Busulfan-Fludarabine-Clofarabine With Allogeneic Stem Cell Transplantation for Advanced Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Advanced, Gleevec Refractory Chronic Myeloid Leukemia. A Randomized Phase II Study.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 72
- 试验地点
- 1
- 主要终点
- Treatment Related Mortality
研究概览
简要总结
The goal of this clinical research study is to find the best dose of clofarabine and fludarabine that can be given with busulfan followed by an allogeneic blood stem cell transplant. Researchers will study whether this combination can help to control the disease, and look at the safety of this combination. Researchers also want to find out if combining busulfan with clofarabine alone or combining busulfan with both fludarabine and clofarabine will improve the treatment, compared with the previous standard method using busulfan and fludarabine alone.
详细描述
Busulfan is a chemotherapy drug that kills cancer cells by binding to DNA (the genetic material of cells). Clofarabine is designed to interfere with the growth and development of cancer cells. Fludarabine is designed to interfere with DNA repair enzymes so that the leukemic cells cannot repair damaged DNA. This may increase the likelihood of the cell dying. These drugs are being given to try to kill cancerous cells and weaken your immune system in order to lower the risk of stem cell transplant rejection.
If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to 1 of 4 study groups. Three (3) of the groups will receive busulfan, fludarabine, and clofarabine at different dose levels. The 4th group will only receive busulfan and clofarabine. As the study continues, participants will be assigned using a method called adaptive randomization. This method works by increasing the chances of being assigned to the group that has had the best results in the study so far. You will know which group you have been assigned to.
Participants will receive busulfan, fludarabine, and/or clofarabine once a day for 4 doses. You will first receive an additional low-level "test" dose of busulfan given by vein to check how your blood levels change over time. This information will be used to decide the next dose needed to reach a target blood level of busulfan. You will have a total of about 6 and 1/2 tablespoons of blood drawn over time to check your busulfan blood levels following one or more of the busulfan treatments. Up to 11 samples of blood will be drawn to check your blood levels of busulfan during the next 11 hours following the test dose and the first high-dose busulfan treatment. Each sample will require about 1 teaspoon of blood. A heparin lock line will be placed in a vein to lower the number of needle sticks needed for these draws. If it is not possible for these blood level tests to be performed for technical or scheduling reasons, you will receive the standard fixed (unchanging) dose of busulfan.
Clofarabine and fludarabine (if applicable) will be given through a central venous catheter (CVC) over 1 hour, once a day, for 4 days. Busulfan will also be given through the CVC over 3 hours.
If you are going to be receiving a transplant from an HLA-nonidentical or unrelated donor, you will also receive thymoglobulin (ATG) over 4 hours on the 3 days before the transplant to further weaken your immune system to reduce the risk of rejecting of the transplant. After the transplant, you will receive tacrolimus, methotrexate, or other immunosuppressive (lowering the immune system) drugs in the standard manner to lower the risk of graft-vs-host disease (GVHD), a reaction of the donor's immune cells against the recipient's body.
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
- — 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis or 1) Acute myeloid leukemia past first remission, in first or subsequent relapse, or induction failures, 2) Myelodysplastic syndromes with intermediate or high risk International Prognostic Scoring System score (IPSS scores) (16), and having failed previous chemotherapy, or 3) Chronic Myeloid Leukemia, Philadelphia-chromosome positive and having failed / being resistant to therapy based on Gleevec or other tyrosine kinase inhibitors.
- •Patient has not been administered intensive systemic chemotherapeutic drugs within 21 days prior to trial enrollment (bone marrow transplant (BMT) Day -9). Gleevec, alternative tyrosine kinase inhibitors, other nonmyelosuppressive agents, low dose cytarabine, hydroxyurea is permitted if indicated to control the leukemia. All tyrosine inhibitor- or other non-myelosuppressive agents have to be terminated at least one week prior to admission for this treatment.
- •No uncontrolled infection. Protocol principal investigator (PI) will be final arbiter if there is uncertainty regarding whether a previous infection is resolved on appropriate antibiotics therapy.
- •age </= 60
- •A related or unrelated donor who is HLA-matched or mismatched in 1 HLA, A, B, C, DR or DQ locus is acceptable (i.e. at least a 9/10 matched related or unrelated donor, matched with molecular high-resolution technique per current standard for the BMT program).
- •ZUBROD performance status <2
- •Life expectancy is not severely limited by concomitant illness.
- •Left ventricular ejection fraction >/=45% No uncontrolled arrhythmias or symptomatic cardiac disease.
- •Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) >/= 50% of expected corrected for hemoglobin. In patients </= 7 years pulmonary function will be assessed per pediatric BMT routine
- •Serum creatinine </= 1.5 mg%.
- •Serum glutamic pyruvic transaminase (SGPT) </= 200 IU/ml, serum bilirubin and alkaline phosphatase within accepted laboratory standard normal limits or considered not clinically significant. No evidence of chronic active hepatitis or cirrhosis. If positive hepatitis serology, discuss with Study Chairman and perform liver biopsy pror to determining study eligibility.
- •Female patient is not pregnant (negative human chorionic gonadotropin (hCG) pregnancy test in all women of child-bearing-potential in accordance with departmental routine).
- •Patient or patient's legal representative, parent(s) or guardian able to sign informed consent.
排除标准
- •Effusion or ascites estimated to be >1L prior to drainage.
- •HIV-positive.
- •Hepatitis C or HBsAg positive
- •Prior stem cell transplant after a myeloablative conditioning program (such as busulfan-based using a total dose of >/= 12 mg/kg given by mouth or >/= 10 mg/kg IV, or a total-body irradiation-based program.
- •Active or prior Central Nervous System (CNS) leukemia
- •Biphenotypic acute leukemia.
研究组 & 干预措施
Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 30 mg/m^2 intravenous (IV) Daily + Fludarabine 30 mg/m^2 IV Daily; + Clofarabine 10 mg/m^2 IV Daily; Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Clofarabine (Drug)
Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 30 mg/m^2 intravenous (IV) Daily + Fludarabine 30 mg/m^2 IV Daily; + Clofarabine 10 mg/m^2 IV Daily; Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Busulfan (Drug)
Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 30 mg/m^2 intravenous (IV) Daily + Fludarabine 30 mg/m^2 IV Daily; + Clofarabine 10 mg/m^2 IV Daily; Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Fludarabine (Drug)
Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 30 mg/m^2 intravenous (IV) Daily + Fludarabine 30 mg/m^2 IV Daily; + Clofarabine 10 mg/m^2 IV Daily; Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Stem Cell Infusion (Other)
Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 30 mg/m^2 intravenous (IV) Daily + Fludarabine 30 mg/m^2 IV Daily; + Clofarabine 10 mg/m^2 IV Daily; Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Thymoglobulin (ATG) (Drug)
Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 30 mg/m^2 intravenous (IV) Daily + Fludarabine 30 mg/m^2 IV Daily; + Clofarabine 10 mg/m^2 IV Daily; Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Filgrastim (Drug)
Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 20 mg/m^2 IV + Fludarabine 20 mg/m^2 IV Daily + Clofarabine 20 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Clofarabine (Drug)
Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 20 mg/m^2 IV + Fludarabine 20 mg/m^2 IV Daily + Clofarabine 20 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Busulfan (Drug)
Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 20 mg/m^2 IV + Fludarabine 20 mg/m^2 IV Daily + Clofarabine 20 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Fludarabine (Drug)
Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 20 mg/m^2 IV + Fludarabine 20 mg/m^2 IV Daily + Clofarabine 20 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Stem Cell Infusion (Other)
Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 20 mg/m^2 IV + Fludarabine 20 mg/m^2 IV Daily + Clofarabine 20 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Thymoglobulin (ATG) (Drug)
Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 20 mg/m^2 IV + Fludarabine 20 mg/m^2 IV Daily + Clofarabine 20 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Filgrastim (Drug)
Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 10 mg/m^2 IV Daily + Fludarabine 10 mg/m^2 IV Daily + Clofarabine 30 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Clofarabine (Drug)
Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 10 mg/m^2 IV Daily + Fludarabine 10 mg/m^2 IV Daily + Clofarabine 30 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Busulfan (Drug)
Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 10 mg/m^2 IV Daily + Fludarabine 10 mg/m^2 IV Daily + Clofarabine 30 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Fludarabine (Drug)
Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 10 mg/m^2 IV Daily + Fludarabine 10 mg/m^2 IV Daily + Clofarabine 30 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Stem Cell Infusion (Other)
Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 10 mg/m^2 IV Daily + Fludarabine 10 mg/m^2 IV Daily + Clofarabine 30 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Thymoglobulin (ATG) (Drug)
Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 10 mg/m^2 IV Daily + Fludarabine 10 mg/m^2 IV Daily + Clofarabine 30 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Filgrastim (Drug)
Arm 4: Busulfan + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 40 mg/m^2 IV Daily + Clofarabine 40 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Clofarabine (Drug)
Arm 4: Busulfan + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 40 mg/m^2 IV Daily + Clofarabine 40 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Busulfan (Drug)
Arm 4: Busulfan + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 40 mg/m^2 IV Daily + Clofarabine 40 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Stem Cell Infusion (Other)
Arm 4: Busulfan + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 40 mg/m^2 IV Daily + Clofarabine 40 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Thymoglobulin (ATG) (Drug)
Arm 4: Busulfan + Clofarabine
4-day Treatment Period Day -6 to Day -2: Busulfan 40 mg/m^2 IV Daily + Clofarabine 40 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.
干预措施: Filgrastim (Drug)
结局指标
主要结局
Treatment Related Mortality
时间窗: First 30 Days
Number of participants with treatment related mortality (death) within the first 30 days following transplantation.
次要结局
未报告次要终点