A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies.
OBJECTIVE
This phase I study assessed the maximum tolerated doses (MTDs), safety, pharmacokinetics, and efficacy of combined tipifarnib and docetaxel treatment in patients with advanced solid malignancies.


METHODS
The study protocol was sensitive to myelosuppression, as both drugs have been associated with this adverse event. Due to myelosuppression incidence, and in order to determine the MTD of docetaxel, multiple treatment regimens were employed. Tipifarnib was administered orally at 200 or 300 mg, twice daily (BID) for 21 days, 14 days, or 7 days for multiple 21-day cycles; intravenous (i.v.) docetaxel was administered on day 1 of each cycle at 60, 75, or 85 mg/m2.


RESULTS
A total of 36 patients entered into the study. For each drug, MTDs were identified (tipifarnib: 300 mg BID for 14 days with 60 mg/m2 docetaxel; tipifarnib: 200 mg BID for 14 days with 75 mg/m2 docetaxel). The major dose-limiting toxicity was myelosuppression, particularly febrile neutropenia (44%). Mutual pharmacokinetic interactions (the effect of docetaxel on tipifarnib pharmacokinetics and the effect of tipifarnib on docetaxel pharmacokinetics) were not evident, as maximum plasma concentration (Cmax) and the area under the serum concentration-time curve (AUC) values of both tipifarnib and docetaxel were similar (p > or = 0.43) whether the two drugs were concomitantly administered or not. Seven of 31 evaluable patients (23%) had an objective response, 11 (35%) had stable disease (six > or = 24 weeks), and the overall clinical benefit rate (objective response and/or stable disease > or = 24 weeks) was 42%.


CONCLUSIONS
Although the high incidence of febrile neutropenia necessitated a multiple scheduling adaptation of tipifarnib compared to the original protocol, the apparent lack of mutual pharmacokinetic interactions, the ability to coadminister tipifarnib and docetaxel near single-agent MTDs, and suggestive evidence of efficacy make this drug combination attractive for further examination.
Awada
Ahmad
A
Jules Bordet Institute, Brussels, Belgium. ahmad.awada@bordet.be
Zhang
Steven
S
Gil
Thierry
T
de Valeriola
Dominique
D
Lalami
Yassine
Y
De Porre
Peter
P
Piccart-Gebhart
Martine J
MJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007107:Immune System / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D015363:Quinolones; D043823:Taxoids; D000077143:Docetaxel; C402769:tipifarnib