First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors
First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors
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DOI：
10.1007/s10637-020-00924-3
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发表时间：
2020-03-20
影响因子：
3.4
通讯作者：
Furuse, Junji
中科院分区：
文献类型：
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作者：
Okano, Naohiro;Naruge, Daisuke;Furuse, Junji
这项开放标签的首次人体研究评估了JPH 203，这是一种新型的选择性L型氨基酸转运蛋白1抑制剂。我们还评估了N-乙酰基转移酶2表型和结果之间的关联。日本晚期实体瘤患者每天接受静脉注射JPH 203治疗7天，然后休息21天，剂量递增至12-85 mg/m2。使用3 + 3设计在第一周期期间评价剂量限制性毒性。该研究招募了17名患者，尽管在接受60 mg/m2的6名患者中的1名患者和第一名接受85 mg/m2的患者中检测到3级肝功能障碍。终止进一步招募，最大耐受剂量定义为60 mg/m2。AUC（无穷大）在12 mg/m2和25 mg/m2之间增加，但在25-40 mg/m2之间未观察到差异。在12 mg/m2剂量下，1例胆道癌（BTC）患者观察到部分缓解，在12 mg/m2和25 mg/m2剂量水平下，6例患者中有3例获得疾病控制。基于这些结果，我们建议II期剂量为25 mg/m（2）。BTC的疾病控制率为60%。2例3级肝功能障碍患者具有快速N-乙酰转移酶2表型，非快速表型的疾病控制更常见（50% vs. 12.5%）。JPH 203似乎耐受性良好，并提供了针对BTC的有希望的活性。N-乙酰转移酶2表型可能有助于预测JPH 203的安全性和有效性。
This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12-85 mg/m(2). Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m(2) and in the first patient to receive 85 mg/m(2). Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m(2). The AUC(infinity) increased between 12 mg/m(2) and 25 mg/m(2), although no differences were observed at 25-40 mg/m(2). Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m(2) dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m(2) and 25 mg/m(2) dose levels. Based on these results, we recommend a phase II dose of 25 mg/m(2). The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203.