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

Purpose: To 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 methods: Children 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.

Results: Sixteen 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-∞)) was 900 ng·h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma.

Conclusion: The 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.

Trial registration: ClinicalTrials.gov NCT00354848.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Pharmacokinetics of cediranib in children and adolescents. Cediranib average concentration-time curves after a single oral dose are plotted for each dose level. Error bars are the standard deviation of the concentration.

Fig 2.

Systemic exposure determined by area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) is proportional to the actual administered dose (mg/m2). Cediranib exposure increased in proportion to dose. Patients with dose-limiting grade 3 nonhematologic toxicity (NH-DLT) seem to have higher AUC than the patient who experienced grade 2 fatigue that was intolerable and dose limiting or patients with no DLT.

Fig 3.

Objective responses in adolescents with sarcoma receiving cediranib. Axial computed tomography images at baseline (left) and post-therapy (right). WHO two-dimensional response criteria were used to evaluate tumor response. Partial responses were achieved in (A) a 17-year-old male with Ewing sarcoma (77% reduction) after receiving four cycles of cediranib (8 mg/m2/d) and (B) a 13-year-old female with synovial sarcoma (67% reduction) in pulmonary metastasis after two cycles of cediranib (17 mg/m2/d, cycle 1; 30% dose reduction, cycle 2). Response was complicated by bilateral pneumothoraces. Minor responses were observed in (C) an 18-year-old male with synovial sarcoma (40% reduction) after two cycles of cediranib (12 mg/m2/d). Response was complicated by pneumothorax, and multiple small pulmonary blebs are noted in the post-treatment computed tomography scan. (D) A 13-year-old female with osteosarcoma showed 34% reduction after two cycles of cediranib (17 mg/m2/d). No pneumothorax occurred in this patient.

Fig A1.

Algorithm for management of hypertension in children and adolescents. Diastolic hypertension (HTN) was defined using age- and sex-specific normal values. Children and adolescents with baseline HTN or those receiving antihypertensive medication were excluded. Single-agent antihypertensive medication (central shaded region) could be used to control mild asymptomatic HTN (diastolic blood pressure [DBP] > 10 and ≤ 25 mmHg above normal) without modification of the cediranib dose. (*) Elevated DBP measurements were repeated twice to confirm the elevation. (†) Upper limit of normal (ULN) was defined as a DBP at the 95th percentile from age- and sex-appropriate normal values. (‡) If DBP > 25 mm Hg above ULN for age (verified) or grade 4 HTN occurred at any time, cediranib was held. Antihypertensive agents were used to control HTN as clinically indicated after cediranib was held. Calcium channel blockers (amlodipine or nifedipine) were recommended for cediranib-related HTN.

Fig A2.

(A) Plasma vascular endothelial growth factor concentrations and (B) plasma soluble vascular endothelial growth factor receptor 2 concentrations before therapy and at the end of cycle 1. Each patient is represented by a unique symbol. Concentrations at baseline and end of cycle 1 are presented for individual patients receiving 8 mg/m2/d (gold), 12 mg/m2/d (blue), or 17 mg/m2/d (gray).