Clinical trial NCT02877277: Epigenetics, Vitamin C and Abnormal Hematopoiesis - Pilot Study
Official title: Restoring Physiological Vitamin C Levels to the Normal Range: Influence on Epigenetic Regulation in Normal and Malignant Hematopoiesis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Myelodysplastic Syndrome
Acute Myeloid Leukemia
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Van Andel Research Institute
First posted: 2016-08-24
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluates whether vitamin C improves responses to epigenetic therapy with DNMTis. Half of the patients will receive vitamin C and DNMTi while the other half will receive placebo and DNMTi.

Detailed description: Recently, it was documented that hematological cancer patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) exhibited severe vitamin C deficiency. Vitamin C is an essential co-factor for ten-eleven translocation (TET) enzymes, which initiate DNA demethylation through oxidation of 5-methylcytosine (mC) to 5-hydroxy-methylcytosine (hmC). In-vitro studies show that vitamin C at physiological doses added to DNA methyltransferase inhibitors (DNMTis), induce a synergistic inhibition of cell proliferation and enhanced apoptosis. These effects are mediated via a viral mimicry response recently associated with cancer stem-like cell death and enhanced immune signals including increased expression of bi-directionally transcribed endogenous retrovirus (ERV) transcripts, increased presence of cytosolic double stranded RNAs, and activation of an interferon inducing cellular response to these transcripts. Data suggest that correction of vitamin C deficiency may improve responses to epigenetic therapy with DNMTis. In the EVITA pilot study, the investigators include MDS/AML patients and explore the potential role of restoring vitamin C within the normal physiological range in treatment of hematological cancer with DNMTis.

Eligibility criteria: Inclusion Criteria:

* MDS/AML patient in treatment with DNMTi

Exclusion Criteria:

* Intake of vitamin C as a dietary supplement including multivitamin
* Non-compliance

Primary outcomes:
measure: Overall 5-hmC/5-mC ratio
timeFrame: Change from baseline to day 84
measure: Overall lysine methylation levels
timeFrame: Change from baseline to day 84
measure: 5-hmC/5-mC ratio at regulatory genomic regions of genes involved in hematopoietic development
timeFrame: Change from baseline to day 84
measure: Accumulation of 5-hmC/5-mC at regulatory regions of ERVs
timeFrame: Change from baseline to day 84
measure: Aberrant histone methylation associated with hematopoietic development
timeFrame: Change from baseline to day 84
measure: Aberrant histone methylation associated with ERVs
timeFrame: Change from baseline to day 84
measure: Expression levels of ERVs
timeFrame: Change from baseline to day 84
measure: Activity of the viral defense pathway measured by RNA and protein expression
timeFrame: Change from baseline to day 84
measure: ERV specific T-cell recognition in vivo
timeFrame: Change from baseline to day 84
Secondary outcomes:
Other outcomes:
Locations:
city: København Ø
country: Denmark
facility: Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Kirsten Grønbæk, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gillberg L, Orskov AD, Nasif A, Ohtani H, Madaj Z, Hansen JW, Rapin N, Mogensen JB, Liu M, Dufva IH, Lykkesfeldt J, Hajkova P, Jones PA, Gronbaek K. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes. Clin Epigenetics. 2019 Oct 17;11(1):143. doi: 10.1186/s13148-019-0739-5.