Phase I Trial of Safingol and Cisplatin

描述(由申请人提供)：现在有令人信服的证据表明，许多细胞毒剂通过激活神经酰胺介导的途径来诱导细胞凋亡。事实上，神经酰胺的细胞内浓度和神经鞘氨醇-1磷酸(S1P)之间存在着微妙的平衡，前者促进细胞凋亡，后者具有抗细胞凋亡作用。在一些系统中，这两个次级信使之间的比例决定了肿瘤细胞的最终命运。萨芬戈(L-苏氨酸二氢鞘氨醇)已被重新确定为鞘氨醇激酶水平上的狮身人面像碱基竞争性抑制剂，导致神经酰胺的诱导和S1P的耗竭，有效地重置神经酰胺-S1P变阻器。10多年前，萨芬戈作为一种增强化疗效果的药物在我们机构进行了测试。这是基于实验室数据，表明赛芬戈增强了化疗诱导的细胞凋亡。萨芬戈与阿霉素联合进行了I期试验。在这项试验中，萨芬戈被发现是安全的，所达到的药理水平与体内化疗的增强有关，临床反应令人鼓舞。考虑到广泛的临床前支持数据和前景看好的初步临床结果，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的增溶问题，以及研究人员无法控制的商业环境，涉及Safingol的临床研究在近十年前就停止了。然而，鉴于其最近发现的新靶点，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性药物(顺铂)结合使用时。萨芬戈已被证明可以增强顺铂的作用。因此，我们建议启动一项萨芬戈联合顺铂的临床研究。为了进行这项研究，我们获得了NCI的突袭拨款。我们的具体目标是：1.对使用萨芬戈联合顺铂的晚期实体肿瘤患者进行I期临床试验；2.研究静脉注射萨芬戈和顺铂的临床PK；3.进行“原则证明”生物测定，以测量神经酰胺产生和/或S1P抑制的程度，这两种方法中的任何一种都可以预测临床结果或毒性。

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.