Phase I clinical and pharmacokinetic (PK) trial of the kinesin spindle protein (KSP) inhibitor MK-0731 in patients with solid tumors

Abstract

2548 Background: KSP is essential for the separation of spindle poles during mitosis and inhibition results in mitotic arrest. MK- 0731 is a potent inhibitor of KSP, with an IC50 of 2.2 nM, and >20,000 fold selectivity against other kinesins. MK-0731 causes mitotic arrest with an EC50 in several tumor cell lines of 3–5 nM. Methods: Phase I study to determine the safety and tolerability, MTD, and PK of MK-0731 administered IV over 24 hrs every 21 days. In part 1, dosing started at 6 mg/m2/24 hr and was escalated until the MTD was reached. In part 2, pts with measurable taxane-resistant cancer were treated at the MTD established in Part 1 (target accrual =22 pts in part 2). Interim Results: 35 pts with solid tumors (M/F 23/12), median age 63 yrs (23 - 79), were treated at doses of 6 to 48 mg/ m2/24hrs (median cycles 3, range 1–10, total cycles=128). Frequent tumor types included prostate (8), ovarian (4), colon (3), bladder (2), neuroendocrine (2), lung (2), breast (2). Prolonged (>5 days) grade 4 neutropenia was observed in 2 pts at 48 mg/m2/24hrs (11 days duration) and 2 pts at 24 mg/m2/24hrs (7 days duration) leading to expansion of cohorts at lower dose levels. At the MTD of 17 mg/ m2/24, there were no DLTs. 14 patients have been enrolled at the MTD in part 2 of the study. Drug related grade 3/4 toxicities were anemia (1), AST (1), hyperglycemia (1), nausea/vomiting (1), neutropenia (7), syncope (1). PK results from the first 20 patients suggest that MK- 0731 concentrations appear to decline monoexponentially or biexponentially following the infusion with terminal t1/2 from ∼4 to 22 hrs. In some patients, steady-state concentrations may not be achieved by the end of the 24 hr infusion. Mean values at the 17 mg/m2/24hrs dose level were Cmax=599 nM, AUC8=14.56 μM·hr, and CL=119 mL/min. AUC, exposures, and end of infusion concentrations appear to increase proportionally with dose. Stable disease for = 4 cycles (range 4- 10) was seen in 16 patients. Conclusion: Treatment with MK-0731 at the MTD of 17 mg/m2/day every 21 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.