Clinical Investigation of the Ceramide NanoLiposome for Advanced Solid Tumors

DESCRIPTIONprovided by applicantKeystone Nanoin partnership with the University of Maryland Greenebaum Cancer CenterUMD GCCproposes a multi site clinical evaluation of the Ceramide NanoLiposomeCNLas a novel anti cancer therapeuticThe overall objective of this project is to advance the CNL through a Phase I clinical trialThe results of this trial will support subsequent trials for the intended initial indication of hepatocellular carcinomaHCCas well as other cancer indicationsHCC is one of the most frequent and deadly cancers worldwide and there are no current treatmentseither approved or in clinical developmentthat substantially alter the course of disease for patients diagnosed with advanced HCCThe combination of synergistic mechanisms of action that result in specific and selective toxicity of the CNL towards cancerous cellsalong with the distinct advantages afforded by liposomal deliverymake the CNL a unique and powerful potential alternative to current HCC therapiesNumerous preclinical studies indicate that the CNL is highly efficaciousinducing tumor regression in HCC models without systemic toxicityThe preclinical development portfolio for the CNL including evaluations of pharmacokineticsbiodistributionmetabolismefficacysafety and toxicology are either published or provided as Appendices of this applicationTo evaluate the clinical utility of the CNLa team of NCI designated Cancer Centers led by the UMD GCCin cooperation with NCI designated Cancer Centers at the University of Virginia Cancer CenterUVACCand the Fred Hollings Cancer Center at the Medical University of South CarolinaMUSChas been assembled to conduct the proposed multi site Phase I clinical trialThis open labeldose escalation study is designed to establish the safety of the CNL and recommended parameters for a Phase II clinical trialSpecific Aims are toEstablish the safety and maximum tolerated doseMTDof the CNLQuantify the pharmacokineticPKprofile of the CNL in humans andExamine disease parameters for evidence of anti cancer responseIf successfulthis research will advance the CNL towards commercialization and realize the mission of the NIH to translate fundamental knowledge of living systems into applications that enhance healthreduce illness and lengthen life PUBLIC HEALTH RELEVANCEThe convergence of biologymedicineand material sciences has led to the engineering of nanoscale materials that have the potential to radically improve cancer therapiesCeramidean endogenous sphingolipidhas great therapeutic potential due to synergistic mechanisms of action including regulation of signaling pathwaysinhibition of glycolysis and disruption of tumorinduced immunotolerance that lead to anti cancer efficacyDelivery of Ceramide in a liposomal formulation enables its use as a therapeutic by mediating solubility during circulationsuitable cell permeability and protection from circulating catabolic enzymes as well as enhanced pharmacokinetics and biodistribution to solid tumorsBuilding on a comprehensive preclinical portfolio for the Ceramide NanoLiposomeCNLthis project proposes a first in human Phase I clinical trial to assess the safety and maximum tolerated dose of the CNL in patients with advanced solid tumors