Acute Myeloid Leukemia, Chronic Myeloid Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Chronic Myeloid Leukemia, CML Myeloid Blast Phase, Acute Myeloid Leukemia, Myelodysplastic Syndrome, Clofarabine, Clofarex, Clolar, Ara-C, Cytarabine, Cytosar, DepoCyt, Cytosine arabinosine hydrochloride, Idarubicin, Idamycin
Brief summary
The goal is to compare the drug combinations clofarabine/idarubicin/ara-C, clofarabine/ara-C, and clofarabine/idarubicin in the treatment of patients with Acute Myeloid Leukemia, high-grade MDS, or myeloid blast phase of Chronic Myeloid Leukemia who have relapsed following their initial therapy.
Detailed description
Clofarabine is a new drug that was designed to help treat leukemia. Ara-C and idarubicin are drugs that are commonly used to help treat leukemia. Before treatment starts, you will be asked questions about your medical history and have a complete physical exam. You will have blood samples (about 1 tablespoon) collected for routine lab tests. You will either have an echocardiogram or a multiple-gated acquisition (MUGA) scan to check on the function of your heart. You will have a sample of bone marrow collected to check on the status of the disease. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. Women who are able to have children must have a negative blood or urine pregnancy test. After each cycle of therapy, you will not receive the next cycle of chemotherapy until your blood counts have recovered and any possible side effects have gone away (for around 3 to 6 weeks). If the disease gets worse or side effects become too severe, treatment will stop. You must stay in Houston for the first 4 to 6 weeks (average) of treatment and are required to return to Houston to receive each additional cycle of chemotherapy (up to 6 days each cycle). You will be assigned to receive treatment with clofarabine plus idarubicin and ara-C. For participants in the clofarabine/idarubicin/ara-C group, the clofarabine will be given by vein over 1 hour once a day for 5 days in a row, on Days 2 to 6 of each cycle. Idarubicin will be given by vein over 30 minutes for 3 days in a row, on Days 1 to 3 of each cycle. Ara-C will be given by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. Idarubicin is usually started around 1 hour after the completion of clofarabine, and ara-C about 4 hours after the start of the clofarabine infusion. This 6 day period is called a cycle of chemotherapy. You will receive at least 1 cycle of therapy. If after 1 or 2 cycles of therapy it is found that the disease is responding to therapy, you may continue to receive therapy for up to 4 additional courses of consolidation therapy. During the consolidation therapy you will also be given treatment courses with ara-C alone. When ara-C is given alone it will be given as a continuous infusion, 24 hours a day, for 5 days in a row. You will be given a portable pump so that this treatment can be done as an outpatient. The combination drug courses and the ara-C courses will alternate (ara-C alone, combination, ara-C alone, combination) for a total of 4 courses. If it is found that the disease is not responding to chemotherapy, you will be taken off the study and your doctor will discuss other treatment options with you. Before you receive each dose of drug(s), you will have a complete physical exam. During treatment, you will have blood (about 1 tablespoon) collected at least once a week during the first 2 courses of therapy, then every 2-4 weeks after. Bone marrow samples will be collected every other week during treatment to check on the status of the disease. The blood and bone marrow samples may be collected more often if your doctor feels it is necessary. If, at any time, the disease gets worse or you experience any intolerable side effects, you will be taken off the study and your doctor will discuss other treatment options with you. After your last course of treatment, you will have a follow-up visit scheduled. At this visit, you will have blood (about 1 tablespoon) collected for routine tests. You will have a sample of bone marrow collected to check on the status of the disease. You will also have a repeat echocardiogram or MUGA scan to check on the function of your heart. This is an investigational study. Clofarabine has been authorized by the FDA to be used in research only. Idarubicin and ara-C are both FDA approved and are commercially available. Up to 120 participants will take part in this study. All will be enrolled at M. D. Anderson.
Interventions
DRUGClofarabine 40mg/m^2
40 mg/m\^2 by vein over 1 hour daily for 5 days.
DRUGIdarubicin 10mg/m^2
10 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle. Clofarabine + Idarubicin plus Ara-C: 6 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle.
DRUGAra-C 0.75 g/m^2
0.75 g/m\^2 by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle.
DRUGClofarabine 22.5mg/m^2
22.5 mg/m\^2 by vein over 1 hour daily for 5 days.
DRUGAra-C 1 g/m^2
1 g/m\^2 by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle.
DRUGIdarubicin 6 mg/m^2
6 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle.
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
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
1. Age \>/= 18 years and \< 60 years. 2. Must be in first relapse of AML, or must receive treatment as first salvage in primary refractory AML; or have high-risk MDS (\>/= 10% blasts) with not more than one prior regimen of chemotherapy (therapy with hematopoietic growth factors, biological or targeted therapies are not counted). Patients in CML myeloid blast phase may receive clofarabine as frontline therapy or in first salvage. 3. Total bilirubin \</= 2mg/dL, Serum glutamic pyruvic transaminase (SGPT) \</= 4 upper limit of normal (ULN), creatinine \</= 2.0mg/dL. 4. Eastern Cooperative Oncology Group (ECOG) performance status \</= 2. 5. Signed informed consent. 6. Male and female patients who are fertile agree to use an effective barrier method of birth control (ie, latex condom, diaphragm, cervical cap, etc) to avoid pregnancy. Female patients need a negative serum or urine pregnancy test within 7 days of study enrollment (applies only if patient is of childbearing potential. Non-childbearing is defined as \>= 1 year postmenopausal or surgically sterilized).
Exclusion criteria
1. Previous treatment with clofarabine. 2. Active, uncontrolled, systemic infection considered opportunistic, life threatening, or clinically significant at the time of treatment, or any severe, concurrent disease, which, in the judgment of the investigator and after discussion with the Principal Investigator, would make the patient inappropriate for study entry. 3. Symptomatic central nervous system (CNS) involvement. 4. Patients who receive other chemotherapy. Patients must have been off previous therapy of \>/= 2 weeks and must have recovered from acute toxicity of all previous therapy prior to enrollment. Treatment may start earlier following discussion with the Principal Investigator. 5. Cardiac ejection fraction \</= 30%.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With a Response | Up to 6 years | Response assessed by blood test or bone marrow aspirate following day 21 of induction and then every 2 weeks thereafter until remission or non-response. Complete remission (CR): Disappearance all clinical and/or radiologic evidence of disease; Neutrophil count \> 1.0 x10\^9/L and platelet count \>100x10\^9/L, and normal bone marrow differential (\< 5% blasts). Complete remission without platelet recovery (CRp): Peripheral blood and bone marrow results as for CR, but with platelet counts of \> 20 x 10\^9/L and \< 100 x 10\^9/L. Partial remission (PR): Peripheral blood count recovery as for CR, but with decrease in marrow blasts of \> 50% and not more than 6-25% abnormal cells in the marrow. All other responses considered as failures. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 6 years | Percentage of participants with complete response following treatment out of all participants in that particular treatment group. Response assessed by blood test or bone marrow aspirate following day 21 of induction and then every 2 weeks thereafter until remission or non-response. Complete remission (CR): Disappearance all clinical and/or radiologic evidence of disease; Neutrophil count \> 1.0 x10\^9/L and platelet count \>100x10\^9/L, and normal bone marrow differential (\< 5% blasts). Complete remission without platelet recovery (CRp): Peripheral blood and bone marrow results as for CR, but with platelet counts of \> 20 x 10\^9/L and \< 100 x 10\^9/L. Partial remission (PR): Peripheral blood count recovery as for CR, but with decrease in marrow blasts of \> 50% and not more than 6-25% abnormal cells in the marrow. All other responses considered as failures. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: December 2003 to October 2009. All participants were recruited at the University of Texas (UT) MD Anderson Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| Clofarabine + Ara-C Clofarabine 40 mg/m\^2 by vein over 1 hour daily for 5 days.
Ara-C : 1 g/m\^2 by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. | 17 |
| Clofarabine + Idarubicin Clofarabine 22.5 mg/m\^2 by vein over 1 hour daily for 5 days.
Idarubicin 10 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle. | 36 |
| Clofarabine + Idarubicin + Ara-C Clofarabine 22.5 mg/m\^2 by vein over 1 hour daily for 5 days.
Idarubicin 6 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle.
Ara-C Starting dose: 0.75 g/m\^2 by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. | 63 |
| Total | 116 |
Baseline characteristics
| Characteristic | Clofarabine + Idarubicin | Clofarabine + Idarubicin + Ara-C | Clofarabine + Ara-C | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 5 Participants | 3 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 58 Participants | 14 Participants | 100 Participants |
| Age, Continuous | 57 years | 51 years | 55 years | 54 years |
| Region of Enrollment United States | 36 participants | 63 participants | 17 participants | 116 participants |
| Sex: Female, Male Female | 26 Participants | 30 Participants | 7 Participants | 63 Participants |
| Sex: Female, Male Male | 10 Participants | 33 Participants | 10 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 17 | 3 / 36 | 8 / 63 |
| other Total, other adverse events | 17 / 17 | 36 / 36 | 63 / 63 |
| serious Total, serious adverse events | 4 / 17 | 13 / 36 | 13 / 63 |
Outcome results
Primary
Participants With a Response
Response assessed by blood test or bone marrow aspirate following day 21 of induction and then every 2 weeks thereafter until remission or non-response. Complete remission (CR): Disappearance all clinical and/or radiologic evidence of disease; Neutrophil count \> 1.0 x10\^9/L and platelet count \>100x10\^9/L, and normal bone marrow differential (\< 5% blasts). Complete remission without platelet recovery (CRp): Peripheral blood and bone marrow results as for CR, but with platelet counts of \> 20 x 10\^9/L and \< 100 x 10\^9/L. Partial remission (PR): Peripheral blood count recovery as for CR, but with decrease in marrow blasts of \> 50% and not more than 6-25% abnormal cells in the marrow. All other responses considered as failures.
Time frame: Up to 6 years
Population: Two participants in the Clofarabine + Idarubicin (CI) arm were not evaluable for response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clofarabine + Ara-C | Participants With a Response | CRp | 2 participants |
| Clofarabine + Ara-C | Participants With a Response | CR | 4 participants |
| Clofarabine + Ara-C | Participants With a Response | PR | 0 participants |
| Clofarabine + Idarubicin | Participants With a Response | CRp | 5 participants |
| Clofarabine + Idarubicin | Participants With a Response | CR | 9 participants |
| Clofarabine + Idarubicin | Participants With a Response | PR | 1 participants |
| Clofarabine + Idarubicin + Ara-C | Participants With a Response | CR | 16 participants |
| Clofarabine + Idarubicin + Ara-C | Participants With a Response | PR | 1 participants |
| Clofarabine + Idarubicin + Ara-C | Participants With a Response | CRp | 7 participants |
Secondary
Overall Response Rate (ORR)
Percentage of participants with complete response following treatment out of all participants in that particular treatment group. Response assessed by blood test or bone marrow aspirate following day 21 of induction and then every 2 weeks thereafter until remission or non-response. Complete remission (CR): Disappearance all clinical and/or radiologic evidence of disease; Neutrophil count \> 1.0 x10\^9/L and platelet count \>100x10\^9/L, and normal bone marrow differential (\< 5% blasts). Complete remission without platelet recovery (CRp): Peripheral blood and bone marrow results as for CR, but with platelet counts of \> 20 x 10\^9/L and \< 100 x 10\^9/L. Partial remission (PR): Peripheral blood count recovery as for CR, but with decrease in marrow blasts of \> 50% and not more than 6-25% abnormal cells in the marrow. All other responses considered as failures.
Time frame: Up to 6 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine + Ara-C | Overall Response Rate (ORR) | 36 Percentage of Participants |
| Clofarabine + Idarubicin | Overall Response Rate (ORR) | 44 Percentage of Participants |
| Clofarabine + Idarubicin + Ara-C | Overall Response Rate (ORR) | 24 Percentage of Participants |