A phase I study of bi-weekly administration of 24-h gemcitabine followed by 24-h irinotecan in patients with solid tumors.
OBJECTIVE
To determine the maximal tolerated doses (MTD) and dose-limiting toxicities (DLT) of combination of 24-h infusions of gemcitabine and irinotecan in patients with advanced solid tumors.


METHODS
Twenty-four patients with advanced solid tumors received gemcitabine as a 24-h IV infusion followed by a 24-h infusion of irinotecan every 2 weeks. Pharmacokinetic parameters of both drugs and their metabolites were estimated by using non-compartmental methods.


RESULTS
Twenty-four patients were fully evaluable for toxicity. DLT was observed in two of six patients at irinotecan/gemcitabine 110/150 mg/m(2) (grade 3 diarrhea and grade 3 GI bleeding). No patient developed acute cholinergic symptoms at any dose. Other toxicities were < or =grade 2 nausea, vomiting, and fatigue. Tumor responses were observed in three patients (one CR: cholangiocarcinoma; two PR: SCLC, gastric neuroendocrine tumor). Stable disease >3 months was found in six patients including five patients who had failed short infusions of either drug. Pharmacokinetic analysis showed that C (max) of each drug and active metabolites were dose-dependent. High dose of gemcitabine increased C (max), AUC, and T(1/2) of irinotecan. However, gemcitabine had minimal effects on SN-38.


CONCLUSIONS
The recommended dose for Phase II studies is gemcitabine 125 mg/m(2) given as a 24-h IV infusion on D1 and D15, followed by a 24-h IV infusion of irinotecan 110 mg/m(2) on D2 and D16. Both pretreated patients and chemo-naive patients seem to tolerate higher doses of this combination without significant toxicities. Objective responses among patients with solid tumors, in particular cholangiocarcinoma and small cell lung cancer merits further investigation.
Saif
Muhammad Wasif
MW
Department of Medicine, Section of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL, USA. wasif.saif@yale.edu
Sellers
Sandra
S
Li
Mao
M
Wang
Wei
W
Cusimano
Linda
L
Wang
Hui
H
Zhang
Ruiwen
R
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D018281:Cholangiocarcinoma / Q000188:drug therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
D003841:Deoxycytidine; D000077146:Irinotecan; D002166:Camptothecin; D000093542:Gemcitabine