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

  • Clinical–Patient Studies
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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/m2 once 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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Abbreviations

AG:

anaplastic glioma

MT:

marimastat

TMZ:

temozolomide

MRI:

magnetic resonance imaging

TTP:

time to progression

PFS:

progression-free survival

AA:

anaplastic astrocytoma

AO:

anaplastic oligodendroglioma

GBM:

glioblastoma and glioblastoma multiforme

AOA:

anaplastic oligoastrocytoma

MG:

mixed anaplastic glioma not otherwise specified

SD:

stable disease

OS:

overall survival

MMPs:

matrix metalloproteinases

KPS:

Karnofsky Performance Status

CR:

complete response

MR:

minor response

PD:

progressive disease

CI:

confidence interval

CTC:

Common Toxicity Criteria

H:

hypotheses

JRT:

joint-related toxicity

EIAED:

enzyme-inducing anticonvulsant

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Acknowledgements

The authors gratefully acknowledge the assistance of Betty Notzon and Joann Aaron for editorial assistance, Jennifer Guidry for manuscript preparation, and Sandra Ictech for assistance in data management. This work was supported in part by research funding from Schering Plough Research Institute, Nutley, NJ.

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Authors and Affiliations

  1. Department of Neuro-Oncology, Unit #431, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Morris D. Groves, Vinay K. Puduvalli, Charles A. Conrad, Mark R. Gilbert, W. K. Alfred Yung, Vivien Liu & Victor A. Levin

  2. Department of Neuropathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Kenneth D. Aldape

  3. Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Kenneth R. Hess

  4. The Mayo Clinic, Jacksonville, FL, USA

    Kurt Jaeckle

Authors
  1. Morris D. Groves
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  2. Vinay K. Puduvalli
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  3. Charles A. Conrad
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  4. Mark R. Gilbert
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  5. W. K. Alfred Yung
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  6. Kurt Jaeckle
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  7. Vivien Liu
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  8. Kenneth R. Hess
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  9. Kenneth D. Aldape
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  10. Victor A. Levin
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Corresponding author

Correspondence to Morris D. Groves.

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Groves, M.D., Puduvalli, V.K., Conrad, C.A. et al. Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: A relationship among efficacy, joint toxicity and anticonvulsant status. J Neurooncol 80, 83–90 (2006). https://doi.org/10.1007/s11060-006-9160-y

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  • DOI: https://doi.org/10.1007/s11060-006-9160-y

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