Abstract A5: Phase I trial and pharmacokinetic study of cediranib in children with recurrent or refractory solid tumors

Abstract

Abstract Cediranib (AZD2171) is an orally bioavailable small molecule inhibitor of the tyrosine kinase activity of VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4) and c-KIT. In adults with solid tumors, the monotherapy dose is 30 to 45 mg daily. At 20 mg, the geometric mean (coefficient of variation) cediranib area under the concentration × time curve (AUC0–∞) in adults (n=4) was 865 ng•h/mL (87%). The purpose of this 3+3 study is to determine the toxicity profile, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of cediranib administered orally once daily in continuous 28 day cycles in children and adolescents with solid tumors. Patients >2 and <19 y with relapsed or refractory solid tumors, excluding primary brain tumors, were eligible. Toxicity was graded according to the CTCAE v 3.0 except for hypertension, which was graded and managed using a protocol defined algorithm specific for children. PK sampling was performed after the first dose. Cediranib was quantified by LC-MS/MS. To date, 15 children (median age 15 y, range 8–18) have been treated 13 are evaluable for DLT assessment. Diagnoses included Ewing sarcoma (n=3), osteosarcoma (n=2), alveolar soft part sarcoma (n=2), synovial sarcoma (n=2), and other solid tumors (n=4). Two subjects enrolled at the starting dose of 12 mg/m2/d experienced DLTs in conjunction with rapidly progressive disease (one developed gr 3 nausea, vomiting, and lethargy, the other developed gr 3 hypertension and prolonged QTc interval). The study was amended to include eligibility criteria and monitoring for cardiac function. Subjects (n=3) were enrolled at 8 mg/m2/d. No DLT was observed. The dose was re-escalated to 12 mg/m2/d, and 1/6 experienced DLT (gr 3 diarrhea). Two subjects have completed one cycle of cediranib 17 mg/m2/d, one had DLT (gr 3 nausea). Non-DLTs include anorexia, fatigue, diarrhea, abdominal pain, nausea, headache, rash, increased thyroid stimulating hormone, decreased left ventricular function, and proteinuria. Asymptomatic pneumothorax associated with necrosis and shrinkage of pulmonary metastases occurred in subjects with Ewings sarcoma (n=1) and synovial sarcoma (n=2). At 12 mg/m2/d dose level (n=6) the geometric mean (CV%) AUC0–∞ was 1050 ng•h/mL (40%), based on preliminary data. After cycle 1 (n=4, 12 mg/m2/d), the median (range) increase in serum VEGF levels was 2.6 fold (2.3 – 8.6 fold) above baseline. Partial responses were observed in Ewing sarcoma (n=1, 8 mg/m2/d) and synovial sarcoma (n=2, 12 mg/m2/d). Once daily dosing of cediranib 12 mg/m2/d appears to be tolerable in children and 17 mg/m2/d is currently being evaluated. The adverse event profile is similar in children and adults. A Phase II study of cediranib in selected childhood solid tumors has been proposed to the Children's Oncology Group. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A5.