Upfront bevacizumab with temozolomide or with temozolomide and irinotecan for unresectable or multifocal glioblastoma.

2055 Background: Patients with unresectable or multifocal glioblastomas (GBs) have a poor prognosis with median survival of 6-10 months. Given the angiogenic phenotype of GB, we conducted two phase II trials of upfront 5-day temozolomide (TMZ) and Bevacizumab (BV) with or without Irinotecan in patients with newly diagnosed unresectable or multifocal GB. METHODS: Before radiation, patients received up to 4 cycles of temozolomide at 200 mg/m(2)/d days 1-5 and BV at 10 mg/kg on days 1 and 15 in each 28-day cycle. In the second trial, Irinotecan was added on days 1 and 15 at 125 mg/M(2) for patients not on an enzyme-inducing anti-epileptic drug (EIAED), or 340 mg/M(2) for patients on an EIAED. An MRI was performed monthly and therapy continued as long as there was no tumor progression, grade 4 non-hematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary endpoint was tumor response using the RANO criteria. RESULTS: In the initial trial of TMZ and BV, 41 patients were enrolled from 10/07 to 9/08. MRI's were available from 31 patients. There were 8 (25.8%) partial responses, 19 (61.3 %) patients with stable disease, and 4 (12.9 %) had disease progression. 19 of the 41 patients enrolled completed four cycles without tumor progression. The regimen was tolerable, with three grade 4 hematologic toxicities. There were 3 venous thromboembolic complications. There were 2 CNS hemorrhages. The median PFS was 5.2 mos (3.2, 9.0 months) and the median OS was 11.7 months (7.1, 15.6 months). In the second trial, Irinotecan was added to TMZ and BV and 41 patients were enrolled between 12/09 and 11/10. The partial response rate was 41%, 44% had stable disease and 15% had progression. 16 of 41 patients completed four cycles without tumor progression. There were 4 patients with grade 4 hematologic toxicity, 7 patients with venous thromboembolic complications and 1 with CNS hemorrhage. The median PFS was 6.7 months (2.0, 10.5 months) and median OS was 10.5 months (7.2, ND months). CONCLUSIONS: Upfront TMZ and BV was well tolerated. Adding Irinotecan to TMZ and BV does not appear to improve survival. Upfront therapy for unresectable or multifocal GB is an excellent platform to determine clinical activity.

Duke Scholars

Author James Emmett Herndon II Biostatistics & Bioinformatics, Division of Biostatistics

Author Henry Seth Friedman Neurosurgery, Neuro-Oncology