A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors

• Published in: Investigational new drugs Vol. 29; no. 3; pp. 467 - 472
• Main Authors: Burris, Howard A., Jones, Suzanne F., Williams, Daphne D., Kathman, Steven J., Hodge, Jeffrey P., Pandite, Lini, Ho, Peter T. C., Boerner, Scott A., LoRusso, Patricia
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.06.2011; Springer Nature B.V
• Subjects: Adult; Alopecia; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Baldness; Benzamides - administration & dosage; Benzamides - adverse effects; Benzamides - pharmacokinetics; Benzamides - therapeutic use; Biopsy; Cancer therapies; Cell cycle; Clinical trials; Demography; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Female; Hematology; Hemoglobin; Humans; Inhibitor drugs; Kinesin - antagonists & inhibitors; Kinesin - metabolism; Male; Medicine; Medicine & Public Health; Nausea; Neoplasms - drug therapy; Neoplasms - pathology; Neurotoxicity; Neutropenia; Neutrophils; Oncology; Patients; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Proteins; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - pharmacokinetics; Quinazolines - therapeutic use; Schedules; Spindle Apparatus - metabolism; Studies; Toxicity; Tumors; Vital signs; United States > US; Phase I; Kinesin spindle protein; Mitosis; Safety; Pharmacokinetics; Ispinesib; SB-715992
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-009-9374-x

Summary Purpose To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic profile of ispinesib when administered as a 1-h intravenous infusion weekly for three consecutive weeks of a 28 day treatment period to patients with advanced solid tumors. Experimental Design Thirty patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase at doses ranging from 1–8 mg/m 2 /week. Pharmacokinetic samples, skin punch biopsies, and tumor biopsies (in patients with accessible tumor) were obtained during cycle 1 of treatment. Disease assessment was performed every two treatment cycles. Results The MTD was defined as 7 mg/m 2 administered as a 1-h infusion weekly for three consecutive weeks of a 28 day schedule. The MTD was exceeded at 8 mg/m 2 due to DLTs of grade 2 (one patient) and grade 3 neutropenia (one patient) that resulted in the inability to administer the Day 15 dose in Cycle 1. The neutrophil nadir occurred at approximately Day 8 with a 3–7 day recovery period. The most common toxicities were nausea, diarrhea, fatigue, and neutropenia. Alopecia, mucositis, and neuropathy were not observed. Stable disease was reported as the best response to treatment in nine patients. Conclusion The recommended dose of ispinesib is 7 mg/m 2 over 1 h weekly for three consecutive weeks of a 28 day treatment cycle.