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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
196
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.
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.
Aalborg University Hospital
Aalborg, Denmark
RECRUITINGAarhus University Hospital
Aarhus, Denmark
RECRUITINGRigshospitalet
Copenhagen, Denmark
RECRUITINGHerlev University Hospital
Copenhagen, Denmark
RECRUITINGOdense University Hospital
Odense, Denmark
ACTIVE_NOT_RECRUITINGZealand University Hospital
Roskilde, Denmark
TERMINATEDSahlgrenska University Hospital
Gothenburg, Sweden
RECRUITINGSkåne University Hospital
Lund, Sweden
RECRUITINGKarolinska University Hospital
Stockholm, Sweden
RECRUITINGUppsala University Hospital
Uppsala, Sweden
RECRUITINGEvent-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
Time frame: 0-54 months
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
Time frame: 0-54 months
Overall survival
Overall survival in months in arm A vs. arm B calculated from the time of randomization to EOS
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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)
Time frame: 0-54 months
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