A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma.

Abstract

2054 Background: Despite high vascularity, duration of response of glioblastoma (GBM) to anti-angiogenic therapy is short. One proposed mechanism of resistance is via co-option of native brain blood vessels and tumor infiltration into normal appearing brain. We designed a Phase I study of cediranib, a VEGFR tyrosine kinase inhibitor, in combination with cilengitide, an integrin inhibitor, to block this infiltrative relapse. Methods: A phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent GBM. Once the MTD was determined, 40 patients enrolled in a dose expansion cohort. Standard eligibility criteria were included and all patients needed to have at least 1 cm of residual disease to assess tumor response. In the dose expansion cohort, 20 patients had received prior anti-VEGF therapy and 20 had never received anti-VEGF therapy. The primary endpoint was the safety of cediranib with cilengitide. Secondary endpoints were overall survival, the proportion of patients alive and progression free at 6 months (APF6), radiographic response (RR), and exploratory analyses of advanced MRI (perfusion, permeability, diffusion imaging) and blood biomarkers. Results: Forty-five patients were enrolled with a median age of 54 (23-80) and a median KPS 80 (60-100). No DLTs were observed and the MTD was cediranib 30mg daily and cilengitide 2000 mg twice weekly. There were no unexpected Grade 3 or 4 toxicities. Thirty patients experienced disease progression, 8 patients went off study for toxicity, and 5 patients withdrew from the study. Thirty nine patients have died. Partial response was seen in 2 patients, stable disease in 13, progression in 21, and 7 patients were not evaluable for RR. Median OS was 6.4 months, median PFS was 2.4 months, and APF6 was 7.5%. Conclusions: Combination cediranib/cilengitide was well tolerated but the median PFS/OS, APF6, and RR were not very promising. Ongoing analysis of the correlative imaging and blood biomarkers may shed light on a subset of patients who might benefit from this regimen and if anti-VEGF therapy blocked the penetration of cilengitide into the tumor. Clinical trial information: NCT00979862.