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Combining Active and Passive DNA Hypomethylation (EVI-3)

Primary Purpose

Myelodysplastic Syndromes, Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia

Status

Recruiting

Phase

Phase 2

Locations

Denmark

Study Type

Interventional

Intervention

Vitamin C

Placebo

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring Vitamin C, Ascorbic acid, Azacitidine, Hypomethylating agents, Randomized, Placebo-Controlled Trial

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Aalborg University HospitalRecruiting
Aarhus University Hospital
RigshospitaletRecruiting
Herlev University HospitalRecruiting
Odense University HospitalRecruiting
Zealand University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Vitamin C

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Overall survival

Overall survival in months in arm A vs. arm B calculated from the time of randomization to EOS

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

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

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)

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

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

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

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.

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)

Full Information

NCT ID

NCT03999723

First Posted

June 25, 2019

Last Updated

October 24, 2022

Sponsor

Kirsten Grønbæk

Collaborators

Van Andel Institute - Stand Up To Cancer Epigenetics Dream Team, Karolinska University Hospital, Skane University Hospital, Sahlgrenska University Hospital, Sweden, University of Southern California, Imperial College London, University of Copenhagen, Zealand University Hospital, Aalborg University Hospital, Odense University Hospital, Technical University of Denmark, Aarhus University Hospital, Uppsala University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT03999723

Brief Title

Combining Active and Passive DNA Hypomethylation

Acronym

EVI-3

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Recruiting

Study Start Date

September 11, 2019 (Actual)

Primary Completion Date

September 2024 (Anticipated)

Study Completion Date

September 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Kirsten Grønbæk

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelodysplastic Syndromes, Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia

Keywords

Vitamin C, Ascorbic acid, Azacitidine, Hypomethylating agents, Randomized, Placebo-Controlled Trial

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

A multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Double-blind masking (Participant, Care Provider, Investigator, (some) Outcomes Assessors)

Allocation

Randomized

Enrollment

196 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Vitamin C

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Dietary Supplement

Intervention Name(s)

Vitamin C

Other Intervention Name(s)

Ascorbic acid

Intervention Description

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.

Intervention Type

Dietary Supplement

Intervention Name(s)

Placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

Event-free survival

Description

Time Frame

0-54 months

Secondary Outcome Measure Information:

Title

Adverse events and serious adverse events

Description

Time Frame

0-54 months

Title

Overall survival

Description

Overall survival in months in arm A vs. arm B calculated from the time of randomization to EOS

Time Frame

0-54 months

Title

Overall response rate

Description

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

Time Frame

0-54 months

Title

Patient-reported outcome (PRO) measures

Description

Time Frame

0-54 months

Title

Variant allele frequency (VAF) of mutated clones

Description

Time Frame

0-54 months

Title

Global 5-hydroxymethylcytosine (5-hmC)/5-methylcytosine (5-mC)

Description

Time Frame

0-54 months

Title

Site specific 5-hmC/5-mC

Description

Time Frame

0-54 months

Title

Gene expression

Description

Time Frame

0-54 months

Title

mRNA expression of HERV and HERV specific T-cell responses

Description

Time Frame

0-54 months

Title

Duration of azacitidine (AZA) therapy

Description

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)

Time Frame

0-54 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Kirsten Grønbæk, Prof., MD

Phone

+45 35 45 60 86

kirsten.groenbaek@regionh.dk

First Name & Middle Initial & Last Name or Official Title & Degree

Astrid Østergaard Mortensen, BSc, Nurse

Phone

+45 35 45 60 80

astrid.oestergaard.mortensen.01@regionh.dk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kirsten Grønbæk, Prof., MD

Organizational Affiliation

Rigshospitalet, Denmark

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Stine Ulrik Mikkelsen, MD

Organizational Affiliation

Rigshospitalet, Denmark

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Anders P Vallentin, MD

Organizational Affiliation

Rigshospitalet, Denmark

Official's Role

Principal Investigator

Facility Information:

Facility Name

Aalborg University Hospital

City

Aalborg

ZIP/Postal Code

9100

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marianne Tang Severinsen, MD, PhD

Phone

+45 97666745

m.severinsen@rn.dk

Facility Name

Aarhus University Hospital

City

Aarhus

Country

Denmark

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jan Maxwell Nørgaard, MD, PhD

Facility Name

Rigshospitalet

City

Copenhagen

ZIP/Postal Code

2100

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kirsten Grønbæk, Prof., MD

Phone

+45 35 45 60 86

kirsten.groenbaek@regionh.dk

First Name & Middle Initial & Last Name & Degree

Astrid Østergaard Mortensen, BSc, Nurse

astrid.oestergaard.mortensen.01@regionh.dk

First Name & Middle Initial & Last Name & Degree

Stine Ulrik Mikkelsen, MD

First Name & Middle Initial & Last Name & Degree

Anders P Vallentin, MD

Facility Name

Herlev University Hospital

City

Copenhagen

ZIP/Postal Code

2730

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Bo Kok Mortensen, MD, PhD

Phone

+45 38686483

bo.kok.mortensen@regionh.dk

Facility Name

Odense University Hospital

City

Odense

ZIP/Postal Code

5000

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Klas Raaschou-Jensen, MD

Phone

+45 23221586

Klas.Raaschou-Jensen@rsyd.dk

Facility Name

Zealand University Hospital

City

Roskilde

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jack Maibom, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

8433390

Citation

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.

Results Reference

background

PubMed Identifier

31037971

Citation

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.

Results Reference

background

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Combining Active and Passive DNA Hypomethylation

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