Digestive Oncology Unit, University Hospital Gasthuisberg, 3000 Leuven, Belgium.
Eur J Cancer. 2013 Jan;49(1):17-24. doi: 10.1016/j.ejca.2012.07.007. Epub 2012 Aug 24.
To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2).
In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks.
Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg.
Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.
为了确定剂量限制毒性（DLTs）、推荐的 II 期试验剂量（RPTD）、安全性、初步抗肿瘤活性和阿柏西普联合伊立替康、5-氟尿嘧啶和亚叶酸（LV5FU2）的药代动力学。
在这项开放标签研究中，38 名晚期实体瘤患者接受阿柏西普 2、4、5 或 6mg/kg 静脉注射，第 1 天，然后在第 1 和第 2 天每天给予伊立替康和 LV5FU2。
4mg/kg 组有 2 例 3/4 级阿柏西普相关 DLT：持续>2 周的蛋白尿和伴有血栓性微血管病的急性肾病综合征。5mg/kg 组有 2 例 DLT（3 级口腔炎和 3 级食管炎反流）和 6mg/kg 组有 3 例 DLT（发热性中性粒细胞减少症、3 级口腔炎和 3 级腹痛）被认为与同时进行的化疗和基础疾病有关。最常见的 3/4 级不良事件是中性粒细胞减少症、高血压和腹泻。9 例患者有部分缓解，其中 5 例为 4mg/kg。22 例患者病情稳定（5 例为 4mg/kg），17 例患者病情稳定超过 3 个月。未检测到抗阿柏西普抗体。在大多数 4mg/kg 的患者中，游离阿柏西普超过结合物。
基于药代动力学、可接受的安全性和令人鼓舞的抗肿瘤活性，选择阿柏西普 4mg/kg 联合伊立替康和 LV5FU2 每 2 周一次作为 RPTD。
