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

Abstract

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/m(2)/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/m(2)/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.

• 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 2 Pg. 440-9 (Apr 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 25684345 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• KIF11 protein, human
• Membrane Proteins
• PMEPA1 protein, human
• Thiadiazoles
• filanesib
• Kinesins

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology)
• Area Under Curve
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Half-Life
• Humans
• Kinesins (antagonists & inhibitors)
• Male
• Maximum Tolerated Dose
• Membrane Proteins
• Middle Aged
• Neoplasms (drug therapy)
• Thiadiazoles (administration & dosage, adverse effects, pharmacokinetics, pharmacology)