Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08

Patrick Y. Wen; W. K Alfred Yung; Kathleen R. Lamborn; Patricia L. Dahia; Yanfeng Wang; Bin Peng; Lauren E. Abrey; Jeffrey Raizer; Timothy F. Cloughesy; Karen Fink; Mark Gilbert; Susan Chang; Larry Junck; David Schiff; Frank Lieberman; Howard A. Fine; Minesh Mehta; H. Ian Robins; Lisa M. DeAngelis; Morris D. Groves; Vinay K. Puduvalli; Victor Levin; Charles Conrad; Elizabeth A. Maher; Kenneth Aldape; Michael Hayes; Laurie Letvak; Merrill J. Egorin; Renaud Capdeville; Richard Kaplan; Anthony J. Murgo; Charles Stiles; Michael D. Prados

doi:10.1158/1078-0432.CCR-06-0773

Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08

Patrick Y. Wen, W. K Alfred Yung, Kathleen R. Lamborn, Patricia L. Dahia, Yanfeng Wang, Bin Peng, Lauren E. Abrey, Jeffrey Raizer, Timothy F. Cloughesy, Karen Fink, Mark Gilbert, Susan Chang, Larry Junck, David Schiff, Frank Lieberman, Howard A. Fine, Minesh Mehta, H. Ian Robins, Lisa M. DeAngelis, Morris D. GrovesVinay K. Puduvalli, Victor Levin, Charles Conrad, Elizabeth A. Maher, Kenneth Aldape, Michael Hayes, Laurie Letvak, Merrill J. Egorin, Renaud Capdeville, Richard Kaplan, Anthony J. Murgo, Charles Stiles, Michael D. Prados

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Abstract

Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib. Experimental Design: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response. Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by ∼68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages. Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

Original language	English (US)
Pages (from-to)	4899-4907
Number of pages	9
Journal	Clinical Cancer Research
Volume	12
Issue number	16
DOIs	https://doi.org/10.1158/1078-0432.CCR-06-0773
State	Published - Aug 15 2006

ASJC Scopus subject areas

Oncology
Cancer Research

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Wen, P. Y., Yung, W. K. A., Lamborn, K. R., Dahia, P. L., Wang, Y., Peng, B., Abrey, L. E., Raizer, J., Cloughesy, T. F., Fink, K., Gilbert, M., Chang, S., Junck, L., Schiff, D., Lieberman, F., Fine, H. A., Mehta, M., Robins, H. I., DeAngelis, L. M., ... Prados, M. D. (2006). Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clinical Cancer Research, 12(16), 4899-4907. https://doi.org/10.1158/1078-0432.CCR-06-0773

Wen, PY, Yung, WKA, Lamborn, KR, Dahia, PL, Wang, Y, Peng, B, Abrey, LE, Raizer, J, Cloughesy, TF, Fink, K, Gilbert, M, Chang, S, Junck, L, Schiff, D, Lieberman, F, Fine, HA, Mehta, M, Robins, HI, DeAngelis, LM, Groves, MD, Puduvalli, VK, Levin, V, Conrad, C, Maher, EA, Aldape, K, Hayes, M, Letvak, L, Egorin, MJ, Capdeville, R, Kaplan, R, Murgo, AJ, Stiles, C & Prados, MD 2006, 'Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08', Clinical Cancer Research, vol. 12, no. 16, pp. 4899-4907. https://doi.org/10.1158/1078-0432.CCR-06-0773

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title = "Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08",

abstract = "Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib. Experimental Design: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response. Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by ∼68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages. Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.",

author = "Wen, {Patrick Y.} and Yung, {W. K Alfred} and Lamborn, {Kathleen R.} and Dahia, {Patricia L.} and Yanfeng Wang and Bin Peng and Abrey, {Lauren E.} and Jeffrey Raizer and Cloughesy, {Timothy F.} and Karen Fink and Mark Gilbert and Susan Chang and Larry Junck and David Schiff and Frank Lieberman and Fine, {Howard A.} and Minesh Mehta and Robins, {H. Ian} and DeAngelis, {Lisa M.} and Groves, {Morris D.} and Puduvalli, {Vinay K.} and Victor Levin and Charles Conrad and Maher, {Elizabeth A.} and Kenneth Aldape and Michael Hayes and Laurie Letvak and Egorin, {Merrill J.} and Renaud Capdeville and Richard Kaplan and Murgo, {Anthony J.} and Charles Stiles and Prados, {Michael D.}",

year = "2006",

month = aug,

day = "15",

doi = "10.1158/1078-0432.CCR-06-0773",

language = "English (US)",

volume = "12",

pages = "4899--4907",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "16",

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TY - JOUR

T1 - Phase I/II study of imatinib mesylate for recurrent malignant gliomas

T2 - North American Brain Tumor Consortium Study 99-08

AU - Wen, Patrick Y.

AU - Yung, W. K Alfred

AU - Lamborn, Kathleen R.

AU - Dahia, Patricia L.

AU - Wang, Yanfeng

AU - Peng, Bin

AU - Abrey, Lauren E.

AU - Raizer, Jeffrey

AU - Cloughesy, Timothy F.

AU - Fink, Karen

AU - Gilbert, Mark

AU - Chang, Susan

AU - Junck, Larry

AU - Schiff, David

AU - Lieberman, Frank

AU - Fine, Howard A.

AU - Mehta, Minesh

AU - Robins, H. Ian

AU - DeAngelis, Lisa M.

AU - Groves, Morris D.

AU - Puduvalli, Vinay K.

AU - Levin, Victor

AU - Conrad, Charles

AU - Maher, Elizabeth A.

AU - Aldape, Kenneth

AU - Hayes, Michael

AU - Letvak, Laurie

AU - Egorin, Merrill J.

AU - Capdeville, Renaud

AU - Kaplan, Richard

AU - Murgo, Anthony J.

AU - Stiles, Charles

AU - Prados, Michael D.

PY - 2006/8/15

Y1 - 2006/8/15

N2 - Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib. Experimental Design: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response. Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by ∼68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages. Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

AB - Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib. Experimental Design: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response. Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by ∼68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages. Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

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Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08

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