Randomized Comparison Between Two Dose Levels of Daunorubicin and Between One Versus Two Cycles of Induction Therapy for Adult Patients With Acute Myeloid Leukemia ≤65 Years
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 721
- 试验地点
- 38
- 主要终点
- response rate after first induction
研究概览
简要总结
The proposed trial will address two clinically important questions for younger patients with newly diagnosed acute myeloid leukemia (AML): the optimal dose of daunorubicin in induction therapy and the necessity of a second induction cycle in patients with a good response after the first induction. The primary endpoint is the rate of good responders. Secondary outcomes will be relapse-free survival, overall survival and minimal residual disease kinetics. Patients will be recruited in about 40 treatment centers of the Study Alliance Leukemia study group over a period of 40 months. The results will be of great clinical relevance: First, the study could facilitate the establishment or confirmation of the optimal daunorubicin dose.
详细描述
In the first part of the trial, patients will be randomly assigned to receive either 90 mg/m2 or 60 mg/m2 daunorubicin in the first induction cycle in addition to standard dosed cytarabine. Assuming a superiority of 90 mg/m2, 436 patients will be recruited. In the second part of the trial, good responders will be randomized to receive either a second or no further induction cycle. Assuming a non-inferiority of the single induction regarding the rate of complete remissions, a number of 360 patients will be included in the second part. Furthermore, in case of a non-inferiority of single versus double induction in good responders, about half of all younger AML patients could be spared a second induction cycle, leading to a reduction in treatment-related mortality, fewer days spent in hospital and improved quality of life.
As a result of the preplanned interim analysis of part I, the sponsor decided to suspend randomization in trial part I and to offer all patients the standard dose of 60 mg/m2 daunorubicin in both induction cycles (part I and II of the trial). Because of this an Amendment was sent to and approved by regulatories and ethics comitee.
The inclusion age was raised to 65 years based on the current German treatment guidelines in which patients up to the age of 65 are considered eligible for intensive induction chemotherapy with DA60 [Onkopedia-Leitlinie 2017].
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed AML other than acute promyelocytic leukemia (APL) according to WHO criteria, i.e. bone marrow aspirate or biopsy must contain ≥20% blasts of all nucleated cells or differential blood count must contain ≥20% blasts. In acute erythroid leukemia, ≥20% blasts in all non-erythroid bone marrow cells. In AML defined by cytogenetic aberrations, the rate of blasts may be <20%. Secondary AMLs are eligible for inclusion.
- •Age 18- inkl.65 years
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Adequate liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:
- •Total bilirubin ≤ 1.5 times the upper limit of normal
- •alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 times upper limit of normal
- •Creatinine ≤ 1.5 times upper limit of normal
排除标准
- •Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by transthoracic two-dimensional echocardiography ("M Mode") or multiple gated acquisition scan (MUGA scan)
- •Signed informed consent
- •Women must fulfill at least one of the following criteria in order to be eligible for trial inclusion:
- •Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum follicle stimulating hormone (FSH) > 40 U/ml)
- •Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
- •Continuous and correct application of a contraception method with a Pearl Index of <1% (e.g. implants, depots, oral contraceptives, intrauterine device - IUD).
- •Sexual abstinence
- •Vasectomy of the sexual partner
- •Exclusion criteria:
- •Patients who are not eligible for standard chemotherapy as assessed by the treating physician
- •Central nervous system manifestation of AML
- •Cardiac disease: i.e. heart failure New York Heart Association (NYHA) III or IV; unstable coronary artery disease (MI more than 6 months prior to study entry is permitted); serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
- •Patients undergoing renal dialysis
- •Chronic pulmonary disease with clinical relevant hypoxia
- •Known HIV or Hepatitis infection
- •Uncontrolled active infection
- •Medical conditions other than AML with an estimated life expectancy below 6 months
- •Previous treatment of AML except hydroxyurea up to 5 days
- •Relapsed or primary refractory AML
- •Acute promyelocytic leukemia
- •Previous anthracycline-containing chemotherapy
- •Treatment with any known non-marketed drug substance or experimental therapy within 4 weeks prior to enrollment
- •Incapability of understanding purpose and possible consequences of the trial
- •Pregnant or breastfeeding women
- •Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance)
研究组 & 干预措施
daunorubicin 60 mg/m2
study part 1 - dose daunorubicin standard dose daunorubicin in induction 1 (60 mg/m2) on days 3-5
干预措施: study part 1 - dose daunorubicin (Drug)
Double induction
study part 2: induction cycles double induction (only patients with good response)
干预措施: induction cycles (Procedure)
Single induction
study part 2: induction cycles single induction (only patients with good response)
干预措施: induction cycles (Procedure)
结局指标
主要结局
response rate after first induction
时间窗: day 15
To investigate whether a higher dose of daunorubicin in induction chemotherapy leads to an increase in hematological good responders defined as having \<5% myeloid blasts on day 15 after start of induction therapy.
Rate complete remissions
时间窗: day 35 after final induction
To investigate whether the rate of complete remissions (CR) after single induction is similar to that after double induction in patients with good response to induction I.
次要结局
- rate cytogenetic and molecular complete remissions(day 35)
- event-free survival (EFS)(5 years)
- relapse-free survival (RFS)(5 years)
- overall survival (OS)(5 years)
- Correlation between Minimal Residual Disease (MRD) and EFS, RFS, OS(day 35)
- Rate of induction deaths(day 60)
- Incidence of serious infectious complications(day 35)
- Sonographic cardiac left ventricular ejection fraction(day 35)
- Serum levels of pro-brain natriuretic peptide (por-BNP) and Troponin-T(day 35)
- Incidence of CTCAE grade ≥3 cardiac complications(day 35)
- Rate of early deaths(week 2)