A Multicentre Open Randomized Phase II Study of the Efficacy and Safety of Azacitidine Alone or in Combination With Lenalidomide in High-risk Myeloid Disease (High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia) With a Karyotype Including Del(5q)
试验速览
- 阶段
- 2 期
- 入组人数
- 72
- 试验地点
- 1
- 主要终点
- Response according to IWG criteria for MDS and AML
研究概览
简要总结
The proposed phase II trial is a multicenter, randomized, open-label study that will evaluate the efficacy and safety of azacitidine alone or in combination with lenalidomide in high-risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) with a karyotype including del(5q). The primary objective will be to evaluate the efficacy in terms of response according to International Working Group (IWG) criteria for MDS and AML after 6 cycles of azacitidine or azacitidine + lenalidomide treatment, or at end of study if this occurs at an earlier time point.
详细描述
This is an prospective open multi-center randomized phase II study of standard dose azacytidine with or without the addition of lenalidomide in high-risk myeloid disease (high-risk MDS and AML) with a karyotype including del(5q). Seventy-two patients, eligible for treatment with azacytidine (Intermedium/INT-2 and High-risk MDS and AML with 20-30 % marrow blasts according to label) will be included.
Azacytidine will be given in a modified standard dose, azacytidine 5+2 (75 mg/m2/ d subcutaneously for 5 days, followed by a 2-day weekend break, followed by azacytidine 75 mg/m2/ d for 2 days every 28 days, no individual dose exceeding 200 mg) for 6 cycles. Cycle interval may be prolonged if toxicity according to predefined criteria occurs. Patients will be randomized to azacytidine (Arm A) or azacytidine + lenalidomide (Arm B). The initial dose of lenalidomide is 10 mg 21/28 days, starting day 1 in each azacytidine cycle and leaving the last week before start of next azacytidine cycle free. The dose should be increased to 20 mg day 1 in cycle 4 if no toxicity according to predefined criteria occurs. The total study period is 24 weeks + additional weeks caused by prolonged cycle interval. Patients, who following a response may be eligible for allo-SCT may exit the study after cycle 3, 4 or 5 and then be subject to end-of-study assessment. Patients who at start of treatment, or any time during study have a neutrophil count <0,5 x 109/l will be treated with Granulocyte-ColonyStimulatingFactor (G-CSF).
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
- •18 years of age at the time of signing the informed consent form.
- •MDS with IPSS Int-2 or High with a karyotype including del(5q).
- •Acute myeloid leukaemia (AML) with multilineage dysplasia and 20-30 % blasts (former RAEB-t) with a karyotype including del(5q).
- •Subject has signed the informed consent form.
- •Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test prior to starting lenalidomide. In addition, sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable, patches, or implantable hormonal contraceptive methods; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on lenalidomide. WCBP must agree to have pregnancy tests every 4 weeks while on lenalidomide.
- •Males (including those who have had a vasectomy) must use barrier contraception (latex condoms) when engaging in reproductive sexual activity with WCBP while on lenalidomide, when temporarily stopping lenalidomide and 28 days after the last dose of lenalidomide.
- •Note: Refractory and relapsed patients can be included as long as they fulfil the inclusion criteria.
排除标准
- •Eligible for upfront allogeneic SCT without prior induction chemotherapy or azacitidine
- •Pregnant or lactating females.
- •Prior therapy with azacitidine
- •Prior therapy with lenalidomide
- •Expected survival less than two months.
- •Acute promyelocytic leukemia (APL)
- •Central nervous system leukemia
- •Serum biochemical values as follows
- •Serum creatinine >2.0 mg/dL (177 mmol/L)
- •Serum aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transferase (ALT)/serum glutamate pyruvate transaminase (SGPT) >3.0 x upper limit of normal (ULN)
- •Serum total bilirubin >1.5 mg/dL
- •Prior allergic reaction to thalidomide
- •Uncontrolled systemic infection
研究组 & 干预措施
azacitidine
干预措施: Azacitidine (Drug)
azacitidine + lenalidomide
干预措施: azacitidine + lenalidomide (Drug)
结局指标
主要结局
Response according to IWG criteria for MDS and AML
时间窗: 25-44 weeks (after 6 cycles of azacitidine or azacitidine+lenalidomide)
Response according to IWG criteria include hematologic response (including transfusion independence), bone marrow response (blast count) and cytogenetic response (karyotype) after 6 cycles of azacytidine or azacytidine+lenalidomide. For patients who can keep the 4 week interval the Time Frame will be 25 weeks. The cycle interval can be extended up to 8 weeks which makes 44 weeks the maximum Time Frame.
次要结局
- Cytogenetic response after 3 cycles using Fluorescence In Situ Hybridization(FISH)(25-44 weeks)
- Safety (number and types of adverse advents) in azacitidine vs azacitidine + lenalidomide groups(25-44 weeks)
- Azacitidine cycle interval between groups(25-44 weeks)
- Survival in azacitidine vs azacitidine + lenalidomide groups(Up to week 156)
- Relapse in azacitidine vs azacitidine + lenalidomide groups(Up to week 156)
- Analysis of a broad spectrum of molecular and cellular events which previously have been identified as related to MDS with del(5q).(25-44 weeks)