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

Maurice A. Wright, Geraldine Morrison, Pengxin Lin, Gregory D. Leonard, Dat Nguyen, Xaiodu Guo, Eva Szabo, Jon L. Hopkins, Jorge P. Leguizamo, Nancy Harold, Suzanne Fioravanti, Barbara Schuler, Brian P. Monahan, M. Wasif Saif, Mary G. Quinn, Janet Pang, Jean L Grem

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Abstract

Purpose: 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. Experimental Design: CPT-11 was first given at four levels (70-140 mg/m2/24 hours), followed by leucovorin 500 mg/m2/0.5 hours and 5-FU 2,000 mg/m2/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m2/48 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 μmol/L at 3,900 mg/m2/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m2/24 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/m2) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.

Original languageEnglish (US)
Pages (from-to)4144-4150
Number of pages7
JournalClinical Cancer Research
Volume11
Issue number11
DOIs
StatePublished - Jun 1 2005

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irinotecan
Leucovorin
Pharmacogenetics
Fluorouracil
Neoplasms
Genotype
Thymidylate Synthase
Glucuronosyltransferase
Antiemetics
Neutropenia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Wright, Maurice A.; Morrison, Geraldine; Lin, Pengxin; Leonard, Gregory D.; Nguyen, Dat; Guo, Xaiodu; Szabo, Eva; Hopkins, Jon L.; Leguizamo, Jorge P.; Harold, Nancy; Fioravanti, Suzanne; Schuler, Barbara; Monahan, Brian P.; Saif, M. Wasif; Quinn, Mary G.; Pang, Janet; Grem, Jean L.

In: Clinical Cancer Research, Vol. 11, No. 11, 01.06.2005, p. 4144-4150.

Research output: Contribution to journalArticle

Wright, MA, Morrison, G, Lin, P, Leonard, GD, Nguyen, D, Guo, X, Szabo, E, Hopkins, JL, Leguizamo, JP, Harold, N, Fioravanti, S, Schuler, B, Monahan, BP, Saif, MW, Quinn, MG, Pang, J & Grem, JL 2005, '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', Clinical Cancer Research, vol. 11, no. 11, pp. 4144-4150. https://doi.org/10.1158/1078-0432.CCR-04-2439
Wright, Maurice A. ; Morrison, Geraldine ; Lin, Pengxin ; Leonard, Gregory D. ; Nguyen, Dat ; Guo, Xaiodu ; Szabo, Eva ; Hopkins, Jon L. ; Leguizamo, Jorge P. ; Harold, Nancy ; Fioravanti, Suzanne ; Schuler, Barbara ; Monahan, Brian P. ; Saif, M. Wasif ; Quinn, Mary G. ; Pang, Janet ; Grem, Jean L. / 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. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 11. pp. 4144-4150.
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abstract = "Purpose: 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. Experimental Design: CPT-11 was first given at four levels (70-140 mg/m2/24 hours), followed by leucovorin 500 mg/m2/0.5 hours and 5-FU 2,000 mg/m2/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m2/48 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 μmol/L at 3,900 mg/m2/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m2/24 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/m2) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.",
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T1 - 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

AU - Wright, Maurice A.

AU - Morrison, Geraldine

AU - Lin, Pengxin

AU - Leonard, Gregory D.

AU - Nguyen, Dat

AU - Guo, Xaiodu

AU - Szabo, Eva

AU - Hopkins, Jon L.

AU - Leguizamo, Jorge P.

AU - Harold, Nancy

AU - Fioravanti, Suzanne

AU - Schuler, Barbara

AU - Monahan, Brian P.

AU - Saif, M. Wasif

AU - Quinn, Mary G.

AU - Pang, Janet

AU - Grem, Jean L

PY - 2005/6/1

Y1 - 2005/6/1

N2 - Purpose: 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. Experimental Design: CPT-11 was first given at four levels (70-140 mg/m2/24 hours), followed by leucovorin 500 mg/m2/0.5 hours and 5-FU 2,000 mg/m2/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m2/48 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 μmol/L at 3,900 mg/m2/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m2/24 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/m2) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.

AB - Purpose: 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. Experimental Design: CPT-11 was first given at four levels (70-140 mg/m2/24 hours), followed by leucovorin 500 mg/m2/0.5 hours and 5-FU 2,000 mg/m2/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m2/48 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 μmol/L at 3,900 mg/m2/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m2/24 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/m2) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.

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