Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™) in Adult Patients With Newly Diagnosed Core-Binding Factor Acute Myeloid Leukemia (CBF-AML)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 204
- 试验地点
- 54
- 主要终点
- Event-free Survival
研究概览
简要总结
This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin [DNR] and cytarabine [Ara-C]) and consolidation therapy (high-dose cytarabine [HDAC]) with or without dasatinib in adult patients with newly diagnosed CBF-AML
详细描述
This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin [DNR] and cytarabine [Ara-C]) and consolidation therapy (high-dose cytarabine [HDAC]) with or without dasatinib in adult patients with newly diagnosed CBF-AML; in the investigational arm, consolidation therapy is followed by a one-year maintenance therapy with dasatinib. Patients with molecular disease persistence or molecular relapse as assessed by quantitative RQ-PCR for the CBF fusion transcripts will be eligible for hematopoietic stem cell transplantation before overt hematologic relapse occurs. Primary endpoint is event-free survival.
AML patients will be assessed for the CBF fusion genes in one of two AMLSG central laboratories within 48 hours of diagnosis, and only patients with CBF-AML will be enrolled.
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
- •Core-binding factor (CBF) AML with molecular diagnosis of RUNX1-RUNX1T1 fusion transcript resulting from t(8;21)(q22;q22.1) (or a variant form) or of CBFB-MYH11 fusion transcript resulting from inv(16)(p13.1q22)/t(16;16)(p13.1;q22) as assessed in one of the central AMLSG reference laboratories (Ulm, Hannover)
- •Age ≥ 18; there is no upper age limit
- •No prior chemotherapy for leukemia except hydroxyurea for up to 5 days during the diagnostic screening phase
- •Non-pregnant and non-nursing. Due to the unknown teratogenic potential of dasatinib in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL with-in 72 hours prior to registration. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control - one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least four weeks before she begins dasatinib therapy. "Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months.
- •Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking dasatinib and for 3 months after therapy is stopped, even if they have undergone a successful vasectomy.
- •Signed written informed consent.
排除标准
- •Performance status WHO >2
- •Pulmonary edema and/or pleural/pericardial effusion within 14 days of day
- •If edema/effusion resolves to CTC Grade ≤1, patients can be treated with dasatinib.
- •Patients with ejection fraction <50% by echocardiography within 14 days of day 1
- •Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or AP >2.5x upper normal serum level; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)
- •Uncontrolled infection
- •Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
- •Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
- •Known positive for HIV, active HBV, HCV, or Hepatitis A infection
- •Bleeding disorder independent of leukemia
- •No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation.
- •No consent for biobanking.
研究组 & 干预措施
Standard arm
Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7.
Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5.
Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours.
Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse.
干预措施: Cytarabine (Drug)
Standard arm
Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7.
Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5.
Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours.
Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse.
干预措施: Daunorubicin (Drug)
Standard arm
Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7.
Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5.
Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours.
Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse.
干预措施: Idarubicin (Drug)
Investigational arm
Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21.
Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse).
干预措施: Dasatinib (Drug)
Investigational arm
Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21.
Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse).
干预措施: Cytarabine (Drug)
Investigational arm
Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21.
Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse).
干预措施: Daunorubicin (Drug)
Investigational arm
Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21.
Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse).
干预措施: Idarubicin (Drug)
结局指标
主要结局
Event-free Survival
时间窗: 4 years
To assess event-free survival (EFS) after intensive induction (daunorubicin and cytarabine) and consolidation (high-dose cytarabine) chemotherapy with or without dasatinib in patients with CBF-AML
次要结局
- overall survival(4 years)
- relapse-free survival(4 years)
- Cumulative incidence of relapse (CIR)(4 years)
- Cumulative incidence of death (CID)(4 years)
- PIA analysis(4 years)
- toxicity(7 months (standard arm) / 19 months (investigational arm))
研究者
Prof. Dr. Hartmut Doehner
Prof. Dr.
University of Ulm