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

Abstract

2001 Background: KSP is essential for the separation of spindle poles during mitosis and inhibition results in mitotic arrest. Function is thought to be limited to mitosis and inhibitors should not cause the peripheral neuropathy seen with other mitotic-inhibitors. 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 (Q21) ds. Results: Eight pts with solid tumors (M/F 6/2), median age 55 yrs (45–72 yrs), were treated at doses of 6 to 48 mg/m2/24hrs. Prolonged (≥5 ds) Grade 4 neutropenia was observed in 2 pts at 48 mg/m2/24 hrs leading to expansion of cohorts at lower dose levels. Other drug related toxicities include diarrhea, alopecia, nail changes, nausea/vomiting, mucositis, abdominal pain, anorexia, phlebitis. PK results suggest that steady-state concentrations may not be achieved by the end of the 24 hr infusion and MK-0731 concentrations appear to decline monoexponentially or biexponentially following the infusion with terminal t1/2 from ∼4 to 11 hrs. Median values at the 48 mg/m2/24 hrs dose level were Cmax = 1223 nM, AUC∞ = 26.585 μM · hr, and CL=122 mL/min. AUC, exposures, and end of infusion concentrations appear to increase proportionally with dose. Conclusions: This is the first study of MK-0731. The MTD was exceeded at 48 mg/m2/24 hrs Q21. Further evaluation will continue at lower doses. [Table: see text]