Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients

Chris H. Takimoto, Geraldine Morrison, Nancy Harold, Mary Quinn, Brian P. Monahan, Roger A. Band, Jeff Cottrell, Aida Guemei, Victor Llorens, Hilary Hehman, Abdel Salam Ismail, Donald Flemming, David M. Gosky, Haruyo Hirota, Sosamma J. Berger, Nathan A. Berger, Alice P. Chen, Jeremy D. Shapiro, Susan G. Arbuck, John Wright & 3 others J. Michael Hamilton, Carmen J. Allegra, Jean L. Grem

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Abstract

Purpose: We conducted a phase I and pharmacologic study of a weekly 96- hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. Patients and Methods: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. Results: In 11 patients who were treated with irinotecan at 12.5 mg/m2/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m2/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 ± 1.10 nmol/L, and the Css of total irinotecan was 28.60 ± 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 ± 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. Conclusion: The recommended phase II dose of irinotecan of 10 mg/m2/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.(C) 2000 by American Society of Clinical Oncology.

Original languageEnglish (US)
Pages (from-to)659-667
Number of pages9
JournalJournal of Clinical Oncology
Volume18
Issue number3
StatePublished - Feb 1 2000

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irinotecan
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Takimoto, C. H., Morrison, G., Harold, N., Quinn, M., Monahan, B. P., Band, R. A., ... Grem, J. L. (2000). Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients. Journal of Clinical Oncology, 18(3), 659-667.
Takimoto, Chris H. ; Morrison, Geraldine ; Harold, Nancy ; Quinn, Mary ; Monahan, Brian P. ; Band, Roger A. ; Cottrell, Jeff ; Guemei, Aida ; Llorens, Victor ; Hehman, Hilary ; Ismail, Abdel Salam ; Flemming, Donald ; Gosky, David M. ; Hirota, Haruyo ; Berger, Sosamma J. ; Berger, Nathan A. ; Chen, Alice P. ; Shapiro, Jeremy D. ; Arbuck, Susan G. ; Wright, John ; Hamilton, J. Michael ; Allegra, Carmen J. ; Grem, Jean L. / Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients. In: Journal of Clinical Oncology. 2000 ; Vol. 18, No. 3. pp. 659-667.
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title = "Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients",
abstract = "Purpose: We conducted a phase I and pharmacologic study of a weekly 96- hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. Patients and Methods: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. Results: In 11 patients who were treated with irinotecan at 12.5 mg/m2/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m2/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 ± 1.10 nmol/L, and the Css of total irinotecan was 28.60 ± 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 ± 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. Conclusion: The recommended phase II dose of irinotecan of 10 mg/m2/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.(C) 2000 by American Society of Clinical Oncology.",
author = "Takimoto, {Chris H.} and Geraldine Morrison and Nancy Harold and Mary Quinn and Monahan, {Brian P.} and Band, {Roger A.} and Jeff Cottrell and Aida Guemei and Victor Llorens and Hilary Hehman and Ismail, {Abdel Salam} and Donald Flemming and Gosky, {David M.} and Haruyo Hirota and Berger, {Sosamma J.} and Berger, {Nathan A.} and Chen, {Alice P.} and Shapiro, {Jeremy D.} and Arbuck, {Susan G.} and John Wright and Hamilton, {J. Michael} and Allegra, {Carmen J.} and Grem, {Jean L.}",
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Takimoto, CH, Morrison, G, Harold, N, Quinn, M, Monahan, BP, Band, RA, Cottrell, J, Guemei, A, Llorens, V, Hehman, H, Ismail, AS, Flemming, D, Gosky, DM, Hirota, H, Berger, SJ, Berger, NA, Chen, AP, Shapiro, JD, Arbuck, SG, Wright, J, Hamilton, JM, Allegra, CJ & Grem, JL 2000, 'Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients', Journal of Clinical Oncology, vol. 18, no. 3, pp. 659-667.

Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients. / Takimoto, Chris H.; Morrison, Geraldine; Harold, Nancy; Quinn, Mary; Monahan, Brian P.; Band, Roger A.; Cottrell, Jeff; Guemei, Aida; Llorens, Victor; Hehman, Hilary; Ismail, Abdel Salam; Flemming, Donald; Gosky, David M.; Hirota, Haruyo; Berger, Sosamma J.; Berger, Nathan A.; Chen, Alice P.; Shapiro, Jeremy D.; Arbuck, Susan G.; Wright, John; Hamilton, J. Michael; Allegra, Carmen J.; Grem, Jean L.

In: Journal of Clinical Oncology, Vol. 18, No. 3, 01.02.2000, p. 659-667.

Research output: Contribution to journalArticle

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T1 - Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients

AU - Takimoto, Chris H.

AU - Morrison, Geraldine

AU - Harold, Nancy

AU - Quinn, Mary

AU - Monahan, Brian P.

AU - Band, Roger A.

AU - Cottrell, Jeff

AU - Guemei, Aida

AU - Llorens, Victor

AU - Hehman, Hilary

AU - Ismail, Abdel Salam

AU - Flemming, Donald

AU - Gosky, David M.

AU - Hirota, Haruyo

AU - Berger, Sosamma J.

AU - Berger, Nathan A.

AU - Chen, Alice P.

AU - Shapiro, Jeremy D.

AU - Arbuck, Susan G.

AU - Wright, John

AU - Hamilton, J. Michael

AU - Allegra, Carmen J.

AU - Grem, Jean L.

PY - 2000/2/1

Y1 - 2000/2/1

N2 - Purpose: We conducted a phase I and pharmacologic study of a weekly 96- hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. Patients and Methods: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. Results: In 11 patients who were treated with irinotecan at 12.5 mg/m2/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m2/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 ± 1.10 nmol/L, and the Css of total irinotecan was 28.60 ± 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 ± 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. Conclusion: The recommended phase II dose of irinotecan of 10 mg/m2/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.(C) 2000 by American Society of Clinical Oncology.

AB - Purpose: We conducted a phase I and pharmacologic study of a weekly 96- hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. Patients and Methods: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. Results: In 11 patients who were treated with irinotecan at 12.5 mg/m2/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m2/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 ± 1.10 nmol/L, and the Css of total irinotecan was 28.60 ± 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 ± 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. Conclusion: The recommended phase II dose of irinotecan of 10 mg/m2/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.(C) 2000 by American Society of Clinical Oncology.

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Takimoto CH, Morrison G, Harold N, Quinn M, Monahan BP, Band RA et al. Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients. Journal of Clinical Oncology. 2000 Feb 1;18(3):659-667.