A Phase I trial combining IV fenretinide and IV safingol to target overproduction

CerRxIncLubbock TXa clinical stage anticancer drug development start up companyrequests critical funding via this SBIR Fast Track Phase I II application to support a highly noveladult Phase I clinical trial of intravenous fenretinidesafingolfor which it licenses both formulation and drug combination IP rightsThis trial will be subcontracted to the academic West Texas basedSouth Plains Oncology ConsortiumSPOCbased at the Texas Tech University Health Sciences CenterTTUHSCFenretinideHPRis a pindependent retinoid selectively cytotoxic to cancer cells via increase of reactive oxygen species and the de novo increase of native long chain D erythro dihydroceramidesSafingol is L threo dihydrosphingosinean artificial stereochemical variant of sphinganinethe native precursor of dihydroceramides in mammalian cellsWe have shown in human and canine cancer cell lines that safingol is incorporated into long livedL threodihydroceramidesOur preclinical data demonstrated that safingol strikingly synergized fenretinide cytotoxicity in vitro by simultaneously increasing both artificial L threo dihydroceramides and native D erythrodihydroceramides in a tumor cell specific mannerWe hypothesized that this novelcancer specific biochemistry might be achievable in human cancers should adequate drug levels be achievable in patient tumors in situVia an NCI RAID grantnovel intravenous emulsion formulations of both fenretinide and safingol suitable for high dose delivery were developedPhase I adult trials of intravenousHPR demonstrated that it is well toleratedachieved high circulating plasmaHPR levelsand produced multiple durable complete responses in relapsed T cell lymphomas with additional signals of activity in solid tumorsA Phase I trial of our intravenous safingol formulation demonstrated that it was well tolerated in combination with cisplatin at safingol doses predicted sufficient to attain the desired dihydroceramide modulationOur IND directedcanine toxicology studies showed that the combination of intravenous safingolfenretinide was well tolerated and lacked hematopoietic toxicity within our target dosingUnder SBIR Phase Iinitial proof of concept clinical combination dosing will be conductedUnder SBIR Phase IIa Phase I dose escalation trial of intravenousHPRsafingol in adult solid tumors and lymphomas will be conductedThe Phase I trial will define the maximally tolerated doseMTDof intravenous safingol when combined with fenretinidethe pharmacokinetics of both agents in combinationobtain ancillary markers of the pharmacodynamic actions of both agents in combination by measuring plasma sphingolipid and sphingosinephosphate levelsandwithin the confines of a phase I trialdetermine the activity of this novel drug combinationThis trial is the first in man to specifically target the dihydroceramide pathway as a cytotoxic cancer treatmentIf successfulthis novel biochemistry may constitute a broad basedpindependent therapy widely active in both adult and pediatric malignancies