This grant supports the clinical study of Keystone Nano's (KN) Ceraxa (C6 Ceramide NanoLiposome) and Vinblastine (VBL) in patients with relapsed/refractory Acute Myeloid Leukemia (AML) at leading NCI cancer centers. A recently completed NCI-supported Phase 1 study in solid tumor patients (NCT 02834611) has shown no Dose Limiting Toxicities and only modest adverse events with Ceraxa at doses up to 323 mg/m2, a dose five times the planned dose for the proposed AML trial. The rationale for the proposed unique and innovative combinatorial strategy of administration of Ceraxa plus Vinblastine is based upon findings from a recently renewed NIH NCI P01 grant (CA171983-06A1) awarded to KN Chief Technical Officer and co-founder, Dr. Mark Kester, where dysfunctional sphingolipid metabolism was shown to contribute to the pathogenesis of AML. Published mechanistic data document that Vinblastine disrupts autophagy leading to the induction of Ceraxa-mediated autophagic-cell death and shunting Ceraxa metabolism into pro-apoptotic sphingolipid metabolites. The objectives of this grant are to: 1) establish a recommended dose of Ceraxa for AML patients and test preliminary efficacy as a monotherapy, 2) establish a Recommended Phase 2 Dose to test Ceraxa in combination with Vinblastine, and 3) test the safety of Ceraxa plus Vinblastine at the RP2D. Secondary objectives of the grant are to: 1) obtain estimates of effectiveness (CR, PR), 2) assess the pharmacokinetics (PK) of Ceraxa and VBL, 3) obtain estimates of the overall survival (OS) at 90 days after treatment with the combination of Ceraxa and VBL, 4) validate putative lipid-based prognostic or therapeutic biomarkers from patient plasma samples; 5) determine the number of red blood cell (RBC) and platelet transfusions needed for supportive care, and 6) estimate the quality of life of participants prior, during, and following treatment with Ceraxa and VBL. KN has an open IND 142902 and IRB approval (IRB-HSR 22000) for the monotherapy study. This grant integrates important translational medicine opportunities - with three research universities, a company, a supporting PO1 team, and a private foundation (Commonwealth Foundation of Virginia) cooperatively conducting research and clinical investigations including exploring genomic, proteomic, and lipidomic impacts of a new AML treatment with a smart clinical trial. All studies will be completed through two specific aims: 1) Manufacture Ceraxa as a Clinical Drug Product; 2) Conduct Ceraxa clinical trials for AML patients at leading cancer centers.
Public Health Relevance Statement: Keystone Nano, in partnership with the University of Virginia Cancer Center, Memorial Sloan Kettering Cancer Center, and Penn State Hershey Cancer Center is developing Ceraxa (Proprietary Ceramide NanoLiposome) and Vinblastine as a new treatment for relapsed / refractory AML patients. These patients have a three-year survival rate of only ten percent, and new therapies are urgently needed. The Ceraxa/Vinblastine combination is novel, never tried therapeutic intervention based on very exciting preclinical data, and strongly supportive mechanistic data. This testing builds on a highly successful dose escalation study of Ceraxa supported by the NCI. The project team will conduct clinical testing advancing the therapies for AML patients and conducting research to support translational medicine and new discovery.
Project Terms: Aftercare; After Care; After-Treatment; post treatment; Animals; inhibitor; Autophagocytosis; autophagy; Award; Cell Death; necrocytosis; Ceramides; Chloroquine; Chlorochin; Khingamin; Clinical Research; Clinical Study; Clinical Trials; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Orphan Drugs; Erythrocytes; Blood erythrocyte; Erythrocytic; Marrow erythrocyte; Red Blood Cells; Red Cell; blood corpuscles; Foundations; Grant; Histone Deacetylase; HDAC; HDAC Proteins; In Vitro; Acute Myelocytic Leukemia; AML - Acute Myeloid Leukemia; Acute Myeloblastic Leukemia; Acute Myelogenous Leukemia; acute granulocytic leukemia; acute myeloid leukemia; Lipids; Metabolism; Intermediary Metabolism; Metabolic Processes; Methods; Microtubules; Micro-tubule; NIH; National Institutes of Health; United States National Institutes of Health; Patents; Legal patent; Patients; Pharmacokinetics; Drug Kinetics; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Privatization; Publishing; QOL; Quality of life; Relapse; Research; Investigators; Researchers; Research Personnel; Running; Sphingolipids; 4-Sphingenine; Sphingosine; Survival Rate; Testing; Time; Universities; Vinblastine; Vincaleucoblastine; Vincaleukoblastine; Virginia; sphingosine 1-phosphate; Surrogate Markers; surrogate bio-markers; surrogate biomarkers; Mediating; Platelet Transfusion; Blood Platelet Transfusion; Plts; Specialist; base; improved; Site; Clinical; Refractory; Phase; Physiological; Physiologic; Medical; prognostic; Disease Progression; Funding; Solid Tumor; Solid Neoplasm; Therapeutic; Supportive Therapy; Supportive care; Protocol; Protocols documentation; System; C(6)-ceramide; C6-ceramide; N-hexanoylsphingosine; N-caproylsphingosine; Remission; Disease remission; membrane structure; Membrane; success; Hydrophobicity; trafficking; Toxicities; Toxic effect; novel; Participant; Amendment; Pathogenesis; intervention therapy; Therapeutic Intervention; Sampling; Proteomics; Adverse Experience; Adverse event; Adverse effects; Genomics; Effectiveness; Dose; Data; Dose-Limiting; MSKCC; Memorial Sloan-Kettering Cancer Center; NCI-Designated Cancer Center; prognostic biomarker; Prognostic Marker; in vivo; Apoptotic; Cancer Center; Cancer Model; CancerModel; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; University of Virginia Cancer Center; UVA Cancer Center; Validation; nano; pre-clinical; preclinical; cost; virtual; design; designing; novel strategies; new approaches; novel approaches; novel strategy; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; innovation; innovate; innovative; combinatorial; translational medicine; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; effective therapy; effective treatment; Biological Markers; bio-markers; biologic marker; biomarker; safety testing; drug candidate; phase 1 study; Phase I Study; Regimen; Institutional Review Boards; IRB; IRBs; nanoliposome; nano liposome; nanoliposomal; predictive marker; predictive biomarkers; predictive molecular biomarker; leukemia treatment; clinical investigation; phase II trial; phase 2 trial; phase I trial; phase 1 trial; trial design; liposomal delivery; liposome delivery; relapse patients; patient biomarkers; therapeutic biomarker; therapeutic marker; lipidomics; Prognosis
