhou, Jay Mettetal, Mengkun Zhang, Arijit Chakravarty, Mark Manfredi, Ely Benaim, Rob Kleinfield, Wen Chyi Shyu. Rational dose and schedule selection for the combination of paclitaxel and the investigational agent alisertib in recurrent ovarian cancer: optimization of therapeutic index based on translational hematological toxicity and exposure-efficacy modeling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1169. doi:10.1158/1538-7445.AM2013-1169