Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: A relationship among efficacy, joint toxicity and anticonvulsant status

Morris D. Groves, Vinay K. Puduvalli, Charles A. Conrad, Mark R. Gilbert, W. K.Alfred Yung, Kurt Jaeckle, Vivien Liu, Kenneth R. Hess, Kenneth D. Aldape, Victor A. Levin

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Abstract

Purpose: Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. Patients and methods: Patients were treated every 28 days with TMZ at 150-200 mg/m2once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. Results: Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46 = 7%, 95% confidence interval (CI) = 1, 18). Median time to progression was 24 weeks (95% CI = 16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI = 35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. Conclusions: Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.

Original languageEnglish (US)
Pages (from-to)83-90
Number of pages8
JournalJournal of Neuro-Oncology
Volume80
Issue number1
DOIs
StatePublished - Oct 1 2006

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temozolomide
Glioma
Anticonvulsants
Joints
Confidence Intervals
Disease-Free Survival
marimastat
Matrix Metalloproteinase Inhibitors
Alkylating Agents

All Science Journal Classification (ASJC) codes

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Groves, Morris D. ; Puduvalli, Vinay K. ; Conrad, Charles A. ; Gilbert, Mark R. ; Yung, W. K.Alfred ; Jaeckle, Kurt ; Liu, Vivien ; Hess, Kenneth R. ; Aldape, Kenneth D. ; Levin, Victor A. / Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas : A relationship among efficacy, joint toxicity and anticonvulsant status. In: Journal of Neuro-Oncology. 2006 ; Vol. 80, No. 1. pp. 83-90.
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title = "Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: A relationship among efficacy, joint toxicity and anticonvulsant status",
abstract = "Purpose: Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. Patients and methods: Patients were treated every 28 days with TMZ at 150-200 mg/m2once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. Results: Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65{\%}); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46 = 7{\%}, 95{\%} confidence interval (CI) = 1, 18). Median time to progression was 24 weeks (95{\%} CI = 16, 56), and the progression-free survival (PFS) rate was 48{\%} at 6 months (95{\%} CI = 35{\%}, 65{\%}), which surpassed the protocol objective of 40{\%}. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. Conclusions: Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.",
author = "Groves, {Morris D.} and Puduvalli, {Vinay K.} and Conrad, {Charles A.} and Gilbert, {Mark R.} and Yung, {W. K.Alfred} and Kurt Jaeckle and Vivien Liu and Hess, {Kenneth R.} and Aldape, {Kenneth D.} and Levin, {Victor A.}",
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Groves, MD, Puduvalli, VK, Conrad, CA, Gilbert, MR, Yung, WKA, Jaeckle, K, Liu, V, Hess, KR, Aldape, KD & Levin, VA 2006, 'Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: A relationship among efficacy, joint toxicity and anticonvulsant status', Journal of Neuro-Oncology, vol. 80, no. 1, pp. 83-90. https://doi.org/10.1007/s11060-006-9160-y

Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas : A relationship among efficacy, joint toxicity and anticonvulsant status. / Groves, Morris D.; Puduvalli, Vinay K.; Conrad, Charles A.; Gilbert, Mark R.; Yung, W. K.Alfred; Jaeckle, Kurt; Liu, Vivien; Hess, Kenneth R.; Aldape, Kenneth D.; Levin, Victor A.

In: Journal of Neuro-Oncology, Vol. 80, No. 1, 01.10.2006, p. 83-90.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas

T2 - A relationship among efficacy, joint toxicity and anticonvulsant status

AU - Groves, Morris D.

AU - Puduvalli, Vinay K.

AU - Conrad, Charles A.

AU - Gilbert, Mark R.

AU - Yung, W. K.Alfred

AU - Jaeckle, Kurt

AU - Liu, Vivien

AU - Hess, Kenneth R.

AU - Aldape, Kenneth D.

AU - Levin, Victor A.

PY - 2006/10/1

Y1 - 2006/10/1

N2 - Purpose: Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. Patients and methods: Patients were treated every 28 days with TMZ at 150-200 mg/m2once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. Results: Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46 = 7%, 95% confidence interval (CI) = 1, 18). Median time to progression was 24 weeks (95% CI = 16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI = 35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. Conclusions: Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.

AB - Purpose: Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. Patients and methods: Patients were treated every 28 days with TMZ at 150-200 mg/m2once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. Results: Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46 = 7%, 95% confidence interval (CI) = 1, 18). Median time to progression was 24 weeks (95% CI = 16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI = 35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. Conclusions: Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.

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