Ceraxa (Ceramide NanoLiposome) and Vinblastine For the Improved Treatment of Relapsed or Refractory Acute Myeloid Leukemia

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ABSTRACT: 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.