A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors.
A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors.
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DOI：
10.1158/1078-0432.ccr-16-2363
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发表时间：
2017-08-15
期刊：
影响因子：
--
通讯作者：
Thomas MB
中科院分区：
文献类型：
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作者：
Britten CD;Garrett-Mayer E;Chin SH;Shirai K;Ogretmen B;Bentz TA;Brisendine A;Anderton K;Cusack SL;Maines LW;Zhuang Y;Smith CD;Thomas MB
鞘氨醇激酶（SK 1和SK 2）通过产生促有丝分裂和促炎脂质鞘氨醇1-磷酸（S1 P）来调节肿瘤生长。这项I期研究调查了ABC 294640的安全性、药代动力学、药效学和抗肿瘤活性，ABC 294640是一种一流的口服SK2抑制剂。在连续队列中，以以下剂量水平向晚期实体瘤患者口服给予递增剂量的ABC 294640：250 mg qd、250 mg bid、500 mg bid和750 mg bid，连续28天为一个周期。获得系列血液样品以测量ABC 294640浓度和鞘脂谱。入组了22例患者，其中21例接受了ABC 294640。最常见的药物相关毒性为恶心、呕吐和疲乏。在750 mg bid组的4例患者中，1例发生剂量限制性3级恶心和呕吐，2例因不同的药物相关毒性而无法完成周期1。将500 mg bid剂量水平确定为推荐的II期剂量。ABC 294640给药导致S1 P水平在前12小时内降低，在24小时恢复至基线。在250 mg qd剂量组中，1例胆管癌患者的最佳缓解为部分缓解，在不同剂量水平的6例各种实体瘤患者中观察到疾病稳定。在500 mg bid时，ABC 294640耐受性良好，并达到生物学相关的血浆浓度。血浆鞘脂水平的变化可能为ABC 294640提供有用的药效学生物标志物。
Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and pro-inflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of ABC294640, a first-in-class orally-available inhibitor of SK2. Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. 22 patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting and fatigue. Among the four patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and two were unable to complete Cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the Recommended Phase II Dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. At 500 mg bid, ABC294640 is well tolerated and achieves biologically-relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.