Our objective is to assess treatment efficacy, safety and pattern of response and recurrence in patients with recurrent high-grade glioma treated with bevacizumab and irinotecan. We reviewed retrospectively 51 patients with recurrent high-grade glioma treated with this combination at the Henry Ford Hermelin Brain Tumor Center from 11/15/2005 to 04/01/2008. The 6-month progression-free survival (PFS) for anaplastic gliomas (AGs) was 78.6 and 63.7% for glioblastoma. The median PFS was 13.4 months for AG and 7.6 months for those with glioblastoma. The overall survival rate (OS) at 6 months was 85.7% for AG and 78.0% for glioblastoma. The 12-month OS was 77.9% for AG and 42.6% for glioblastoma. The median OS time for AGs was not reached and was 11.5 months for those with glioblastoma. Thirty-six out of 51 (70.59%) patients demonstrated partial (32/51) or complete (4/51) radiographic response to treatment and 8/51 (15.69%) remained stable. Of the 38 who demonstrated progression on post-gadolinium studies, 23 showed distant progression with or without local recurrence. Seven patients showed progression on FLAIR without concordant findings on post-Gd sequences. Six patients (11.76%) discontinued treatment due to a treatment-emergent adverse event, including one with end-stage renal failure and another with gastric perforation. No symptomatic intracranial hemorrhages were reported. Patients with recurrent high-grade glioma treated with bevacizumab plus irinotecan demonstrate an excellent radiographic response rate and improved clinical outcome when compared to historical data. The high rate of distant tumor progression suggests that tumors may adapt to inhibition of angiogenesis by increased infiltration and vascular co-option.

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Background Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biological activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase II trial were to determine safety and efficacy of cilengitide when combined with radiation and temozolomide for newly diagnosed glioblastoma (GBM) and to select a dose for comparative clinical testing. Methods A total of 112 patients were accrued. Eighteen patients received standard RT+TMZ with cilengitide in a safety run-in phase followed by a randomized phase II with ninety-four patients assigned to either 500 or 2000 mg dose groups. The trial was designed to estimate overall survival benefit when compared with the NABTT internal historical control or the published EORTC 26981 data. Results Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for those receiving the 500 mg dose, 20.8 months for those receiving the 2000mg dose, 30 months for patients with methylated MGMT promoters and 17.4 months for unmethylated patients. For patients ages 70 and younger, the median survival and survival at 24 months was superior to that observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27% (p=0.008) respectively). Conclusions Cilengitide is well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with GBM regardless of MGMT status. From an efficacy and safety standpoint, future trials of this agent in this population should utilize the 2000 mg dose.

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Precis: Since MET is emerging as a key mediator of resistance to anti-VEGF therapy, the VEGFR-2 and MET inhibitor cabozantinib is of interest in glioblastoma. This phase I study identified the maximum tolerated dose of cabozantinib in conjunction with standard therapy (radiation and temozolomide) for newly diagnosed high-grade glioma.Key words: Glioblastoma, high-grade glioma, cabozantinib, anti-angiogenic therapy, signal transduction inhibitors Page 2 of 20 CancerThis article is protected by copyright. All rights reserved. Accepted ArticleAbstract Background