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Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies.

Aflibercept 联合 S-1 治疗日本晚期实体恶性肿瘤患者的安全性、耐受性和药代动力学的 I 期剂量递增研究。

  • 影响因子:2.87
  • DOI:10.1007/s10637-019-00888-z
  • 作者列表:"Doi T","Boku N","Onozawa Y","Takahashi K","Kawaguchi O","Ohtsu A
  • 发表时间:2020-01-06
Abstract

:Background Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3-6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.

摘要

背景: Aflibercept 是一种结合 VEGF-a 、 VEGF-B 和胎盘生长因子的重组融合蛋白,通过阻断血管生成抑制肿瘤生长。本 I 期剂量递增研究的目的是确定日本实体瘤患者中 aflibercept 联合 S-1 的推荐 II 期剂量 (RP2D)。患者和方法 3-6 例转移性或不可切除实体瘤患者的序贯队列,这些患者既往至少有一个标准治疗失败或不适合此类治疗, 每 2 周接受递增剂量的阿柏西普,从 2 mg/kg 开始,结合 40 mg/m2 的 S-1,每天两次(80 mg/m2/天; 4 周开/2 周休)。剂量递增是基于剂量限制性毒性 (DLT) 的发生率。采集血样进行药代动力学分析。结果在第一剂量水平 (aflibercept 2 mg/kg 加 S-1),6 例患者中有 1 例出现 DLT (4 级蛋白尿)。Aflibercept 剂量因此升级到 4 mg/kg; 在此剂量水平下治疗的 3 例患者中有 1 例 DLT (2 级胸腔积液), 另一名患者在 DLT 评估期后出现 3 级可逆性后部白质脑病综合征。因此,额外的患者被纳入第一剂量水平,以探索安全性和耐受性。该研究随后提前终止。日本患者未达到最大耐受剂量,RP2D 未确定。结论 aflibercept 2 mg/kg 联合 S-1 在日本晚期实体瘤患者中的耐受性和安全性得到证实。

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影响因子:6.50
发表时间:2020-03-31
来源期刊:Cancer letters
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