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First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced
Patricia M LoRusso1, Priscila H Goncalves, Lindsay Casetta
1Wayne State University/Karmanos Cancer Institute, 4100 John R Street, Detroit, MI, 48201, USA, patricia.lorusso@yale.edu.
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.
Insights
Filanesib, a kinesin spindle protein (KSP) inhibitor, showed acceptable tolerability and target engagement in a Phase 1 study for advanced solid tumors. The maximum tolerated dose was established, with no observed neurotoxicity.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Filanesib (ARRY-520) is a selective kinesin spindle protein (KSP) inhibitor designed to induce mitotic arrest and tumor cell death.
- KSP inhibition is a targeted approach for cancer therapy.
Purpose of the Study:
- To evaluate dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) of filanesib.
- To assess the pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of filanesib in patients with advanced solid tumors.
Main Methods:
- A first-in-human Phase 1, 3+3 dose-escalation study of filanesib administered intravenously.
- Two dosing schedules were evaluated: Day 1 of a 3-week cycle (Initial) and Days 1-2 of a 2-week cycle (Alternate).
- PK, pharmacodynamics (monopolar spindle formation), and efficacy were assessed. An expansion cohort was conducted at the MTD.
Main Results:
- The MTD for filanesib was 2.50 mg/m²/cycle on both schedules.
- Neutropenia was a DLT, leading to the use of prophylactic filgrastim and a highest tolerated dose of 3.20 mg/m²/cycle on the Alternate Schedule.
- Dose-proportional PK, a half-life of ~70 hours, and evidence of KSP inhibition via monopolar spindle formation were observed. No neurotoxicity was reported. Best response was stable disease in 18% of patients.
Conclusions:
- Filanesib demonstrated acceptable tolerability and target-specific pharmacodynamic effects at established doses.
- The study provides a basis for further clinical investigation of filanesib in advanced solid tumors.
- Evidence of KSP inhibition supports filanesib's mechanism of action in patients.
