Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors Journal Article


Authors: Saltz, L. B.; Kanowitz, J.; Kemeny, N. E.; Schaaf, L.; Spriggs, D.; Staton, B. A.; Berkery, R.; Steger, C.; Eng, M.; Dietz, A.; Locker, P.; Kelsen, D. P.
Article Title: Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors
Abstract: Purpose: To determine the maximum-tolerable dose (MTD) of fluorouracil (5FU) when given with fixed doses of leucovorin and irinotecan (CPT-11), to define the dose-limiting toxicities of this combination, and to evaluate the effect of 5FU on the pharmacokinetics of CPT-11. Patients and Methods: CPT- 11, leucovorin, and 5FU were administered in repeated 6-week cycles that consisted of weekly treatment with all three drugs for 4 consecutive weeks followed by a 2-week break. On day 1 of treatment, CPT-11 alone was given by 90-minute infusion, and pharmacokinetic sampling was performed over 24 hours. Leucovorin and 5FU were administered by brief intravenous injection on day 2. On days 8, 15, and 22, CPT-11 infusion was immediately followed by leucovorin and then 5FU. A second 24-hour pharmacokinetic sampling was performed on day 8, which permitted comparison of the pharmacokinetics of CPT-11 with and without 5FU. For the second 6-week cycle, leucovorin was administered first, followed by 5FU and then CPT-11, and a third pharmacokinetic sampling was performed. Results: Forty-two patients were entered onto this trial. The CPT- 11 dose was initially fixed at 100 mg/m2. Leucovorin was fixed at 20 mg/m2. 5FU doses of 210, 265, 340, 425, and 500 mg/m2 were studied. When the 500- mg/m2 dose of 5FU was found to be tolerable, this was then maintained and CPT-11 was escalated to 125 and then 150 mg/m2. This final CPT-11 dose exceeded the MTD. Neutropenia was the major dose-limiting toxicity. Diarrhea was common, but was rarely dose-limiting. Coadministration of 5FU had no substantial effect on the pharmacokinetics of CPT-11 or SN-38. Among the 38 patients with colorectal cancer, six partial responses (PRs) were seen in this predominantly 5FU-refractory patient population. Conclusion: 5FU does not substantially affect the metabolism of CPT-11 to its active metabolite, SN-38. The combination of CPT-11 125 mg/m2, 5FU 500 mg/m2, and leucovorin 20 mg/m2 is feasible and tolerable on this schedule.
Keywords: adult; clinical article; aged; middle aged; clinical trial; neutropenia; fluorouracil; advanced cancer; area under the curve; diarrhea; solid tumor; neoplasms; colorectal cancer; computer assisted tomography; nausea; antineoplastic combined chemotherapy protocols; carcinoembryonic antigen; 7 ethyl 10 hydroxycamptothecin; antineoplastic agents, phytogenic; camptothecin; dexamethasone; irinotecan; folinic acid; granisetron; ondansetron; loperamide; drug blood level; high performance liquid chromatography; phase 1 clinical trial; leucovorin; oral drug administration; antidotes; humans; human; male; female; priority journal; article
Journal Title: Journal of Clinical Oncology
Volume: 14
Issue: 11
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 1996-11-01
Start Page: 2959
End Page: 2967
Language: English
PUBMED: 8918493
PROVIDER: scopus
DOI: 10.1200/JCO.1996.14.11.2959
DOI/URL:
Notes: Article -- Export Date: 22 November 2017 -- Source: Scopus
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MSK Authors
  1. Leonard B Saltz
    580 Saltz
  2. David R Spriggs
    309 Spriggs
  3. David P Kelsen
    332 Kelsen
  4. Nancy Kemeny
    346 Kemeny