Acute Myeloid Leukemia, Myelodysplastic Syndrome, Chronic Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, AML, Myelodysplastic Syndrome, MDS, Chronic Myeloid Leukemia, CML, Busulfan, Busulfex, Myleran, Fludarabine, Fludara, Fludarabine Phosphate, Clofarabine, Clofarex, Clolar, Allogeneic stem cell transplantation, ASCT, Stem Cell, Gleevec, Imatinib Mesylate
Brief summary
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.
Detailed description
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. The allogeneic stem cells (bone marrow or peripheral blood stem cells) will also be given through the CVC. You will receive the drug G-CSF (filgrastim) as an injection under the skin once a day, starting 1 week after the transplant, until your blood cell levels return to normal. Patients usually stay in the hospital for about 4 weeks after stem cell transplantation. After you are released from the hospital, you will continue to be monitored as an outpatient for infections and transplant-related complications for at least 100 days after the transplant. You will have blood tests (about 4 tablespoons of blood) and bone marrow aspirations performed at 1, 3, 6, and 12 months after the transplant, to check if the disease is in remission (has not come back). Your health status will be followed with the help of your local doctor to find out if the leukemia or MDS comes back, as well as to check the length of your survival. This is an investigational study. All of the drugs used in this study are approved by the FDA for treatment of cancer. Busulfan has been approved for use in stem cell transplantation. The use of these drugs together with stem cell transplant is experimental. Up to 70 patients will take part in this study. All will be enrolled at the M. D. Anderson Cancer Center.
Interventions
DRUGClofarabine
Day -6 to Day -3 for Arm 1 = 10 mg/m\^2 intravenous (IV) Daily; Arm 2 = 20 mg/m\^2 IV Daily; Arm 3 = 30 mg/m\^2 IV Daily; Arm 4 = 40 mg/m\^2 IV Daily
DRUGBusulfan
Day -6 to Day -3 for Arm 1: 30 mg/m\^2 IV Daily; Arm 2: 20 mg/m\^2 IV Daily; Arm 3: 10 mg/m\^2 IV Daily; Arm 4: 40 mg/m\^2 IV Daily. Test dose Day -8 32 mg/ m\^2 IV over 45 min, rest on Day -7.
DRUGFludarabine
Day -6 to Day -3 for Arm 1: 30 mg/m\^2 IV Daily; Arm 2: 20 mg/m\^2 IV Daily; Arm 3: 10 mg/m\^2 IV Daily
OTHERStem Cell Infusion
Day 0 stem cell infusion (Bone marrow or peripheral blood progenitor cells (PBPC))
Day -3 to Day -1 at 0.5 mg/kg IV on Day -3; 1.5 mg/kg on Day -2 and 2.0 mg/kg on Day -1.
DRUGFilgrastim
Subcutaneous injection daily, starting 1 week after Stem Cell Transplant.
Sponsors
Genzyme, a Sanofi Company
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 60 Years
Healthy volunteers
No
Inclusion criteria
1. 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. 2. 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. 3. 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. 4. age \</= 60 5. 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). 6. ZUBROD performance status \<2 7. Life expectancy is not severely limited by concomitant illness. 8. Left ventricular ejection fraction \>/=45% No uncontrolled arrhythmias or symptomatic cardiac disease. 9. 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 10. Serum creatinine \</= 1.5 mg%. 11. 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. 12. Female patient is not pregnant (negative human chorionic gonadotropin (hCG) pregnancy test in all women of child-bearing-potential in accordance with departmental routine). 13. Patient or patient's legal representative, parent(s) or guardian able to sign informed consent.
Exclusion criteria
1. Effusion or ascites estimated to be \>1L prior to drainage. 2. HIV-positive. 3. Hepatitis C or HBsAg positive 4. 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. 5. Active or prior Central Nervous System (CNS) leukemia 6. Biphenotypic acute leukemia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Related Mortality | First 30 Days | Number of participants with treatment related mortality (death) within the first 30 days following transplantation. |
Countries
United States
Participant flow
Recruitment details
Recruitment Details: September 25, 2006 to March 30, 2011. All participants were recruited at the University of Texas (UT) MD Anderson Cancer Center.
Pre-assignment details
Of the 72 enrolled participants, one participant was not eligible and not treated. In the initial phase, the first 20 participants were fairly randomized to each of the 4 treatment arms. The rest of the participants were adaptively randomized among the arms in period 2.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 18 |
| 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. | 7 |
| 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. | 29 |
| 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. | 17 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Adaptive Randomization | Death | 0 | 0 | 1 | 0 |
| Adaptive Randomization | No Response | 0 | 1 | 0 | 0 |
| Adaptive Randomization | Not Evaluable | 1 | 0 | 0 | 1 |
| Initial Phase Randomization | Disease Progression | 0 | 1 | 1 | 0 |
| Initial Phase Randomization | No Response | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine | Total | Arm 4: Busulfan + Clofarabine | Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine | Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine |
|---|---|---|---|---|---|
| Age, Continuous | 33 years | 46 years | 47 years | 38 years | 54 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 15 Participants | 3 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 54 Participants | 14 Participants | 24 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 64 Participants | 17 Participants | 26 Participants | 6 Participants |
| Region of Enrollment United States | 18 participants | 71 participants | 17 participants | 29 participants | 7 participants |
| Sex: Female, Male Female | 10 Participants | 31 Participants | 6 Participants | 14 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 40 Participants | 11 Participants | 15 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 71 | 1 / 71 | 4 / 71 | 1 / 71 |
| other Total, other adverse events | 18 / 72 | 7 / 72 | 29 / 72 | 16 / 72 |
| serious Total, serious adverse events | 15 / 71 | 6 / 71 | 27 / 71 | 15 / 71 |
Outcome results
Primary
Treatment Related Mortality
Number of participants with treatment related mortality (death) within the first 30 days following transplantation.
Time frame: First 30 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine | Treatment Related Mortality | 0 participants |
| Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine | Treatment Related Mortality | 0 participants |
| Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine | Treatment Related Mortality | 0 participants |
| Arm 4: Busulfan + Clofarabine | Treatment Related Mortality | 0 participants |