Dose escalation and pharmacokinetic study of irinotecan in combination with paclitaxel in patients with advanced cancer.
OBJECTIVE
Based on preclinical data demonstrating synergy between camptothecin analogues and taxanes, we determined the maximum tolerated dose (MTD) of irinotecan that could be given in combination with a fixed dose of paclitaxel of 75 mg/m2, when both drugs were delivered on a weekly schedule. The pharmacokinetics of this combination were explored to determine whether the sequence of administration affected the elimination of irinotecan.


METHODS
For the first cycle patients with advanced cancer were treated with irinotecan given as a 90-min infusion followed immediately by paclitaxel given at a dose of 75 mg/m2 over 1 h. The sequence of drug administration was reversed in subsequent cycles for most patients. Chemotherapy was given weekly for 4 weeks, followed by a 2-week rest. In selected patients, plasma concentrations of irinotecan were determined by high-performance liquid chromatography during the first 24 h of cycle 1 and after the first dose of cycle 2 to determine whether the order of drug administration affected the elimination of irinotecan, or the toxicologic effects of the chemotherapy.


RESULTS
A total of 53 cycles were delivered to 21 patients. Reversible neutropenia was dose-limiting. Suppression of the other blood cell elements was modest. There was one partial response in a man with a previously treated cholangiocarcinoma that lasted 26 weeks. Prolonged stabilization of disease (6 months or more) was observed in five of the patients (24%). At the recommended dose of irinotecan (50 mg/m2), transfusions of red cells and platelets were not required. The sequence of drug administration produced no significant differences in the pharmacokinetic parameters of irinotecan or SN-38, which were similar to the values reported when irinotecan is administered alone. The most prominent nonhematologic toxicities were mild diarrhea and fatigue.


CONCLUSIONS
The recommended dose of irinotecan on this schedule is 50 mg/m2. The sequence of drug administration affects neither the elimination of irinotecan nor the chemotherapy-related toxicity. This combination is well tolerated and causes minimal clinical side effects.
Murren
J R
JR
Department of Medicine, Yale University School of Medicine and the Yale Cancer Center, New Haven, CT 06520, USA.
Peccerillo
K
K
DiStasio
S A
SA
Li
X
X
Leffert
J J
JJ
Pizzorno
G
G
Burtness
B A
BA
McKeon
A
A
Cheng
Y
Y
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D017239:Paclitaxel; D002166:Camptothecin