A phase I and pharmacokinetic study of ixabepilone in combination with Carboplatin in patients with advanced solid malignancies.
OBJECTIVE
To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety.


METHODS
Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B).


RESULTS
Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B).


CONCLUSIONS
Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.
Plummer
Ruth
R
Northern Centre for Cancer Treatment, Newcastle upon Tyne, United Kingdom. ruth.plummer@ncl.ac.uk
Woll
Penella
P
Fyfe
David
D
Boddy
Alan V
AV
Griffin
Melanie
M
Hewitt
Paula
P
Carmichael
James
J
Namouni
Fouad
F
Cohen
Marvin
M
Verrill
Mark
M
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D034261:Epothilones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D034261:Epothilones; D016190:Carboplatin; C430592:ixabepilone