Phase I/II study of vandetanib for patients with recurrent malignant gliomas.

Abstract

2083 Background: EGFR and VEGFR signaling have been implicated in the development and growth of glioblastoma, and simultaneous inhibition of both of these signal transduction pathways has the potential to be a more effective therapeutic approach than inhibiting a single pathway. Vandetanib is an inhibitor of VEGFR-2 and EGFR tyrosine kinase activities, which has previously been shown to have anti-tumor activity in histologically diverse pre-clinical models of human cancer, including subcutaneous and orthotopic models of human glioma. Methods: A phase I study evaluated the MTD of vandetanib in patients on enzyme-inducing antiepileptics (EIAEDs). Eligibility criteria were histologically proven glioblastoma (GBM), anaplastic glioma (AG), progressive low-grade glioma (LGG), or radiographically diagnosed brainstem gliomas, radiologic progression after RT, age ≥ 18, KPS ≥ 60, and adequate bone marrow and organ function. There was no limit on the number of prior relapses or chemotherapies. Doses were escalated on a 3 + 3 design, with dose levels of 300, 400, 500, 700, and 900 mg QD. MTD was defined as the highest dose with DLTs in 1/6 or fewer patients. In phase II, patients with histologically proven AG were eligible, with other eligibility criteria as outlined above. Patients on EIAEDs were excluded from the phase II study. Patients received vandetanib 300 mg QD on 4- week cycles. Primary endpoint was PFS6. Results: In phase I, 15 patients were evaluated (8 GBM; 5 AG, 2 LGG). Median age 44 (18-66); median KPS 90 (80-100); median prior chemotherapies 1 (1-5). The MTD was determined to be 400 mg. There was 1/6 DLT (grade 3 rash) at this dose. At 500 mg there were 2/6 DLTs; one grade 3 prolonged QTc, and one grade 4 DVT/PE. In the phase II trial, there were 32 patients with AG. Median age 41 (18-69), median KPS 90 (60-100), median prior chemotherapies 2 (0-6). There were 2 PRs, and 13 SDs. One patient remains progression-free on study for over 21 months. PFS6 was 13.2% (95% CI: 4.2-27.5%), and median PFS was 1.8 mo (95% CI: 0.89-2.66 mo). Median OS was 7.4 mo (95% CI: 3.9-12.5 mo). Conclusions: Vandetanib is well tolerated, with a MTD of 400 mg QD in patients taking EIAEDs. In patients not on EIAEDs, vandetanib 300 mg QD had only limited monotherapy activity in recurrent AG. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca