Phase I study of vandetanib (ZD6474) administered during and after irradiation (RT) in children with diffuse intrinsic pontine glioma (DIPG)

Abstract

10020 Background: Children with DIPG have a dismal prognosis despite use of RT, which is the mainstay of therapy. All chemotherapy regimens used so far demonstrated no benefit. EGFR and VEGFR pathways are considered important in tumorigenesis of DIPG. Methods: We conducted a traditional phase I study combining oral vandetanib (VEGFR-2 and EGFR inhibitor) during and after local RT in children with DIPG. Five dosage levels were tested (50, 65, 85, 110, and 145mg/m2 per day). Vandetanib and RT started on the same day. The first 6 weeks of therapy constituted the dose-limiting toxicity (DLT)-evaluation period. Correlative studies consisted of pharmacokinetic analysis (PK), pharmacodynamic studies in blood, and standard and investigational imaging (before and 1, 3, and 6 weeks after start of therapy). Results: Twenty-one patients were enrolled on study (50 [n = 3], 65 [n = 3], 85 [n = 3], 110 [n = 6], and 145mg/m2 [n = 6]). Two patients experienced DLT consisting of rash/mucositis (level 4) and diarrhea (level 5). The maximum-tolerated dose (MTD) of vandetanib was not reached. Other significant toxicities included lymphopenia grade 3/4 (n = 10), grade 3 neutropenia and hypophosphatemia (one each), grade 2 proteinuria (n = 2), grade 2 hypertension (n = 4), and mild QTc prolongation (n = 7) .Once the phase I component was completed, two extra patients were enrolled at dosage level 5; one of them developed grade 4 seizure secondary to posterior reversible encephalopathy syndrome. PK (n = 21) showed similar drug clearance and volume of distribution compared to adults. However, drug exposure at steady state normalized by dose seemed higher in children. Increased tumor perfusion during the first 6 weeks of therapy was observed in the first 12 patients analyzed. Conclusions: Although MTD was not reached, we recommend administration of vandetanib at a dose of 110mg/m2 per day during and after local RT in children. Further combination studies of vandetanib in children with DIPG are planned. No significant financial relationships to disclose.