EVI-3: Combining Active and Passive DNA Hypomethylation

Sponsor

Kirsten Grønbæk (Other)

Overall Status

Recruiting

CT.gov ID

NCT03999723

Collaborator

Van Andel Research Institute (Other), Karolinska University Hospital (Other), Skane University Hospital (Other), Sahlgrenska University Hospital, Sweden (Other), Oslo University Hospital (Other), Helsinki University Central Hospital (Other), University of Southern California (Other), Imperial College London (Other), University of Copenhagen (Other), Zealand University Hospital (Other), Aalborg University Hospital (Other), Odense University Hospital (Other), Technical University of Denmark (Other), Aarhus University Hospital (Other), Norrland University Hospital (Other), Uppsala University Hospital (Other)

196

Enrollment

Locations

Arms

53.7

Anticipated Duration (Months)

32.7

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia	Dietary Supplement: Vitamin C Dietary Supplement: Placebo	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

196 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

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

Primary Purpose:

Treatment

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

Actual Study Start Date :

Sep 11, 2019

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Event-free survival [0-54 months]
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 [0-54 months]
Number and ratio of patients with a (serious) adverse event 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 [0-54 months]
Overall survival in months in arm A vs. arm B calculated from the time of randomization to EOS
Overall response rate [0-54 months]
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 [0-54 months]
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 [0-54 months]
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) [0-54 months]
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 [0-54 months]
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 [0-54 months]
Change in expression of genes involved in viral defense pathways, cell differentiation and tumor suppression 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 [0-54 months]
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 [0-54 months]
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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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:

Patients eligible for allogeneic stem cell transplantation
Prior therapy with hypomethylating agents
Any matter constituting an exclusion criterion for treatment with azacitidine
Patients receiving other active cancer treatment, including investigational agents, with the exception of hydroxyurea for white blood cell control and granulocyte colony-stimulating factor
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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Aalborg University Hospital	Aalborg	Denmark	9100
2	Aarhus University Hospital	Aarhus	Denmark
3	Rigshospitalet	Copenhagen	Denmark	2100
4	Herlev University Hospital	Copenhagen	Denmark	2730
5	Odense University Hospital	Odense	Denmark	5000
6	Zealand University Hospital	Roskilde	Denmark