Phase I Trial of Safingol and Cisplatin

Sloan-Kettering Institute For Cancer Res, New York NY

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Abstract

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.