The Children's Hospital of Philadelphia, Division of Oncology-CTRB4016, 3501 Civic Center Blvd, Philadelphia, PA 19104, USA.
J Clin Oncol. 2010 Dec 10;28(35):5174-81. doi: 10.1200/JCO.2010.30.9674. Epub 2010 Nov 8.
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.
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.
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.
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.
确定 Cediranib 口服、每日一次、连续给药用于治疗儿童和青少年实体瘤的毒性谱、剂量限制毒性（DLTs）、最大耐受剂量（MTD）、药代动力学和药效学。
患有难治性实体瘤（不包括原发性脑肿瘤）的儿童和青少年符合入组条件。起始剂量为 12 mg/m²/d 的患者出现 DLT（1 例为 3 级恶心、呕吐、乏力，另 1 例为高血压和校正后 QT 间期延长）时，剂量下调至 8 mg/m²/d，随后上调至 12 和 17 mg/m²/d。第 1 周期进行药代动力学和药效学研究。采用世界卫生组织（WHO）标准评价疗效。
16 例患者（中位年龄 15 岁，范围 8-18 岁）可评估毒性。12 mg/m²/d 起始剂量入组的患者中出现 DLT（1 例为 3 级恶心、呕吐、乏力，另 1 例为高血压和校正后 QT 间期延长）。随后，3 例患者可耐受 8 mg/m²/d。另有 7 例患者入组至 12 mg/m²/d，其中 1 例发生 DLT（3 级腹泻）。4 例患者上调至 17 mg/m²/d，其中 2 例发生 DLT（1 例为 3 级恶心，1 例为不耐受的 2 级乏力）。非剂量限制毒性包括左心室功能障碍、促甲状腺激素升高、手掌-足底红斑感觉异常、体重减轻和头痛。Cediranib 的 MTD 为 12 mg/m²/d（成人固定剂量等效剂量为 20 mg）。12 mg/m²/d 时，药时曲线下面积（AUC）从 0 到无穷大（AUC(0-∞)）的中位数为 900 ng·h/mL，与接受 20 mg 剂量的成人相似。骨肉瘤、尤文肉瘤和滑膜肉瘤患者观察到客观缓解。
用于治疗儿童颅外实体瘤的 Cediranib 推荐单药剂量为 12 mg/m²/d，口服，每日一次，连续给药。目前正在开展一项 Cediranib 的 II 期研究。
