Randomized Phase II Trial Seeking the Most Promising Drug Association With Azacitidine- in Higher Risk Myelodysplastic Syndromes
试验速览
- 阶段
- 2 期
- 入组人数
- 320
- 试验地点
- 1
- 主要终点
- Remission, complete, partial or medullary after 6 cycles
研究概览
简要总结
In order to improve the overall survival benefit observed with AZA in higher risk MDS, its combination with other active drugs in MDS must be tested.
Among drugs that have demonstrated to be active as a single agent in MDS and have preclinical potential additive or synergistic activity with AZA are Histone deacetylase (HDAC) inhibitors including Valproic acid, Lenalidomide and idarubicin. Phase I studies have already been conducted or are being conducted combining those agents to demethylating agents, showing a low toxicity profile and significant responses in high risk MDS. In this phase II randomized trial, we want to identify the most promising combination of Azacitidine and another drug (among 3 drugs: Valproic acid, Lenalidomide and Idarubicin) in higher risk MDS, by comparison to Azacitidine alone. Of note, based on efficacy and toxicity, one or several combinations may be stopped, and others, previously tested in phase I trials, included after protocol amendment.
详细描述
The main objective of this phase II randomized trial is to identify, among 3 combinations of Azacitidine and another drug evaluated simultaneously, the most promising combination(s) for the treatment of higher risk MDS (IPSS Int-2 and High) compared to Azacitidine alone. The 3 tested drugs in combination with Azacitidine are: Valproic Acid, Lenalidomide and Idarubicin.
The aim of this trial is to identify, in a situation where several potentially interesting drugs tested in combination with AZA exist, the most promising combination(s) based on efficacy compared to azacitidine alone, based on a two-stage design that allows a formal efficacy comparison between the K=3 investigational treatment groups and the control group.
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
- None
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
- •age>=18 years
- •Must be able to adhere to the study visit schedule and other protocol requirements
- •Documented diagnosis of MDS, including AREB-t according to FAB classification or CMML (with WBC < 13,000/mm3) that meets IPSS criteria for intermediate-2 or high-risk.
- •Patients should be willing to use adequate contraceptive methods during all the duration of the study
排除标准
- •Treatment with AZA or Decitabine in the previous 6 months
- •Previous treatment with any HDAC inhibitor (Sodium valproate, Vorinostat, depsipeptide ou NSC-630176, MS 275, LAQ-824, PXD-101, LBH589, MGCD0103, CRA024781, etc). If Sodium Valproate (Depakine®) was used for seizure, a wash-out period of at least 30 days is required and an appropriate treatment replacement should be performed.
- •Ongoing treatment with corticosteroids exceeding 30mg of prednisone per day. A wash out period of at least 7 days is required.
- •HIV infection
- •Creatinine > 1.5 ULN
- •Serum AST or ALT > 3.0 x upper limit of normal (ULN)
- •Serum total bilirubin > 1.5 mg/dl (except for unconjugated hyperbilirubinemia due to Gilbert's disease or secondary to MDS).
- •≥ grade-2 neuropathy
- •Previous history of Acute myeloblastic leukemia (with marrow blasts>30%)
- •Previous history of allogeneic stem cell transplantation
- •Contra-indication to Anthracyclines: Myocardiopathy, uncontrolled infection, serious renal or hepatic impairment; associated with yellow fever vaccine
- •Known hypersensitivity to the active substance or to any of the excipients of Vidaza®, of valproate, of divalproate, of valpromide, of Lenalidomide, of thalidomide, of idarubicin and/or anthracyclines
- •Patients with a history of severe congestive heart failure, clinically unstable cardiac or pulmonary disease
- •All hepatitis or known personal or familial severe hepatitis, particularly due to drugs
- •Depression with suicidal tendency
- •Use of MILLEPERTUIS, mefloquine
- •No medical insurance in the French Health system
- •Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 3 years.
- •Pregnant or lactating females
- •Eligibility for allogeneic stem cell transplantation
- •very altered general condition , with WHO performance status of 4, or life expectancy of less than 6 months
研究组 & 干预措施
Azacitidine alone
干预措施: Azacitidine (Drug)
Azacitidine +Valproic acid
干预措施: Azacitidine associated with Valproic acid (Drug)
Azacitidine +Lenalidomide
干预措施: Azacitidine associated with Lenalidomide (Drug)
Azacitidine + Idarubicine
干预措施: Azacitidine associated with Idarubicine (Drug)
结局指标
主要结局
Remission, complete, partial or medullary after 6 cycles
时间窗: 6 months
Achievement of remission, complete, partial or medullary, according to the IWG 2006 criteria39 (see section 10 below) after 6 cycles
次要结局
- Duration of response(within 3 years)
- Number of adverse events(3 years)
- Progression to acute myeloid leukemia(3 years)
- Stable disease with hematological improvement(3 and 6 months)
- Overall survival(3 years)