Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Myelodysplastic Syndrome, MDS, Chronic Myelomonocytic Leukemia, CMML, Clofarabine, Clofarex, Clolar, Chemotherapy
Brief summary
The goal of this clinical research study is to learn if clofarabine given by mouth on a weekly schedule can help to control MDS. The safety of clofarabine given by mouth will also be studied.
Detailed description
Clofarabine is a new chemotherapy drug that is designed to interfere with the growth and development of cancer cells. If you are found to be eligible, you will be randomly assigned (as in the roll of dice) to one of 2 treatment groups. Participants in Group 1 will take a lower dose of clofarabine than Participants in Group 2. You have an equal chance of being assigned to either of the 2 treatment groups. Neither you nor your study doctor can choose your assignment. Later (after the first 40 patients), the assignment will favor the better treatment arm until one arm is selected as the significantly better one, or until 80 patients are treated in total. When you have been assigned to a treatment group, you will receive clofarabine as tablets once a day for 5 days in a row. This will be repeated every 4-8 weeks. Each 4-8 week period is considered 1 cycle of treatment. Original patients who are still on study (original patients who received or are still receiving 30 mg/m2) have already been reduced to lower doses on subsequent courses or had treatment discontinued/completed. These patients will be asked to sign a new informed consent document to be made aware of the new developments in this study. Each dose of clofarabine should be taken with 4 ounces of water in the morning, on an empty stomach. You must not eat or drink anything besides water from midnight the night before you take the study drug until 1 hour after taking the morning dose. You should take clofarabine every morning at about the same time. If vomiting occurs within 15 minutes of taking clofarabine, the dose may be repeated. If vomiting occurs more than 15 minutes after taking clofarabine, the dose cannot be replaced or made up. Coffee and other caffeinated liquids cannot be taken before dosing and for 1 hour after dosing. All clofarabine doses should be taken either in the outpatient or inpatient setting by qualified and trained site personnel or given with appropriate instructions to you and/or your care provider to take at home. At the start of each cycle, you will receive enough clofarabine for 1 cycle of therapy. You should store the clofarabine in its original container at room temperature. You should keep the container closed when not in use, and out of the reach of children. 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 4 to 8 weeks). You must stay in Houston for the first treatment cycle (about 4 to 8 weeks) and will be required to return to Houston before receiving each additional cycle of chemotherapy (up to 6 days each cycle). Before every treatment cycle, your doctor will perform a physical exam, including measurement of your weight and vital signs (blood pressure, heart rate, temperature, and breathing rate). You will be asked about the level of your daily activities and how you are feeling. You will have blood samples (about 1-2 teaspoons) collected for routine lab tests 1-2 times a week for the first cycle, then every 2-4 weeks while on therapy. Repeat bone marrow samples will be collected every 1-3 cycles. However, if you complete the study before the third cycle, the bone marrow may be taken then. You may choose to have check-up visits and blood tests with your local doctor. If you show a response and do not experience any severe side effects, you can receive up to a total of 12 cycles of therapy. During each cycle, clofarabine will be given the same way as during the first cycle. However, the dose of clofarabine may be lowered during later cycles to decrease the risk of side effects that may have occurred in previous cycles. If 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. This is an investigational study. Clofarabine given by vein is approved by the FDA for treatment of pediatric acute lymphoblastic leukemia. Its use in this study is experimental. Up to 80 patients will take part in this study. All will be enrolled at MD Anderson.
Interventions
DRUGClofarabine
Starting dose 10 mg (Group 1) or 20 mg (Group 2) as tablets once a day for 5 days in a row and repeated every 4-8 weeks. Each 4-8 week period is a cycle.
Sponsors
Genzyme, a Sanofi Company
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Patients with MDS and \>/= 5% blasts or IPSS risk intermediate or high; patients with Chronic myelomonocytic leukemia (CMML). 2. No prior intensive chemotherapy or high-dose ara-C (\>/= 1g/m2). 3. Prior biologic therapies, targeted therapies, or single agent chemotherapy allowed. 4. Patients must have been off chemotherapy for 2 weeks prior to entering this study and recovered from the toxic effects of that therapy, unless there is evidence of rapidly progressive disease. 5. Hydroxyurea is permitted for control of counts prior to treatment. 6. Procrit, GCSF are allowed before therapy. 7. Performance 0-2 (ECOG). Adequate organ function including the following:Adequate liver function (bilirubin of \< 2mg/dl), and renal function (creatinine \< 2mg/dl), and SGPT (ALT) \< 3 X ULN. Adequate cardiac functions (NYHA cardiac III-IV excluded). 8. Signed informed consent.
Exclusion criteria
1. Nursing and pregnant females. Patients of childbearing potential should practice effective methods of contraception. Child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 2. Active and uncontrolled infections. 3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements. 4. Prior clofarabine treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With a Complete Remission (CR) | After 3 courses of treatment, up to 24 weeks. | Complete Remission (CR): Normalization of the peripheral blood and bone marrow with \<5% bone marrow blasts, a peripheral blood granulocyte count \> (1.0 x 109/ L, and a platelet count \> 100 x 109/L). Partial Remission: as above except for the presence of 6-15% marrow blasts, or 50% reduction if \<15% at start of treatment. Hematologic Improvement: meets all criteria for CR except for platelet recovery to \>100 x 109/L. Clinical Benefit: Platelets increase by 50% and to above 30 x 109/L untransfused (if lower than that pretherapy); or granulocytes increase by 100% and to above 109/L (if lower than that pretherapy); or hemoglobin increase by 2 g/dl; or transfusion independent; or splenomegaly reduction by \> 50%; or monocytosis reduction by \> 50% if pretreatment \> 5 x 109/L. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: March 2006 to July 2012. All patients registered at The University of Texas M.D. Anderson Cancer Center.
Pre-assignment details
Sixty-five participants were registered, one participant did not receive study treatment. The study consisted of two parts, Phase 1 and a randomized Phase 2 portion.
Participants by arm
| Arm | Count |
|---|---|
| Oral Clofarabine Original dose of 40 mg oral reduced to 30mg and than lower dose of either 10 mg (Group 1) or 20 mg (Group 2) tablets once a day for 5 days in a row and repeated every 4-8 week cycle. | 32 |
| Randomized, Oral Clofarabine 10mg Arm A: 10 mg tablets once a day for 5 days in a row and repeated every 4-8 week cycle. | 17 |
| Randomized, Oral Clofarabine 20mg Arm B: 20 mg tablets once a day for 5 days in a row and repeated every 4-8 week cycle. | 16 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 2 (Randomized) | Screen Failure | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Oral Clofarabine | Randomized, Oral Clofarabine 10mg | Randomized, Oral Clofarabine 20mg | Total |
|---|---|---|---|---|
| Age, Continuous | 70.0 years | 67.5 years | 72.5 years | 70.0 years |
| Region of Enrollment United States | 32 participants | 17 participants | 16 participants | 65 participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Male | 23 Participants | 10 Participants | 9 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 16 / 16 | 16 / 16 |
| serious Total, serious adverse events | 16 / 32 | 8 / 16 | 12 / 16 |
Outcome results
Primary
Participants With a Complete Remission (CR)
Complete Remission (CR): Normalization of the peripheral blood and bone marrow with \<5% bone marrow blasts, a peripheral blood granulocyte count \> (1.0 x 109/ L, and a platelet count \> 100 x 109/L). Partial Remission: as above except for the presence of 6-15% marrow blasts, or 50% reduction if \<15% at start of treatment. Hematologic Improvement: meets all criteria for CR except for platelet recovery to \>100 x 109/L. Clinical Benefit: Platelets increase by 50% and to above 30 x 109/L untransfused (if lower than that pretherapy); or granulocytes increase by 100% and to above 109/L (if lower than that pretherapy); or hemoglobin increase by 2 g/dl; or transfusion independent; or splenomegaly reduction by \> 50%; or monocytosis reduction by \> 50% if pretreatment \> 5 x 109/L.
Time frame: After 3 courses of treatment, up to 24 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oral Clofarabine | Participants With a Complete Remission (CR) | Complete Remission | 8 Participants |
| Oral Clofarabine | Participants With a Complete Remission (CR) | Partial Remission | 0 Participants |
| Oral Clofarabine | Participants With a Complete Remission (CR) | Hematologic Improvement | 3 Participants |
| Oral Clofarabine | Participants With a Complete Remission (CR) | Clinical Benefit | 3 Participants |
| Randomized, Oral Clofarabine 10mg | Participants With a Complete Remission (CR) | Clinical Benefit | 0 Participants |
| Randomized, Oral Clofarabine 10mg | Participants With a Complete Remission (CR) | Complete Remission | 3 Participants |
| Randomized, Oral Clofarabine 10mg | Participants With a Complete Remission (CR) | Hematologic Improvement | 1 Participants |
| Randomized, Oral Clofarabine 10mg | Participants With a Complete Remission (CR) | Partial Remission | 0 Participants |
| Randomized, Oral Clofarabine 20mg | Participants With a Complete Remission (CR) | Clinical Benefit | 0 Participants |
| Randomized, Oral Clofarabine 20mg | Participants With a Complete Remission (CR) | Partial Remission | 0 Participants |
| Randomized, Oral Clofarabine 20mg | Participants With a Complete Remission (CR) | Hematologic Improvement | 3 Participants |
| Randomized, Oral Clofarabine 20mg | Participants With a Complete Remission (CR) | Complete Remission | 0 Participants |