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A phase I trial of MK-0731, a kinesin spindle protein (KSP) inhibitor, in patients with solid tumors
Kyle Holen1, Robert DiPaola, Glenn Liu
1University of Wisconsin Carbone Cancer Center, 600 Highland Ave., Madison, WI 53792-5666, USA. kdh@medicine.wisc.edu
Purpose:
The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP.
Experimental Design:
In part 1, patients with advanced solid tumors received MK-0731 intravenously over 24 h every 21 days starting at 6 mg/m(2), escalating until MTD was reached. In part 2, patients with taxane-resistant tumors received the MTD. Plasma samples were collected to analyze the pharmacokinetics of MK-0731. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0.
Results:
In part 1, 21 patients (median age 63 years) were treated with MK-0731 at doses ranging from 6 to 48 mg/m(2)/24 h for median four cycles. The dose-limiting toxicity was neutropenia and the MTD was 17 mg/m(2)/24 h. At the MTD, AUC (±SD) was 10.5 (±7.3) microM × hour, clearance (±SD) was 153 mL/min (±84), and t(1/2) was 5.9 h. In part 2, 22 patients received the MTD and there were no DLTs. Although there were no objective tumor responses, four patients (with cervical, non-small cell lung, and ovarian cancers) had prolonged stable disease.
Conclusions:
MK-0731 at the MTD of 17 mg/m(2)/day every 21 days in patients with solid tumors had few grade 3 and 4 toxicities with the major DLTs at higher doses being myelosuppression. Anti-tumor efficacy was suggested by the length of stable disease in selected patients with taxane-resistant tumors.
Insights
MK-0731, a kinesin spindle protein inhibitor, was evaluated in patients with advanced solid tumors. The maximum tolerated dose (MTD) was 17 mg/m(2)/day, with myelosuppression as the main dose-limiting toxicity. Prolonged stable disease was observed in some patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Kinesin spindle protein (KSP) is crucial for mitotic spindle pole separation.
- KSP inhibition leads to mitotic arrest, making it a target for cancer therapy.
Purpose of the Study:
- To assess the safety, tolerability, and anti-tumor activity of MK-0731, a KSP inhibitor.
- To determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of MK-0731.
- To evaluate the pharmacokinetic profile of MK-0731 in patients with advanced solid tumors.
Main Methods:
- Phase I trial with dose escalation of MK-0731 administered intravenously over 24 hours every 21 days.
- Part 1: Dose escalation to determine MTD in patients with advanced solid tumors.
- Part 2: MTD administration in patients with taxane-resistant tumors; pharmacokinetic analysis and tumor response evaluation using RECIST v1.0.
Main Results:
- The MTD of MK-0731 was determined to be 17 mg/m(2)/24 h, with neutropenia as the primary DLT at higher doses.
- Pharmacokinetic parameters at MTD: AUC 10.5 μM×h, clearance 153 mL/min, t(1/2) 5.9 h.
- No objective tumor responses were observed, but four patients with cervical, non-small cell lung, and ovarian cancers achieved prolonged stable disease.
Conclusions:
- MK-0731 at the MTD of 17 mg/m(2)/day every 21 days demonstrated an acceptable safety profile with limited high-grade toxicities.
- Myelosuppression was the main dose-limiting toxicity at higher doses.
- The study suggests potential anti-tumor efficacy of MK-0731, indicated by stable disease in a subset of patients with taxane-resistant tumors.
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