Desjardins et al studies.30,31 Several single institutional studies are underway to evaluate the addition of BV to RT and TMZ for newly diagnosed GBM patients. The results of the interim analysis for safety and tolerability of the ﬁrst 10 patients treated by the UCLA group has been published.32 The safety analysis showed that one patient experienced a presumed radiation-induced optic neuropathy. The toxicities that could be potentially related to the treatment combination were relatively high incidences of fatigue (20% grade 3–4 post RT), myelotoxicity (20% and 30% grade 3–4 during RT and post RT, respectively), wound breakdown (10% and 10% grade 3–4 during RT and post RT, respectively), and deep venous thrombosis (30% grade 3–4 post RT) and pulmonary embolism (20% grade 3–4 post RT). They concluded that the observed toxicities were acceptable for continued enrollment toward the overall target group of 70 patients. In addition, a multi-center, randomized phase III clinical trial for newly diagnosed GBM patients is being planned. Receptor tyrosine kinases (RTKs) inhibitors are typically small molecules that competitively block tyrosine or serine/ threonine kinase domains located intracellularly. Preliminary results of VEGF RTK inhibitors under evaluation for MG patients have been reported. Nine of 16 patients (56%) treated with cediranib (AZD2171, AstraZeneca, UK), a potent, oral, pan-VEGFR, PDGFR and c-kit inhibitor, achieved a radiographic response while 3 additional patients achieved stable disease. In addition, 8 of 11 patients (73%) were able to reduce pre-treatment corticosteroid dosing. A median PFS of 111 days and median OS of 211 days were observed in this small cohort of patients. Collaborative imaging studies revealed that decreased contrast enhancement was accompanied by significant decreases in tumor vessel size, permeability, blood volume and ﬂow, consistent with “normalization” of tumor vessels. Of note, reversal of tumor vessel normalization was observed following drug interruption.33 The authors concluded that similar to other antiangiogenic therapies that target only tumor endothelium, monotherapy with AZD2171 may not improve overall survival, suggesting the need to combine cytotoxic therapies with AZD2171. A multi-center, randomized clinical trial is planned to evaluate cediranib versus lomustine versus the combination of cediranib plus lomustine in patients with recurrent GBM. VEGF-TRAP (Regeneron, Inc., NY, USA), a 110 kDa soluble protein containing extracellular VEGF receptor sequences (VEGFR1 and VEGFR2) fused to a IgG backbone,34 acts as a soluble protein decoy VEGF receptor 18 that binds circulating VEGF, thereby preventing it from interacting with its receptors on tumor endothelial cells.35,36 VEGF-TRAP potentates RT in prelicinical GBM xeno- grafts.37 A phase II trial of VEGF-TRAP monotherapy for patients with TMZ-resistant recurrent GBM or anaplastic glioma at ﬁrst relapse was completed by the North American Brain Tumor Consortium (NABTC). Forty-eight patients were enrolled (32 GBM and 16 anaplastic glioma). Response rates of 50% for the anaplastic glioma cohort and 30% for the GBM cohort were observed. Grade 3 adverse events included fatigue, hypertension, hand-foot syndrome, lymphopenia, thrombosis and proteinuria. One ischemic stroke and one systemic hemorrhage (grade 4 toxicities) were reported. They also observed that VEGF-TRAP induced a rapid and pro- longed decrease in free levels of VEGF and PIGF, conﬁrming the sequestration of target growth factors.38 A multi-center clinical trial incorporating VEGF-TRAP with RT and TMZ is planned for newly diagnosed GBM patients. Vatalanib (PTK787/ZK222584; Novartis) is a novel, oral, small-molecule ATP-mimetic inhibitor of VEGFRs that has shown anti-glioma activity in preclinical studies.39 A phase I multi-institutional trial of PTK787 as monotherapy found that the agent was well tolerated with dose-limiting toxicities of deep vein thrombosis, liver enzyme elevation, insomnia, cerebral edema, fatigue, and nausea/vomiting.40 Of 31 evaluable patients, one patient presented a PR (response rate of 4%) and 20 patients experienced disease stabilization (65%).41 Combination of vatalanib with either TMZ or lomustine demonstrated response rate of 8% and time-to-progression of 16.1 weeks for the TMZ group and 12.1 weeks for the lomustine group.42 Epidermal growth factor Another attractive therapeutic target is the epidermal growth factor receptor (EGFR). Approximately half of GBM tumors exhibit ampliﬁcation of EGFR. In addition, EGFR is over- expressed in many MG independently of the ampliﬁcation status.43 EGFRvIII, a mutant EGFR variant, is present in approximately 40% of GBM tumors, and its expression confers a negative prognosis.44 Geﬁnitib (ZD1839, Iressa®; AstraZeneca) is a novel, oral, low-molecular weight ATP mimetic of the anilinoquinazoline family that reversibly inhibits the tyrosine kinase activity of EGFR. A phase II trial of geﬁnitib in ﬁrst relapse GBM showed a median event-free survival of 8.1 weeks, a 6-month PFS of 17%, and no radio- graphic responses.45 Other studies of geﬁtinib have failed to show survival beneﬁts.46,47 Erlotinib (OSI-774, Tarceva®; OSI Pharmaceuticals) is an orally active quinazoline derivative Biologics:Targets & Therapy 2009:3