Phase II trial of bevacizumab and fotemustine in recurrent grade III gliomas.

2075 Background: Bevacizumab (BV) has shown activity in recurrent grade III gliomas, and few data are available on the combination of BV and nitrosoureas. Fotemustine (FTM) is a nitrosourea with elevated lipophilic properties. Methods: In this phase II study patients with grade III gliomas recurrent after surgery, radiation therapy and concomitant/adjuvant temozolomide were eligible. The treatment consisted of an induction phase with BV at 10mg/kg intravenously on day 1 and 15 and FTM at 75mg/m2 intravenously on day 1 and 8, followed after a 3 week interval by a maintenance phase with BV 10mg/kg and FTM 75mg/m2 every 3 weeks until tumor progression or unacceptable toxicity. Patients had undergone clinical and MRI assessment 1 month after the start of treatment and thereafter every 2 months. The primary endpoint was progression-free survival at 6 months (PFS-6), whereas secondary end-points were response rate (RR), based on RANO criteria, progression-free survival (PFS), overall survival (OS), and safety. Results: From May 2008 to September 2011, 32 patients (males 23, females 9, median age 46) were enrolled. PFS-6, PFS -12 and median PFS were 31%, 7% and 5 months (range: 1-43+), respectively. OS-6, OS-12 and median OS were 78%, 37.8% and 8.6 months (3.5-43+), respectively. Response rates were as follows: 4 CR (12.5%), 12 PR (37.5%), 14 SD (44%) and 2 PD (6%). A significant neurological improvement was observed in 48% of symptomatic patients, being steroids reduced or withdrawn in 83% of patients. 29/32 (91%) patients have progressed and patterns of tumor progression were local in 20 (69%), multicentric in previous multicentrinc tumors in 5 (17%), gliomatosis-like in 3 (10%) and local plus leptomeningeal seeding in 1 (4%). 23/29 patients had salvage treatment after failure. Toxicities after BV were as expected; 5 patients interrupted FTM for grade III-IV myelotoxicity. We did not observe any additional toxicity from the combination. Conclusions: The combination of bevacizumab and fotemustine in grade III gliomas recurrent after standard treatment seems to have some activity.