Posted on: 06/07/2006

Phase I/II Trial of Twice-Daily Temozolomide and Celecoxib for Treatment of Relapsed Malignant Glioma: Final Data
S Pannullo,1 J Burton,2 J Serventi,1 P Stieg,1 S Hariharan,3 R Elsoueidi,2 I El-Jassous,2
C Balmaceda1
1New York Presbyterian Hospital-Weill Cornell Medical Center/Columbia University Medical Center, New York, NY; 2Staten Island University Hospital, Staten Island, NY; 3JFK Medical Center, Edison, NJ, and Pfizer Inc., New York, NY
Background: Anaplastic astrocytoma (AA) and glioblastoma (GBM) overexpress the cyclooxygenase-2 (COX-2) enzyme. COX-2 inhibitors demonstrate preclinical efficacy in glioma models and have non-overlapping toxicity with chemotherapy, prompting a phase I/II clinical trial for patients with recurrent/progressive AA or GBM utilizing a regimen of combined temozolomide and celecoxib.
Methods: For phase I, a modified Fibonacci design was used with 3 patients/cohort. Temozolomide was given as a fixed loading dose of 200 mg/m2 followed by 9 doses of 90 mg/m2 BID for 5 days. Celecoxib was given in 5 dose levels starting at 60 mg/m2 BID, escalating to 240 mg/m2 BID (maximum 480 mg BID) for 10 days. Cycles were repeated every 28 days until disease progression or toxicity occurred.
Results: 46 patients (28 male, 18 female) received 247 cycles of therapy. 37 patients had GBM, 9 AA. Prior treatment was radiation (N = 46) and chemotherapy (N = 12). No patient received prior temozolomide. Median age was 54 years (range, 34 to 74 years).No dose-limiting toxicity was observed. Hematologic toxicity was mild with grade 3/4 neutropenia occurring in 3 of 235 cycles and grade 3 thrombocytopenia in 3 of 235 and did not recur following temozolomide dose reduction. Grade 1/2 constipation was common, occurring in 28% of patients. No thrombotic events occurred. Overall response rate after 6 cycles was 72%. Among the ITT population, 1 (2%) had CR, 7 (15%) had PR, 5 (11%) had SD, and 28 (61%) had PD. Average duration of response was 6.0 months (range, 2 to 15 months). Median survival from time of trial entry for recurrent disease was 8 months (8 months for GBM, 10 months for AA). Median survival from initial tumor diagnosis was 15 months (15 months GBM, 23 months AA).
Conclusion: A regimen of twice-daily temozolomide and celecoxib is safe and potentially effective for the treatment of recurrent/progressive GBM and AA. This combination warrants further study, especially in newly diagnosed patients, given the current use of temozolomide in newly diagnosed GBM and the possible additional value of addition of COX-2 inhibitors in the up-front setting.

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