Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma

A North American brain tumor consortium study

Michael D. Prados, W. K.A. Yung, Kurt Jaeckle, H. Ian Robins, Minesh P. Mehta, Howard A. Fine, Patrick Y. Wen, Timothhy F. Cloughesy, Susan M. Chang, M. Kelly Nicholas, David Schiff, Harry S. Greenberg, Larry Junck, Karen L. Fink, Kenneth R. Hess, John Kuhn

Research output: Contribution to journalArticle

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Abstract

This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme-inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m2 i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m2 increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m2 of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the dosage range of 350 to 800 mg/m2, but no relationship between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m2 dose, the AUC for CPT-11 (21.6 μg × h/ml) matched the AUC (21.6 μg × h/ml) in the non-EIAED group treated with 350 mg/m2 of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m2 when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.

Original languageEnglish (US)
Pages (from-to)44-54
Number of pages11
JournalNeuro-Oncology
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2004

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irinotecan
Brain Neoplasms
Glioma
Anticonvulsants
Area Under Curve
Enzymes
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Prados, M. D., Yung, W. K. A., Jaeckle, K., Robins, H. I., Mehta, M. P., Fine, H. A., ... Kuhn, J. (2004). Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American brain tumor consortium study. Neuro-Oncology, 6(1), 44-54. https://doi.org/10.1215/S1152851703000292
Prados, Michael D. ; Yung, W. K.A. ; Jaeckle, Kurt ; Robins, H. Ian ; Mehta, Minesh P. ; Fine, Howard A. ; Wen, Patrick Y. ; Cloughesy, Timothhy F. ; Chang, Susan M. ; Nicholas, M. Kelly ; Schiff, David ; Greenberg, Harry S. ; Junck, Larry ; Fink, Karen L. ; Hess, Kenneth R. ; Kuhn, John. / Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma : A North American brain tumor consortium study. In: Neuro-Oncology. 2004 ; Vol. 6, No. 1. pp. 44-54.
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abstract = "This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme-inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m2 i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m2 increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m2 of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the dosage range of 350 to 800 mg/m2, but no relationship between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m2 dose, the AUC for CPT-11 (21.6 μg × h/ml) matched the AUC (21.6 μg × h/ml) in the non-EIAED group treated with 350 mg/m2 of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m2 when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.",
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Prados, MD, Yung, WKA, Jaeckle, K, Robins, HI, Mehta, MP, Fine, HA, Wen, PY, Cloughesy, TF, Chang, SM, Nicholas, MK, Schiff, D, Greenberg, HS, Junck, L, Fink, KL, Hess, KR & Kuhn, J 2004, 'Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American brain tumor consortium study', Neuro-Oncology, vol. 6, no. 1, pp. 44-54. https://doi.org/10.1215/S1152851703000292

Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma : A North American brain tumor consortium study. / Prados, Michael D.; Yung, W. K.A.; Jaeckle, Kurt; Robins, H. Ian; Mehta, Minesh P.; Fine, Howard A.; Wen, Patrick Y.; Cloughesy, Timothhy F.; Chang, Susan M.; Nicholas, M. Kelly; Schiff, David; Greenberg, Harry S.; Junck, Larry; Fink, Karen L.; Hess, Kenneth R.; Kuhn, John.

In: Neuro-Oncology, Vol. 6, No. 1, 01.01.2004, p. 44-54.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma

T2 - A North American brain tumor consortium study

AU - Prados, Michael D.

AU - Yung, W. K.A.

AU - Jaeckle, Kurt

AU - Robins, H. Ian

AU - Mehta, Minesh P.

AU - Fine, Howard A.

AU - Wen, Patrick Y.

AU - Cloughesy, Timothhy F.

AU - Chang, Susan M.

AU - Nicholas, M. Kelly

AU - Schiff, David

AU - Greenberg, Harry S.

AU - Junck, Larry

AU - Fink, Karen L.

AU - Hess, Kenneth R.

AU - Kuhn, John

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Y1 - 2004/1/1

N2 - This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme-inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m2 i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m2 increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m2 of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the dosage range of 350 to 800 mg/m2, but no relationship between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m2 dose, the AUC for CPT-11 (21.6 μg × h/ml) matched the AUC (21.6 μg × h/ml) in the non-EIAED group treated with 350 mg/m2 of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m2 when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.

AB - This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme-inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m2 i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m2 increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m2 of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the dosage range of 350 to 800 mg/m2, but no relationship between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m2 dose, the AUC for CPT-11 (21.6 μg × h/ml) matched the AUC (21.6 μg × h/ml) in the non-EIAED group treated with 350 mg/m2 of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m2 when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.

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