Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme.
OBJECTIVE
Novel therapies are needed for patients with recurrent glioblastoma multiforme (GBM). Because there is evidence that temozolomide (TMZ) has some activity in GBM and is well tolerated, and because of laboratory evidence that metalloproteinases are important in glioma cell invasion, the combination of TMZ and the matrix metalloproteinase inhibitor marimastat (MRM) in patients with recurrent GBM was studied.


METHODS
Forty-four patients with recurrent GBM after standard radiotherapy were enrolled. For 19 patients, this therapy was their first chemotherapy after tumor progression after irradiation; 25 others had received chemotherapy previously. TMZ 150 to 200 mg/m(2) days 1 to 5 and MRM 50 mg days 8 to 28 was administered at 28-day intervals for two cycles; then patients were reevaluated. Treatment continued until progression of tumor or toxicity developed.


RESULTS
Joint and tendon pain was the major therapy-related toxicity and was reported in 47% of patients. Five patients (11%) were removed from the study because of intolerable joint pain. For all patients, the progression-free survival (PFS) at 6 months was 39%. Median PFS was 17 weeks, median overall survival was 45 weeks, and 12-month PFS was 16%.


CONCLUSIONS
The combination of TMZ and MRM resulted in a PFS at 6 months that exceeded the literature target by 29%. This drug combination met phase II study criteria; further study in recurrent patients with GBM might be warranted. Further study of therapy-induced joint pain is necessary.
Groves
Morris D
MD
Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Puduvalli
Vinay K
VK
Hess
Kenneth R
KR
Jaeckle
Kurt A
KA
Peterson
Pamela
P
Yung
W K Alfred
WK
Levin
Victor A
VA
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D003606:Dacarbazine; C100342:marimastat; D000077204:Temozolomide