Phase I Trial of Safingol and Cisplatin

Safingol 和顺铂的 I 期试验

• 批准号: 6937372
• 负责人: GARY K SCHWARTZ
• 金额: $ 26.45万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-10 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6937372
• 关键词: antineoplastics; breast neoplasms; ceramics; cisplatin; clinical research; clinical trial phase I; combination chemotherapy; human subject; human therapy evaluation; intravenous administration; kinase inhibitor; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; ovary neoplasms; patient oriented research; sphingosine; stomach neoplasms; tissue /cell culture

DESCRIPTION (provided by applicant): There is now convincing evidence that many cytotoxic agents induce apoptosis by their ability to activate ceramide-mediated pathways. In fact, a delicate balance exists between the intracellular concentration of ceramide, which is pro-apoptotic, and sphingosine-1 phosphate (S1P), which is anti-apoptotic. In some systems the ratio between these two secondary messengers determines the ultimate fate of the tumor cell. Safingol (l-threo-dihydrosphingosine) has been re-identified as a competitive inhibitor of sphingoid bases at the level of sphingosine kinase, resulting in induction of ceramide and depletion of S1P, effectively re-setting the ceramide-S1P rheostat. Over 10 years ago Safingol was tested at our institution as an agent that potentiated the effect of chemotherapy. This was based on laboratory data indicating that Safingol enhanced chemotherapy-induced apoptosis. A phase I trial combining Safingol with doxorubicin was performed. In this trial Safingol was found to be safe, pharmacological levels achieved were associated with potentiation of chemotherapy in vivo, and the clinical responses were encouraging. Considering the broad preclinical supportive data and the promising preliminary clinical results, it seemed that further development of the drug was justified. Nevertheless, in light of issues due to the drug's solubilization in a lipid emulsion, as well as commercial circumstances that were beyond the investigator's control, clinical research involving Safingol was discontinued almost a decade ago. However, in view of its recently identified new target, there is renewed interest in this drug, especially in combination with cytotoxics (cisplatin) that also generate ceramide. Safingol has been shown to potentiate the effect of cisplatin. Therefore, we have proposed initiating a clinical study with Safingol in combination with cisplatin. In order to conduct this study, we have been awarded a RAID grant by the NCI. Our specific aims are to: 1. perform a phase I clinical trial in patients with advanced solid tumors with Safingol in combination with cisplatin; 2. investigate the clinical PK of intravenous Safingol and cisplatin in combination; 3. conduct "proof of principle" biological assays to measure the degree of ceramide production and/or S1P inhibition, either of which may be predictive of clinical outcome or toxicity.

描述（由申请人提供）：现在有令人信服的证据表明许多细胞毒性剂通过其激活神经酰胺介导的途径的能力来诱导细胞凋亡。事实上，促凋亡的神经酰胺和抗凋亡的 1 磷酸鞘氨醇 (S1P) 的细胞内浓度之间存在微妙的平衡。在一些系统中，这两个第二信使之间的比例决定了肿瘤细胞的最终命运。 Safingol（l-苏式二氢鞘氨醇）已被重新鉴定为鞘氨醇激酶水平的鞘氨醇碱的竞争性抑制剂，导致神经酰胺的诱导和 S1P 的消耗，有效地重新设置神经酰胺-S1P 变阻器。十多年前，我们的机构对 Safingol 作为增强化疗效果的药物进行了测试。这是基于表明 Safingol 增强化疗诱导的细胞凋亡的实验室数据。进行了 Safingol 与多柔比星联合的 I 期试验。在这项试验中，Safingol 被发现是安全的，所达到的药理学水平与体内化疗的增强作用相关，并且临床反应令人鼓舞。考虑到广泛的临床前支持数据和有希望的初步临床结果，该药物的进一步开发似乎是合理的。然而，鉴于药物在脂肪乳剂中溶解的问题，以及研究者无法控制的商业环境，涉及 Safingol 的临床研究在大约十年前就停止了。然而，鉴于其最近确定的新靶点，人们对这种药物重新产生了兴趣，特别是与也产生神经酰胺的细胞毒素（顺铂）结合使用。 Safingol 已被证明可以增强顺铂的作用。因此，我们建议启动Safingol联合顺铂的临床研究。为了进行这项研究，我们获得了 NCI 的 RAID 资助。我们的具体目标是：1.在晚期实体瘤患者中进行Safingol联合顺铂的I期临床试验； 2.考察静脉注射Safingol与顺铂联合应用的临床PK； 3.进行“原理验证”生物测定来测量神经酰胺产生和/或S1P抑制的程度，其中任何一个都可以预测临床结果或毒性。