National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba, Japan.
Osaka University Graduate School of Medicine, Osaka, Japan.
J Immunother Cancer. 2019 Aug 14;7(1):219. doi: 10.1186/s40425-019-0679-9.
Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface in many cancers and predicts poor prognosis. DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors.
Step 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1-20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated.
Thirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3CD56CD16) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3CD56CD137 to CD3CD56CD16 cells increased on day 3.
Twenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells.
Phase 1 Study of DS-8895a in patients with advanced solid tumors ( NCT02004717 ; 7 November 2013 to 2 February 2017); retrospectively registered on 9 December 2013.
促红细胞生成素产生肝细胞受体 A2（EPHA2）在许多癌症的细胞表面过度表达，预示着预后不良。DS-8895a 是一种人源化抗-EPHA2 IgG1 单克隆抗体，经去岩藻糖化修饰以增强抗体依赖性细胞毒性活性。我们进行了一项两步、I 期、多中心、开放标签研究，以确定 DS-8895a 在晚期实体瘤患者中的安全性、耐受性和药代动力学。
第 1 步是在晚期实体瘤患者中进行剂量递增队列研究（6 个剂量水平，0.1-20mg/kg），以确定第 2 步的剂量。第 2 步是 EPHA2 阳性食管癌和胃癌患者的剂量扩展队列。DS-8895a 每 2 周静脉输注一次，持续整个研究过程，28 天评估剂量限制性毒性（DLT）。评估安全性、药代动力学、肿瘤反应和潜在的生物标志物。
共纳入 37 例患者（第 1 步：22 例，第 2 步：15 例[9 例胃癌，6 例食管癌]）。尽管第 1 步（剂量水平 6，20mg/kg）观察到 1 例 DLT（4 级血小板计数下降），但未达到最大耐受剂量；第 2 步使用了最高剂量（20mg/kg）。37 例患者中，24 例（64.9%）发生与药物相关的不良事件（AE），包括 3 例（8.1%）发生 3 级及以上 AE。19 例（51.4%）发生输注相关反应，但可管理。所有患者均因疾病进展（33 例）或 AE（4 例）而停止研究。最大和谷浓度的 DS-8895a 血清浓度呈剂量依赖性增加。1 例胃癌患者获得部分缓解，13 例患者获得稳定疾病。DS-8895a 给药结束时和开始后 4 小时，血清炎症细胞因子一过性增加。DS-8895a 给药后 4 小时，CD16 阳性自然杀伤（NK）细胞（CD3CD56CD16）的比例下降，第 3 天 CD3CD56CD137 与 CD3CD56CD16 细胞的比值增加。
在晚期实体瘤患者（n=21）中，每 2 周静脉输注 20mg/kg 的 DS-8895a 通常是安全且耐受良好的。DS-8895a 的暴露似乎呈剂量依赖性增加，并诱导激活的 NK 细胞。
DS-8895a 治疗晚期实体瘤的 I 期研究（NCT02004717；2013 年 11 月 7 日至 2017 年 2 月 2 日）；2013 年 12 月 9 日回顾性注册。
