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First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors

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Summary

Purpose Filanesib (ARRY-520) is a highly selective, targeted inhibitor of kinesin spindle protein (KSP) inhibitor that induces mitotic arrest and subsequent tumor cell death. This first-in-human Phase 1 study evaluated dose-limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for filanesib administered as a 1-h 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 3-week cycle (Initial Schedule) or Days 1 and 2 of each 2-week cycle (Alternate Schedule). A standard 3 + 3 dose-escalation 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 Forty-one patients received filanesib. The MTD was equivalent for both the Initial and Alternate Schedules (2.50 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 3.20 mg/m2/cycle). Neurotoxicity related to filanesib was not observed. Dose-proportional increases in filanesib exposure were observed. The half-life 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 target-specific pharmacodynamic effects.

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Acknowledgments

Medical 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 contributions.

Compliance with ethical standards

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Disclosure of potential conflicts of interest

K. Litwiler, M. Ptaszynski, D. Roseberry, S. Rush, J. Schreiber and H.M. Simmons are current or former employees of Array BioPharma Inc. and hold or have held stock and/or stock options in Array BioPharma Inc. P.M. LoRusso, E.A. Sausville, P.H. Goncalves, L. Casetta and J.A. Carter declare that they have no conflicts of interest.

Funding

This study was funded by Array BioPharma, Inc., Boulder, CO.

Ethical standards

This 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.

Prior presentations

Preliminary results presented in poster format at the 2010 American Society of Clinical Oncology Annual Meeting; Chicago, Illinois, USA; 4–8 June 2010. J Clin Oncol 2010;28:15 s(suppl; abstr 2570).

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Author notes

  1. Patricia M. LoRusso

    Present address: Yale University School of Medicine, New Haven, CT, USA

Authors and Affiliations

  1. Wayne State University/Karmanos Cancer Institute, 4100 John R Street, Detroit, MI, 48201, USA

    Patricia M. LoRusso, Priscila H. Goncalves & Lindsay Casetta

  2. Greenebaum Cancer Center, University of Maryland, 22 South Greene Street, Baltimore, MD, 21201, USA

    Judith A. Carter & Edward A. Sausville

  3. Array BioPharma Inc., 3200 Walnut Street, Boulder, CO, 80301, USA

    Kevin Litwiler, Dale Roseberry, Selena Rush, Jennifer Schreiber, Heidi M. Simmons & Mieke Ptaszynski

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  1. Patricia M. LoRusso
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Correspondence to Patricia M. LoRusso.

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LoRusso, P.M., Goncalves, P.H., Casetta, L. et al. First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors. Invest New Drugs 33, 440–449 (2015). https://doi.org/10.1007/s10637-015-0211-0

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