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，许多细胞毒性药物通过激活神经酰胺介导的途径来诱导细胞凋亡。事实上，细胞内神经酰胺（促凋亡）和鞘氨醇-1磷酸（S1P）的浓度之间存在着微妙的平衡，鞘氨醇-1磷酸（S1P）具有抗凋亡作用。在某些系统中，这两种次级信使的比例决定了肿瘤细胞的最终命运。在鞘氨酸激酶水平上，Safingol （l-threo-dihydrosphingosine）被重新鉴定为一种竞争性的鞘碱抑制剂，导致神经酰胺的诱导和S1P的消耗，有效地重新设置了神经酰胺-S1P变阻器。十多年前，沙芬果在我们的机构作为一种增强化疗效果的药物进行了测试。这是基于实验室数据表明，沙芬郭林增强化疗诱导的细胞凋亡。进行了沙芬郭尔与阿霉素联合的I期试验。在这项试验中，沙芬郭尔被发现是安全的，达到的药理学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有希望的初步临床结果，似乎进一步开发该药物是合理的。然而，考虑到药物在脂质乳剂中的溶解性问题，以及研究者无法控制的商业环境，涉及Safingol的临床研究几乎在十年前就停止了。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，特别是与同样产生神经酰胺的细胞毒（顺铂）联合使用。沙芬郭林已被证明能增强顺铂的作用。因此，我们建议启动沙芬郭林联合顺铂的临床研究。为了进行这项研究，我们已经获得了NCI的RAID拨款。我们的具体目标是：1。在晚期实体瘤患者中进行沙芬郭林联合顺铂的I期临床试验；2. 观察沙芬郭尔与顺铂联合静脉注射的临床PK；3. 进行“原理证明”的生物测定，以测量神经酰胺产生和/或S1P抑制的程度，其中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.