Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, University Health Network, University of Toronto, 610 University Avenue, 5-700, Toronto, Ontario M5G 2M9, Canada.
Br J Cancer. 2012 Aug 7;107(4):604-11. doi: 10.1038/bjc.2012.319. Epub 2012 Jul 17.
To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.
Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.
Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.
The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.
评估阿柏西普的安全性、药代动力学（PKs）和药效学，并确定阿柏西普联合培美曲塞和顺铂的推荐 II 期剂量（RP2D）。
阿柏西普以 2、4 或 6 mg/kg 的递增剂量与培美曲塞（500 mg/m²）联合顺铂（75 mg/m²）固定剂量联合使用，每 3 周给药一次。采集血样进行 PK 分析。定量检测血清抗阿柏西普抗体，以评估其对系统阿柏西普浓度的影响。
共纳入 18 例患者。1 例患者在 4 mg/kg 剂量时出现 3 级低磷血症（剂量限制毒性；DLT），促使扩大队列。在 4 mg/kg 队列或 6 mg/kg 剂量队列中未观察到进一步的 DLT。最常见的所有级别不良事件（AE）包括（%）：疲劳（89）、贫血（89）、恶心（83）、低钠血症（78）和中性粒细胞减少症（72）。与抗血管内皮生长因子治疗一致的≥3 级 AE 包括（%）：高血压（22）、肺栓塞（11）和深静脉血栓形成（6）。5 例患者（28%）出现轻度神经认知障碍。未观察到可逆性后部白质脑病综合征（RPLS）发作。
这项 I 期研究的结果允许在 II 期研究中进一步评估阿柏西普联合培美曲塞和顺铂的疗效。阿柏西普的 RP2D 为 6 mg/kg，静脉给药，每 3 周一次，与培美曲塞和顺铂联合使用。
