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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 196
- 试验地点
- 14
- 主要终点
- Event-free survival
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind masking (Participant, Care Provider, Investigator, (some) Outcomes Assessors)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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)
结局指标
主要结局
Event-free survival
时间窗: 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
次要结局
- Overall survival(0-54 months)
- Site specific 5-hmC/5-mC(0-54 months)
- Adverse events and serious adverse events(0-54 months)
- Overall response rate(0-54 months)
- Variant allele frequency (VAF) of mutated clones(0-54 months)
- mRNA expression of HERV and HERV specific T-cell responses(0-54 months)
- Duration of azacitidine (AZA) therapy(0-54 months)
- Patient-reported outcome (PRO) measures(0-54 months)
- Global 5-hydroxymethylcytosine (5-hmC)/5-methylcytosine (5-mC)(0-54 months)
- Gene expression(0-54 months)
研究者
Kirsten Grønbæk
Professor, MD, DMSc
Rigshospitalet, Denmark