?Keystone Nano, in partnership with the University of Maryland Greenebaum Cancer Center (UMD-GCC), proposes a multi-site clinical evaluation of the Ceramide NanoLiposome (CNL) as a novel anti-cancer therapeutic. The overall objective of this project is to advance the CNL through a Phase I clinical trial. The results of this trial will support subsequent trials for the intended initial indication of hepatocellular carcinoma (HCC) as well as other cancer indications. HCC is one of the most frequent and deadly cancers worldwide and there are no current treatments, either approved or in clinical development, that substantially alter the course of disease for patients diagnosed with advanced HCC. The combination of synergistic mechanisms of action that result in specific and selective toxicity of the CNL towards cancerous cells, along with the distinct advantages afforded by liposomal delivery, make the CNL a unique and powerful potential alternative to current HCC therapies. Numerous preclinical studies indicate that the CNL is highly efficacious, inducing tumor regression in HCC models without systemic toxicity. The preclinical development portfolio for the CNL including evaluations of pharmacokinetics, biodistribution, metabolism, efficacy, safety and toxicology are either published or provided as Appendices of this application. To evaluate the clinical utility of the CNL, a team of NCI-designated Cancer Centers led by the UMD-GCC, in cooperation with NCI-designated Cancer Centers at the University of Virginia Cancer Center (UVACC) and the Fred Hollings Cancer Center at the Medical University of South Carolina (MUSC), has been assembled to conduct the proposed multi-site Phase I clinical trial. This open-label, dose escalation study is designed to establish the safety of the CNL and recommended parameters for a Phase II clinical trial. Specific Aims are to 1) Establish the safety and maximum tolerated dose (MTD) of the CNL, 2) Quantify the pharmacokinetic (PK) profile of the CNL in humans and 3) Examine disease parameters for evidence of anti-cancer response. If successful, this 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 health, reduce illness and lengthen life.
Public Health Relevance Statement: Public Health Relevance: The convergence of biology, medicine, and material sciences has led to the engineering of nanoscale materials that have the potential to radically improve cancer therapies. Ceramide, an endogenous sphingolipid, has great therapeutic potential due to synergistic mechanisms of action including regulation of signaling pathways, inhibition of glycolysis and disruption of tumor- induced immunotolerance that lead to anti-cancer efficacy. Delivery of Ceramide in a liposomal formulation enables its use as a therapeutic by mediating solubility during circulation, suitable cell permeability and protection from circulating catabolic enzymes as well as enhanced pharmacokinetics and biodistribution to solid tumors. Building on a comprehensive preclinical portfolio for the Ceramide NanoLiposome (CNL), this 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.
NIH Spending Category: Bioengineering; Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Liver Cancer; Liver Disease; Nanotechnology; Orphan Drug; Rare Diseases
Project Terms: alternative treatment; anti-cancer therapeutic; base; BAY 54-9085; Biodistribution; Biology; Blood Circulation; Cancer Center; cancer therapy; Cancerous; Cell Death Induction; Cells; Ceramides; Clinical; clinical investigation; Clinical Research; Clinical Trials; commercialization; design; Development; Diagnosis; Disease; Dose; Drug Kinetics; effective therapy; efficacy testing; Engineering; Enzymes; Evaluation; Formulation; Glycolysis Inhibition; Health; Human; Impairment; improved; In Vitro; in vivo; Intravenous; Knowledge; Laboratories; Lead; Life; Lipid Bilayers; liposomal delivery; Liposomes; Liver; liver function; Malignant Neoplasms; manufacturing scale-up; Marketing; Maryland; materials science; Maximum Tolerated Dose; Mediating; Medical; Medicine; Metabolism; Mission; Modeling; Multi-Institutional Clinical Trial; N-caproylsphingosine; nano; nanoliposome; nanoscale; Nanotechnology; National Cancer Institute; novel; Oncologist; open label; Organism; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physiological; pre-clinical; preclinical evaluation; preclinical study; Primary carcinoma of the liver cells; Production; programs; Publishing; Regulation; Research; research clinical testing; response; Role; Safety; Series; Signal Pathway; Signal Transduction; Site; Small Business Innovation Research Grant; Solid Neoplasm; Solubility; South Carolina; Sphingolipids; Staging; standard of care; systemic toxicity; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Translating; tumor; United States National Institutes of Health; Universities; University of Virginia Cancer Center
