Preliminary Data from a Multicenter, Phase II, Randomized, Non-Comparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly-Diagnosed Glioblastoma (GBM) (S45.006)

Objective: We conducted a randomized phase II study of vandetanib in patients with newly-diagnosed GBM in combination with radiation (RT) and temozolomide (TMZ). Background EGFR and VEGFR signaling have been implicated in the development and growth of GBM. In addition, angiogenesis inhibitors may enhance radiation sensitivity. Vandetanib is an inhibitor of VEGFR-2 and EGFR tyrosine kinase activities. Design/Methods: We planned to randomize a total of 114 newly-diagnosed GBM patients in a ratio of 1:2 to Arm A: RT/TMZ or Arm B: vandetanib 100 mg daily + RT/TMZ. All pts received RT (60 Gy) and concurrent TMZ 75 mg/m 2 daily, followed by adjuvant TMZ for up to 12 cycles (150-200 mg/m 2 on days 1-5 of each 28 day cycle). Pts with age ≥ 18, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS) and safety. Results: We enrolled 106 pts (36 in Arm A, 70 in Arm B) with median age 59 yrs (range: 23-83) and median KPS 90 (range: 60-100). Most frequent Gr ≥ 3 AEs in the vandetanib arm were lymphopenia (20%), thrombosis (12.5%), transaminitis (8%) and leukopenia (5%). Preliminary median OS is 487 days with 95% CI (350, NR) in Arm A and 503 days with 95% CI (451, 634) in Arm B. Median PFS is 141 days with 95% CI (104. 252) in Arm A and 127 days with 95% CI (93. 165) in Arm B. Due to an unplanned interim analysis demonstrating no survival difference, enrollment was terminated early and the study was closed. Conclusions: Although reasonably well-tolerated, the addition of vandetanib to standard chemoradiation in newly-diagnosed GBM may not significantly prolong OS compared to the parallel control arm. Updated efficacy and toxicity data will be presented. Supported by: AstraZeneca. Disclosure: Dr. Lee has received personal compensation for activities with Norvartis and Genentech as an advisory board member.Dr. Lee has received personal compensation in an editorial capacity for UpToDate, Inc. Dr. Batchelor has received personal compensation for activities with Roche Diagnostics Corporation, Genentech, Inc., Merck & Co. Inc., and Millennium. Dr. Batchelor has received personal compensation in an editorial capacity for UpToDate Inc. Dr. Batchelor has received research support from Pfizer Inc, AstraZeneca Pharmaceuticals and Millennium. Dr. Kaley has nothing to disclose. Dr. Schiff has received personal compensation for activities with Novocure and Genentech. Dr. Schiff has received research support from Exelixis. Dr. Lassman has received personal compensation for activities with Schering-Plough Corp., ImClone Systems, Genentech, Inc., Eisai Inc., Cephalon, Inc., Physicians Education Resource, The Robert Michael Educational Institute, and Medical Communications Media.Dr. Lassman has received research support from Keryx Biopharmaceuticals, Genentech, and Schering Plough Corp. Dr. Wong has received research support from AstraZeneca Pharmaceuticals, Exelixis, Novartis and NovoCure as a researcher. Dr. Mikkelsen has received personal compensation for activities with Merck and Roche. Dr. Purow has nothing to disclose. Dr. Drappatz has nothing to disclose. Dr. Norden has nothing to disclose. Dr. Beroukhim has received personal compensation for activities with Novartis as a consultant. Dr. Beroukhim holds stock and/or stock options in AstraZeneca, which sponsored research in which Dr. Beroukhim was involved as an investigator. Dr. Beroukhim holds stock and/or stock options in Baxter, CareFusion, Edwards Lifesciences, and Cardinal Health. Dr. Beroukhim has received research support from Novartis. Dr. Weiss has received personal compensation for activities with a consulting firm as RT expert. Dr. Weiss has received research support from Aposence. Dr. Alexander has nothing to disclose. Dr. McCluskey has nothing to disclose. Dr. Gerard has nothing to disclose. Dr. Teulings has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Muzikansky has nothing to disclose. Dr. Wen has received personal compensation for activities with Merck & Co., and Novartis as consutant and/or speaker. Dr. Wen has received personal compensation in an editorial capacity for UptoDate. Dr. Wen has received research support from Amgen Inc, AstraZeneca Pharmaceuticals, Eisai Inc, Exelixis, Genentech, Inc., Medimmune, Merck & Co., Novartis, Sanofi-Aventis Pharmaceuticals and Vascular Biogenics.