# Clinical Trial of Ceramide nanoLiposomes in AML

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2020 · $603,354

## Abstract

PROJECT SUMMARY
Acute Myeloid Leukemia (AML) is the 2nd most common type of leukemia diagnosed with a 5-year survival rate
of only 27%. Though dose-intensive induction and consolidation chemotherapy induces clinical complete
remission in the majority of patients suitable for treatment, most relapse whereas others develop refractory
AML. Recently, the Bcl-2 inhibitor, venetoclax, demonstrated improved clinical outcomes when combined with
the conventional therapeutic, cytarabine (AraC), in relapsed and refractory AML. Based upon efficacy in
preclinical models, we hypothesize that liposomal delivery of the pro-apoptotic bioactive lipid C6-ceramide will
augment the efficacy of this low dose AraC/venetoclax standard-of-care regimen and have a meaningful
clinical impact in treating relapsed/refractory AML. This hypothesis will be examined in three Specific Aims. In
Specific Aim 1, a Phase 1b (dose escalation)/2a (dose-expansion) clinical trial for ceramide nanoLiposomes
(CNL) in relapsed/refractory AML patients treated in combination with low dose AraC and venetoclax (pre-IND
#142902, UVA Protocol Review Committee Approval #5414, CAV trial) will be conducted. The premise of this
trial is supported by the fact that CNL has already reached its putative MTD in an FDA (IND 109471,
NCT02834611) NCI-supported (U43 CA186118) Phase 1 trial for solid tumors, where CNL has been well-
tolerated with multiple patients exhibiting stable disease. In Specific Aim 2, we examine the underlying
cooperativity between CNL, AraC, and venetoclax in AML. We show that co-administration of CNL with AraC
and/or venetoclax exerts multiple synergistic mechanisms of efficacy. First, we demonstrate that this regimen
increases the ratio of pro-apoptotic C16- and C18-ceramides over less apoptotic C24 ceramides. Utilizing
molecular strategies in both in vitro and in vivo models, we will test the hypothesis that this is mediated by
ceramide synthases and determine how ceramide synthases regulate AML survival. Second, we show that
CNL reduces venetoclax-induced elevation of pro-survival proteins. We will test the hypothesis that this effect
is STAT3-dependent using molecular approaches in preclinical models. In Specific Aim 3, we show that the
ratio of C18 to C24 ceramides predicts progression-free survival in AML patients, which is the first application
of this ratio as a biomarker for cancer. We will extend and confirm sphingolipid metabolites or ratios as
biomarkers of AML biology and prognosis utilizing large, well-characterized AML samples as a validation
cohort. while also investigating clinical samples from Specific Aim 1 to assess biomarkers of CNL efficacy.
Published and unpublished observations demonstrate that high-expression of enzymes that decrease
ceramide levels (acid ceramidase, sphingosine kinase, glucosylceramide synthase) and reduce pro-apoptotic
ceramides (e.g. C16/C18) leads to lower survival in AML patients. Together, the proposed studies will test the
clinical app...

## Key facts

- **NIH application ID:** 9937367
- **Project number:** 2P01CA171983-06A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** MARK KESTER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $603,354
- **Award type:** 2
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937367

## Citation

> US National Institutes of Health, RePORTER application 9937367, Clinical Trial of Ceramide nanoLiposomes in AML (2P01CA171983-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9937367. Licensed CC0.

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