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


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.
Groves
Morris D
MD
Department of Neuro-Oncology, Unit #431, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. mgroves@mdanderson.org
Puduvalli
Vinay K
VK
Conrad
Charles A
CA
Gilbert
Mark R
MR
Yung
W K Alfred
WK
Jaeckle
Kurt
K
Liu
Vivien
V
Hess
Kenneth R
KR
Aldape
Kenneth D
KD
Levin
Victor A
VA
D000927:Anticonvulsants / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D007592:Joint Diseases / Q000139:chemically induced*; D007596:Joints / Q000187:drug effects; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D003606:Dacarbazine; D003577:Cytochrome P-450 Enzyme System; C100342:marimastat; D000077204:Temozolomide