A phase I pharmacologic and pharmacogenetic trial of sequential 24-hour infusion of irinotecan followed by leucovorin and a 48-hour infusion of fluorouracil in adult patients with solid tumors.
OBJECTIVE
In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions.


METHODS
CPT-11 was first given at four levels (70-140 mg/m(2)/24 hours), followed by leucovorin 500 mg/m(2)/0.5 hours and 5-FU 2,000 mg/m(2)/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m(2)/48 hours.


RESULTS
Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 micromol/L at 3,900 mg/m(2)/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m(2)/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with >/=1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype.


CONCLUSIONS
Doses (mg/m(2)) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.
Wright
Maurice A
MA
Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Morrison
Geraldine
G
Lin
Pengxin
P
Leonard
Gregory D
GD
Nguyen
Dat
D
Guo
Xaiodu
X
Szabo
Eva
E
Hopkins
Jon L
JL
Leguizamo
Jorge P
JP
Harold
Nancy
N
Fioravanti
Suzanne
S
Schuler
Barbara
B
Monahan
Brian P
BP
Saif
M Wasif
MW
Quinn
Mary G
MG
Pang
Janet
J
Grem
Jean L
JL
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; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007260:Infusion Pumps; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009503:Neutropenia / Q000139:chemically induced; D010597:Pharmacogenetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D013940:Thymidylate Synthase; D000099148:UGT1A1 Enzyme