A Phase 1 Trial and Pharmacokinetic Study of Cediranib, an Orally Bioavailable Pan–Vascular Endothelial Growth Factor Receptor Inhibitor, in Children and Adolescents With Refractory Solid Tumors

Abstract

A B S T R A C T PurposeTo determine the toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of cediranib administered orally, once daily, continuously in children and adolescents with solid tumors. Patients and MethodsChildren and adolescents with refractory solid tumors, excluding primary brain tumors, were eligible. DLT at the starting dose of 12 mg/m 2 /d resulted in de-escalation to 8 mg/m 2 /d and subsequent re-escalation to 12 and 17 mg/m 2 /d. Pharmacokinetic and pharmacodynamic studies were performed during cycle 1. Response was evaluated using WHO criteria. ResultsSixteen patients (median age, 15 years; range, 8 to 18 years) were evaluable for toxicity. DLTs (grade 3 nausea, vomiting, fatigue in one; hypertension and prolonged corrected QT interval in another) occurred in patients initially enrolled at 12 mg/m 2 /d. Subsequently, 8 mg/m 2 /d was well tolerated in three patients. An additional seven patients were enrolled at 12 mg/m 2 /d; one had DLT (grade 3 diarrhea). At 17 mg/m 2 /d, two of four patients had DLTs (grade 3 nausea; intolerable grade 2 fatigue). Non-dose-limiting toxicities included left ventricular dysfunction, elevated thyroid stimulating hormone, palmar-plantar erythrodysesthesia, weight loss, and headache. The MTD of cediranib was 12 mg/m 2 /d (adult fixed dose equivalent, 20 mg). At 12 mg/m 2 /d, the median area under the plasma concentration-time curve extrapolated to infinity (AUC 0-ϱ ) was 900 ng⅐h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma. ConclusionThe recommended monotherapy dose of cediranib for children with extracranial solid tumors is 12 mg/m 2 /d administered orally, once daily, continuously. A phase II study is in development.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…Among the identified studies, QTc prolongation was seen in 14% of patients treated with cediranib101, 102, 103, 104 and 21% of patients treated with vadimezan (ASA404) 108, 109, 175. Caution and periodic ECG monitoring is advised during the treatment with these agents.…”

Synovial sarcoma diagnosis and management in the era of targeted therapies

“…Cediranib monotherapy showed one PR and one minor response in two patients with synovial sarcoma [45]. Minimal effect was seen with sorafenib, with stable disease of limited duration in 50% of the patients with synovial sarcoma (n ¼ 12) [46], and sunitinib resulting in one stable disease in four patients [47].…”

Phase 1 clinical trials for sarcomas: the cutting edge

“…In a pediatric phase 1 study, objective responses were seen in Ewing's sarcoma, synovial sarcoma, and osteosarcoma patients with pulmonary metastases [12]. A patient with alveolar soft part sarcoma (ASPS) had disease stabilization.…”