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

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. Experi...

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Bibliographic Details
Published in:Investigational new drugs 2011-06, Vol.29 (3), p.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: Article
Language:English
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
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Description
Summary: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.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-009-9374-x