Phase I study of aflibercept (VEGF Trap) and temozolomide in newly diagnosed, high-grade glioma.

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2043 Background: Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGFA, VEGF-B and placental growth factor (PlGF), depleting circulating levels of these growth factors. Methods: The Adult Brain Tumor Consortium (ABTC) conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed high-grade gliomas (HGG). Three cohorts were examined: Cohort 1: Aflibercept with radiotherapy and concomitant temozolomide; Cohort 2: Aflibercept and adjuvant temozolomide using the 5/28 regimen; and Cohort 3: Aflibercept and adjuvant temozolomide using the 21/28 day regimen. Eligibility criteria included histologically proven newly-diagnosed glioblastoma (GBM) or anaplastic glioma (AG), > 18 yrs old, KPS > 60, adequate bone marrow reserve and organ function. Patients initially received 2 mg/kg of aflibercept every 2 weeks. If no dose-limiting toxicities (DLT's) were observed the dose was increased to the single agent dose of 4mg/kg every 2 weeks in the next cohort of patients. No further dose escalation was permitted. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose where DLT's occurred in fewer than 1/6 patients. At least 6 patients were treated at the MTD. Once this was defined, an additional 9 patients were treated for a total of 15 patients. Results: To date 48 patients have been enrolled, of whom 43 were evaluable. Median age was 56.9 years (23.91-69.19); median KPS 90 (70-100). The MTD of aflibercept for all 3 cohorts was 4mg/kg every 2 weeks. DLTs at the MTD were: Cohort 1: 0/6 patients; Cohort 2: 2/15 patients (G3 DVT, G4 ANC; Cohort 3: 3/15 patients (G4 biopsy-confirmed thrombotic microangiopathy; G3 rash, G4 thrombocytopenia). Conclusions: The combination of aflibercept and TMZ was generally well tolerated. The recommended phase II dose of aflibercept with radiotherapy and concomitant and adjuvant temozolomide is 4mg/kg every 2 weeks.