Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor.
The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1-14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5-224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg x m(-2) given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P=0.004) and 38.0% (P<0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg x m(-2).
Sparreboom
A
A
Department of Medical Oncology, Erasmus MC - Daniel den Hoed Cancer Center, 3075 EA, Rotterdam, the Netherlands. Sparreb@mail.nih.gov
Kehrer
D F S
DF
Mathijssen
R H J
RH
Xie
R
R
de Jonge
M J A
MJ
de Bruijn
P
P
Planting
A S T
AS
Eskens
F A L M
FA
Verheij
C
C
de Heus
G
G
Klaren
A
A
Zhang
S
S
Verhaeghe
T
T
Palmer
P A
PA
Verweij
J
J
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D015363:Quinolones; D000077146:Irinotecan; C402769:tipifarnib; D002166:Camptothecin