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.