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.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
The recommended dose of ispinesib is 7 mg/m(2) over 1 h weekly for three consecutive weeks of a 28 day treatment cycle.
Burris
Howard A
HA
The Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203, USA. hburris@tnonc.com
Jones
Suzanne F
SF
Williams
Daphne D
DD
Kathman
Steven J
SJ
Hodge
Jeffrey P
JP
Pandite
Lini
L
Ho
Peter T C
PT
Boerner
Scott A
SA
Lorusso
Patricia
P
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003710:Demography; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008941:Spindle Apparatus / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D011799:Quinazolines; C508757:ispinesib; D016547:Kinesins