Phase I trial of vatalanib (PTK787) in combination with standard radiation and temozolomide in patients with newly diagnosed glioblastoma
2035 Background: Anti-vascular endothelial growth factor (VEGF) agents are hypothesized to work synergistically with chemotherapy and radiation (RT). Vatalanib (MW 347, T1/2 4.6 h) is an oral, pan-VEGFR tyrosine kinase inhibitor that has shown activity in patients with recurrent glioblastoma. Methods: This phase I study was designed to determine the maximal tolerated dose of vatalanib in combination with RT and TMZ for patients with newly diagnosed GBM who were taking enzyme-inducing anti-epileptic drugs. RT and TMZ were administered at standard doses. Vatalanib was initiated 5 days prior to the start of RT and continued daily until tumor progression, unacceptable toxicity or a maximum of up to 12 cycles of post-RT TMZ. Cohorts of 3 patients were treated during RT and TMZ at doses of 250mg daily, 250mg BID, or 500mg BID of vatalanib. Following the completion of RT, patients were treated with vatalanib 750mg BID for the remainder of the study. Results: Nineteen patients were enrolled of which 17 took 5 or more days of vatalanib (1 patient withdrew consent prior to start of vatalanib and 1 withdrew consent after only 1 dose). The median age was 58 and the median KPS was 90. Eight patients had a diagnostic biopsy only. The MTD has not been reached. Potentially related grade 3–4 toxicities included elevated transaminases (2 patients), thrombocytopenia (1 patient), leukopenia (1 patient), neutropenia (1 patient), depressed level of consciousness (1 patient), and fatigue (1 patient). Only 1 patient suffered an asymptomatic intracerebral hemorrhage and no patient experienced wound dehiscence or infection. Five patients remain on vatalanib and the median follow-up for all patients is 6.5 months. Seven patients have died. The best responses for the 13 patients who completed combination RT/TMZ/vatalanib was 2 PR, 7 SD, and 2 PD. Two patients were clinically stable with biopsy proven pseudoprogression. Median PFS is 18.4+ months and OS has not been reached. Conclusions: Vatalanib is safe and well tolerated when added to standard RT and TMZ. The MTD has not been reached and dose escalation continues in this population of patients on enzyme inducing anti-epileptic drugs. [Table: see text]