Population-based phase I trial of irinotecan and epirubicin.
OBJECTIVE
Preclinical studies have demonstrated anticancer synergism with the combination of inhibitors of topoisomerases I and II. A population-based phase I trial was conducted to determine a population-based maximum tolerated dose (pMTD) for combining 2 topoisomerase inhibitors, irinotecan and epirubicin.


METHODS
Two cohorts of patients with advanced solid tumors were enrolled: 27 patients had and 22 patients had not received prior chemotherapy. In each cohort, irinotecan and epirubicin were administered beginning at a predetermined dose level. The dose for each subsequent 21-day cycle was escalated or de-escalated within each patient based on the dose-limiting toxicity observed in the previous cycle and according to a predetermined schema of dose levels. An MTD was determined for each patient (iMTD) and the iMTDs were used to determine a pMTD for each cohort of patients.


RESULTS
The most common dose-limiting toxicity included neutropenia (51%), asthenia (10%), diarrhea (8%), and nausea/emesis (4%). The iMTDs ranged from dose level -3 to dose level 6. For previously chemotherapy-treated patients, the pMTD was 100 mg/m2 of irinotecan and 50 mg/m2 of epirubicin. For chemonaive patients, the pMTD was 150 mg/m2 of irinotecan and 50 mg/m2 of epirubicin.


CONCLUSIONS
We have determined the pMTD of irinotecan and epirubicin administered every 3 weeks using a population-based approach. The pMTD is recommended for conducting phase II trials.
Lau
Derick
D
Department of Internal Medicine, University of California, Davis Cancer Center, Sacramento, CA 95817, USA. derick.lau@ucdmc.ucdavis.edu
Johl
Jewel
J
Huynh
Minh
M
Davies
Angela
A
Tanaka
Michael
M
Lara
Primo
P
Gandara
David
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000633:toxicity*; D001247:Asthenia / Q000139:chemically induced; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D004357:Drug Synergism; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D059004:Topoisomerase I Inhibitors
D059004:Topoisomerase I Inhibitors; D015251:Epirubicin; D000077146:Irinotecan; D002166:Camptothecin