Phase I study of vandetanib with radiation therapy and temozolomide for newly diagnosed glioblastoma

Abstract

2031 Background: There is increasing evidence that angiogenesis inhibition may potentiate the effects of radiation therapy (RT) and chemotherapy in patients with glioblastoma (GBM). In addition, inhibition of the epidermal growth factor receptor (EGFR) may be of therapeutic benefit, as EGFR is often upregulated in GBM and contributes to radiation resistance. We conducted a phase I study of vandetanib, an inhibitor of VEGFR2 and EGFR, in patients with newly-diagnosed GBM in combination with RT and temozolomide (TMZ). Methods: Using a standard 3 + 3 dose escalation design, 13 newly-diagnosed GBM patients received vandetanib with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant TMZ for up to 12 cycles (150–200 mg/m2 on days 1–5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤1/6 dose-limiting toxicities (DLT). Eligible patients were adults with newly-diagnosed GBM or gliosarcoma, Karnofsky performance status of ≥60%, normal organ function, and not taking enzyme-inducing anti-epileptic drugs. MTD was determined by evaluation of DLTs during the first 12 weeks of therapy. Results: Six patients were treated with vandetanib at 200 mg daily. 2/6 patients developed DLTs (grade 5 gastrointestinal hemorrhage and grade 3 thrombocytopenia in one patient and grade 4 neutropenia in one patient). Seven patients were treated at 100 mg daily with no DLTs observed, establishing 100 mg daily as the MTD. Of 10 evaluable patients, one had a minor response (10%), defined as 25% to <50% reduction in enhancing area for 8 weeks; eight had stable disease (80%), defined as <25% increase or decrease; and one had progressive disease (10%). Conclusions: These data suggest that vandetanib may be combined with RT and TMZ in GBM patients. A randomized phase II study in which patients receive RT and TMZ with or without vandetanib 100 mg daily is underway. [Table: see text]