Epigenetics, Vitamin C and Abnormal Hematopoiesis - Pilot Study

Not Applicable

Completed

• Conditions: Myelodysplastic Syndrome; Acute Myeloid Leukemia
• Interventions: Dietary Supplement: Vitamin C; Dietary Supplement: Placebo

• Registration Number: NCT02877277
• Lead Sponsor: Rigshospitalet, Denmark

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.

Study Timeline

• Study Start: 2016-08-08
• Study First Submitted: 2016-08-09
• Study First Submitted QC: 2016-08-18
• Study First Posted: 2016-08-24
• Primary Completion: 2017-05-29
• Study Completion: 2017-05-29
• Status Verified: 2018-09
• Last Update Submitted: 2018-09-20
• Last Update Posted: 2018-09-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• MDS/AML patient in treatment with DNMTi

Exclusion Criteria

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vitamin C	Vitamin C	Oral intake of vitamin C tablet (500 mg) daily for 56 days
Placebo	Placebo	Oral intake of placebo tablet daily for 56 days

Primary Outcome Measures

Name	Time	Method
Overall 5-hmC/5-mC ratio	Change from baseline to day 84
Overall lysine methylation levels	Change from baseline to day 84
5-hmC/5-mC ratio at regulatory genomic regions of genes involved in hematopoietic development	Change from baseline to day 84
Accumulation of 5-hmC/5-mC at regulatory regions of ERVs	Change from baseline to day 84
Aberrant histone methylation associated with hematopoietic development	Change from baseline to day 84
Aberrant histone methylation associated with ERVs	Change from baseline to day 84
Expression levels of ERVs	Change from baseline to day 84
Activity of the viral defense pathway measured by RNA and protein expression	Change from baseline to day 84
ERV specific T-cell recognition in vivo	Change from baseline to day 84

Trial Locations

Locations (1)

Rigshospitalet; 🇩🇰 København Ø, Denmark