Firstinhuman phase 1 study of filanesib ARRY52

Authors: Patricia M LoRusso Priscila H Goncalves Lindsay Casetta Judith A Carter Kevin Litwiler Dale Roseberry Selena Rush Jennifer Schreiber Heidi M Simmons Mieke Ptaszynski Edward A Sausville

Publish Date: 2015/02/17

Volume: 33, Issue: 2, Pages: 440-449

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Abstract

Purpose Filanesib ARRY520 is a highly selective targeted inhibitor of kinesin spindle protein KSP inhibitor that induces mitotic arrest and subsequent tumor cell death This firstinhuman Phase 1 study evaluated doselimiting toxicities DLTs and determined a maximum tolerated dose MTD for filanesib administered as a 1h intravenous infusion on 2 treatment schedules in patients with advanced solid tumors The pharmacokinetics PK pharmacodynamics and preliminary efficacy of filanesib were also evaluated Methods Filanesib was administered on Day 1 of each 3week cycle Initial Schedule or Days 1 and 2 of each 2week cycle Alternate Schedule A standard 3 + 3 doseescalation design was employed An expansion cohort was conducted at the MTD of the Initial Schedule Filanesib PK was evaluated in plasma both schedules and urine Initial Schedule only Monopolar spindle formation was evaluated in biopsies taken from patients in the expansion cohort Results Fortyone patients received filanesib The MTD was equivalent for both the Initial and Alternate Schedules 250 mg/m2/cycle The prevalence of neutropenia as a DLT for both schedules necessitated adding prophylactic filgrastim to another dose escalation on the Alternate Schedule highest tolerated dose 320 mg/m2/cycle Neurotoxicity related to filanesib was not observed Doseproportional increases in filanesib exposure were observed The halflife for filanesib was ~70 h Monopolar spindles in patient biopsy samples indicated KSP inhibition Stable disease was the best tumor response observed in 18  7/39 of evaluable patients Conclusion Filanesib provided exposures with acceptable tolerability and evidence of targetspecific pharmacodynamic effectsMedical writing support was provided by Allison L Marlow and Sara Symons Additional clinical pharmacology support was provided by Burgess Freeman Sharon Karan Jason Neale and Micaela Reddy Additional translational medicine support was provided by Duncan Walker and Brian Tunquist The authors thank the participating patients their families study Investigators the clinic nurses and the study coordinators at both institutions for their invaluable contributionsK Litwiler M Ptaszynski D Roseberry S Rush J Schreiber and HM Simmons are current or former employees of Array BioPharma Inc and hold or have held stock and/or stock options in Array BioPharma Inc PM LoRusso EA Sausville PH Goncalves L Casetta and JA Carter declare that they have no conflicts of interestThis study was conducted in accordance with applicable ICH Good Clinical Practice guidelines and was approved by the institutional review boards of all participating sites Written informed consent was obtained from all individual participants included in the study

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