Combining Active and Passive DNA Hypomethylation (EVI-3)

Combining Active and Passive DNA Hypomethylation: A Randomized, Placebo-Controlled Phase II Study of the Efficacy and Safety of Oral Vitamin C in Combination With Azacitidine in Patients With Higher-Risk MDS, CMML-2 or Low-Blast Count AML

This is a multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study of the efficacy and safety of oral vitamin C supplement in combination with azacitidine in patients with higher-risk MDS, CMML-2 or low-blast count AML. The primary purpose is to investigate if oral vitamin C supplementation to azacitidine, compared with azacitidine + placebo, can increase the effectiveness of epigenetic therapy in patients with higher-risk myeloid malignancies, who are not candidates for allogeneic hematopoietic stem cell transplantation.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia
• Intervention / Treatment: Dietary supplement: Vitamin C; Dietary supplement: Placebo

Detailed Description

EVI-3 is a phase 2 international, multicentre, randomized, parallel-group, placebo-controlled, double-blind study of the efficacy and safety of oral vitamin C supplement in combination with azacitidine (AZA) in patients with higher-risk myeloid malignancies with or without mutations in genes recurrently affected in myeloid malignancies. Treatment allocation is in 1:1 ratio (vitamin C vs. placebo) by block randomization stratified by clinical site. Study entry is staggered. Patients are randomized to either oral vitamin C 1000 mg daily or placebo from start of AZA treatment until end of study (EOS) or until AZA treatment is discontinued at the discretion of the treating physician, whichever occurs earlier. The accrual time is estimated to 48 months and 6 months follow-up, thus, maximum treatment duration will be approximately 54 months. A total of 196 patients is planned for enrollment.

Study visits are scheduled at baseline, after 1st AZA treatment cycle, after 6 AZA treatment cycles, and, if AZA treatment is continued, at EOS or end of AZA treatment. Evaluations at study visits include bone marrow investigation, peripheral blood tests, patient-reported outcome measures, adverse events and compliance. Bone marrow aspirate and peripheral blood will be collected for biobank at each study visit.

All patients will undergo follow-up once yearly from EOS. Follow-up will include information on duration of AZA therapy, survival and disease progression from myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) to acute myeloid leukemia (AML), if diagnosed following a clinical indication for a bone marrow test.

• Study Type: Interventional
• Enrollment (Estimated): 196
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kirsten Grønbæk, Prof., MD; Phone Number: +45 35 45 60 86; Email: kirsten.groenbaek@regionh.dk
• Study Contact Backup: Name: Krista Smidt Bech, BSc, Nurse; Phone Number: +45 35 45 60 80; Email: krista.smidt.bech.01@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9100
    • Recruiting
    • Aalborg University Hospital
    • Contact: Marianne Tang Severinsen, MD, PhD; Phone Number: +45 97666745; Email: m.severinsen@rn.dk
  • Aarhus, Denmark
    • Recruiting
    • Aarhus University Hospital
    • Contact: Anne S Roug, MD; Email: annrou@rm.dk
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet
    • Contact: Kirsten Grønbæk, Prof., MD; Phone Number: +45 35 45 60 86; Email: kirsten.groenbaek@regionh.dk
    • Contact: Krista Smidt Bech, BSc, Nurse; Phone Number: +45 35 45 60 80; Email: krista.smidt.bech.01@regionh.dk
    • Sub-Investigator: Stine Ulrik Mikkelsen, MD, PhD
    • Sub-Investigator: Ali Al-Mousawi, MD
  • Copenhagen, Denmark, 2730
    • Recruiting
    • Herlev University Hospital
    • Contact: Bo Kok Mortensen, MD, PhD; Phone Number: +45 38686483; Email: bo.kok.mortensen@regionh.dk
  • Odense, Denmark, 5000
    • Active, not recruiting
    • Odense University Hospital
  • Roskilde, Denmark
    • Terminated
    • Zealand University Hospital
• Sweden
  • Gothenburg, Sweden
    • Recruiting
    • Sahlgrenska University Hospital
    • Contact: Hege Gravdahl Garelius, MD; Email: hege.garelius@vgregion.se
  • Lund, Sweden
    • Recruiting
    • Skåne University Hospital
    • Contact: Lars Nilsson, MD, PhD; Email: lars.nilsson@skane.se
  • Stockholm, Sweden
    • Recruiting
    • Karolinska University Hospital
    • Contact: Eva Hellström-Lindberg, Prof., MD; Email: eva.hellstrom-lindberg@ki.se
  • Uppsala, Sweden
    • Recruiting
    • Uppsala University Hospital
    • Contact: Elisabeth Ejerblad, MD; Email: elisabeth.ejerblad@akademiska.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients eligible for treatment with azacitidine with one of the following diagnoses according to World Health Organization 2016:

• MDS Higher-risk MDS according to the IPSS-R, i.e., intermediate- to very high-risk (IPSS-R score > 3)
• CMML CMML with 10-29 percent marrow blasts without myeloproliferative disorder
• AML AML with 20-30 percent blasts (low-blast count AML)

Note: Patients with therapy-related MDS are eligible if they have not received radiation or chemotherapy for six months.

Exclusion Criteria:

• Patient eligible for allogeneic stem cell transplantation
• Prior therapy with hypomethylating agents
• Any matter constituting an exclusion criterion for treatment with azacitidine
• Patient receiving other active cancer treatment, including investigational agents, with the exception of hydroxyurea for white blood cell (WBC) control, G-CSF, and low permanent doses of steroid (≤ 25 mg oral prednisolone per day) for inflammatory disorders
• Therapeutic radiation or chemotherapy within the past 6 months
• History of allergic reactions to ascorbic acid
• History of kidney or urinary tract stones requiring intervention within the past year
• Lack of ability to understand the information given, or lack of willingness to sign a written informed consent document
• Unwillingness to comply with the protocol
• Unwillingness to discontinue any and all use of vitamin C medication/supplementation including multivitamin at least 3 days (but preferably longer) prior to inclusion and baseline sampling
• Planned azacitidine treatment after allogeneic stem cell transplantation
• Eastern Cooperative Oncology Group (ECOG) performance status ≥3
• Uncontrolled comorbidity including impaired hepatic function (total serum bilirubin >1.5 × upper limit of the normal range (ULN), serum alanine transaminase >3 × ULN, chronic hepatitis with decompensated cirrhosis), disabling psychiatric disease, severe neurologic disease, severe metabolic disease, or severe cardiac disease (NYHA class 3-4)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin C; Oral vitamin C (ascorbic acid) will be given in a dose of 1000 mg daily (two capsules of 500 mg once daily) starting day 1 in the 1st azacitidine (AZA) cycle (D1/C1) and continuing until discontinuation of AZA or end of study, whichever occurs earlier.	Dietary supplement: Vitamin C; Oral vitamin C (ascorbic acid) 1000 mg daily will be administered from day 1 in the 1st AZA cycle (D1/C1) and continued until discontinuation of AZA or EOS as combination treatment.; Other Names: Ascorbic acid
Placebo Comparator: Placebo; Placebo will be administered orally as two capsules once daily that look and taste identical to the capsules containing vitamin C. Treatment will start day 1 in the 1st azacitidine (AZA) cycle (D1/C1) and continuing until discontinuation of AZA or end of study, whichever occurs earlier. The content of the placebo capsules is glucose monohydrate, potato starch, gelatin, magnesium stearate and talc.	Dietary supplement: Placebo; Placebo capsules (two capsules once daily) will be administered from day 1 in the 1st AZA cycle (D1/C1) and continued until discontinuation of AZA or EOS.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	Event-free survival in months in the group of patients receiving oral vitamin C + AZA (arm A) vs. the group of patients receiving placebo + AZA (arm B) calculated from the time of randomization to EOS. Event is defined as death, relapse, progression or lack of a response at 6 AZA cycles as defined by IWG 2006 (MDS and CMML) and ELN 2017 (AML) response criteria	0-54 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events and serious adverse events	Number and ratio of patients with adverse events in arm A vs. arm B assessed from the time of administration of intervention (day 1, AZA cycle 1 = D1/C1) to EOS. Total number of adverse events and serious adverse events and the number per year from D1/C1 to EOS in arm A vs. arm B. Number of patients discontinuing the intervention and discontinuation rate in arm A vs. arm B from D1/C1 to EOS	0-54 months
Overall survival	Overall survival in months in arm A vs. arm B calculated from the time of randomization to EOS	0-54 months
Overall response rate	Rate of overall response and rates of individual responses (as according to international consensus criteria), including best response, in arm A vs. arm B after 6 AZA cycles and at EOS	0-54 months
Patient-reported outcome (PRO) measures	Change in PRO measures including health-related quality of life scores (EORTC QLQ-C30 and Hematological Malignancy (HM)-PRO) from baseline to end of 1st AZA cycle, after 6 AZA cycles and EOS, if AZA treatment ongoing, respectively, in arm A vs. arm B. Numerical PRO scores after the 1st AZA cycle and after 6 AZA cycles (and EOS), respectively, in arm A vs. arm B	0-54 months
Variant allele frequency (VAF) of mutated clones	Change in VAF of mutated clones (in percentage points and in percentage) in bone marrow mononuclear cells from baseline to end of 6th AZA cycle and to end of treatment (if occurring before EOS) in arm A vs. arm B. Number and ratio of patients with appearance of new mutations between baseline and end of 6th AZA cycle (and end of treatment) in arm A vs. arm B. Total number of new mutations in arm A vs. arm B from baseline to end of 6th AZA cycle (and end of treatment)	0-54 months
Global 5-hydroxymethylcytosine (5-hmC)/5-methylcytosine (5-mC)	Change in global 5-hmC/5-mC in bone marrow CD34+ cells from baseline to end of 1st AZA cycle, end of 6th AZA cycle and end of treatment (if occurring before EOS), respectively, in arm A vs. arm B. Global 5-hmC/5-mC in bone marrow CD34+ cells at end of 1st AZA cycle and end of 6th AZA cycle (and end of treatment), respectively, in arm A vs. arm B	0-54 months
Site specific 5-hmC/5-mC	Change in 5-hmC/5-mC at specific loci at promoters/enhancers/long terminal repeats (LTRs) or at other regulatory genomic regions of tumor suppressors, oncogenes, genes involved in hematopoietic development or human endogenous retrovirus (HERV) in bone marrow CD34+ cells from baseline to end of 1st AZA cycle, end of 6th AZA cycle and end of treatment (if occurring before EOS), respectively, in arm A vs. arm B. Site specific 5-hmC/5-mC in bone marrow CD34+ cells at end of 1st AZA cycle and end of 6th AZA cycle (and end of treatment), respectively, in arm A vs. arm B	0-54 months
Gene expression	Change in expression of genes involved in viral defense pathways, cell differentiation and tumor suppression and oncogenes in bone marrow CD34+ cells from baseline end of 1st AZA cycle, end of 6th AZA cycle and end of treatment (if occurring before EOS), respectively, in arm A vs. arm B. Expression of genes involved in viral defense pathways, cell differentiation and tumor suppression in bone marrow CD34+ cells at end of 1st AZA cycle and end of 6th AZA cycle (and end of treatment), respectively, in arm A vs. arm B	0-54 months
mRNA expression of HERV and HERV specific T-cell responses	Change in levels of mRNA expression of HERV in bone marrow CD34+ cells and HERV specific T-cell responses from baseline to end of 1st AZA cycle, end of 6th AZA cycle and end of treatment (if occurring before EOS), respectively, in arm A vs. arm B. Levels of HERV mRNA in bone marrow CD34+ cells and HERV specific T-cell responses at end of 1st AZA cycle and end of 6th AZA cycle (and end of treatment), respectively, in arm A vs. arm B.	0-54 months
Duration of azacitidine (AZA) therapy	Duration of AZA therapy in patients randomized to AZA + oral vitamin C (arm A) compared to patients randomized to AZA + placebo (arm B) assessed at end of study (EOS)	0-54 months

Collaborators and Investigators

• Sponsor: Kirsten Grønbæk
• Collaborators: Odense University Hospital; Karolinska University Hospital; Zealand University Hospital; Aarhus University Hospital; University of Copenhagen; Imperial College London; University of Southern California; Sahlgrenska University Hospital, Sweden; Aalborg University Hospital; Skane University Hospital; Uppsala University Hospital; Technical University of Denmark; Van Andel Institute - Stand Up To Cancer Epigenetics Dream Team
• Investigators: Study Director: Kirsten Grønbæk, Prof., MD, Rigshospitalet, Denmark; Principal Investigator: Stine Ulrik Mikkelsen, MD, PhD, Rigshospitalet, Denmark; Principal Investigator: Ali Al-Mousawi, MD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. doi: 10.1093/jnci/85.5.365.
• Goswami P, Oliva EN, Ionova T, Else R, Kell J, Fielding AK, Jennings DM, Karakantza M, Al-Ismail S, Lyness J, Collins GP, McConnell S, Langton C, Al-Obaidi MJ, Oblak M, Salek S. Paper and electronic versions of HM-PRO, a novel patient-reported outcome measure for hematology: an equivalence study. J Comp Eff Res. 2019 May;8(7):523-533. doi: 10.2217/cer-2018-0108. Epub 2019 Apr 30.

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2019
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: June 25, 2019
• First Submitted That Met QC Criteria: June 26, 2019
• First Posted (Actual): June 27, 2019

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Vitamin C; Azacitidine; Ascorbic acid; Randomized, Placebo-Controlled Trial; Hypomethylating agents
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Chronic Disease; Myelodysplastic Syndromes; Leukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: H-18040929

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No