Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Decitabine, Dacogen, 5-AZA, Valproic Acid, Myelodysplastic Syndrome, Acute Myelogenous Leukemia, MDS, AML
Brief summary
The goal of this clinical research study is to find out if decitabine, given with or without valproic acid, can help to control AML or MDS. The safety of both treatments will also be studied.
Detailed description
Decitabine and valproic acid are both designed to cause changes in different groups of proteins that are attached to DNA (the genetic material of cells), which may cause cancer cells to die. Researchers want to see if a combination of valproic acid with decitabine can help improve disease response as well as how long responses last in treating MDS and AML. 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 2 groups. Participants in one group will receive decitabine. Participants in the other group will receive decitabine and valproic acid. You will have an equal chance of being assigned to either group at first. After 20 participants are enrolled in each group, you will have a greater chance of being assigned to the group that is showing better results. Participants in both groups will receive decitabine on Day 1 through a central venous catheter (CVC) in a vein over 1 hour each day for 5 days. A central venous catheter is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure. Participants who are assigned to also get valproic acid will take the drug by mouth on Days 1-7 (7 days in a row). On Day 0 (the day before treatment begins) or on Day 1, you will have a physical exam, including measurement of your vital signs. Blood (about 2 teaspoons) will be drawn on or about Days 0 or 1, 5, and 10 (if your routine blood tests were found to be abnormal) to learn the status of the disease. Routine blood draws (about 4 teaspoons) will be done 1-2 times weekly for the first cycle and then every 2-4 weeks in further cycles. You will have another bone marrow aspiration to check disease response to treatment, and then you will have one every 1-3 cycles. One (1) cycle of treatment is 4-8 weeks long. You may remain on this study as long as you are benefitting or up to 2 years after you first achieve a complete response. Your dose level may be decreased depending on the side effects you may experience. However, if the disease gets worse or you experience any intolerable side effects, you will be taken off this study. This is an investigational study. Decitabine is FDA approved and commercially available for the treatment of MDS. Valproic acid is FDA approved and commercially available for the treatment of seizure disorders. Up to 150 patients will take part in this study. All will be enrolled at MD Anderson.
Interventions
DRUGValproic Acid
50 mg/kg orally daily for 7 days
DRUGDecitabine
20 mg/m\^2 IV over 1 hour daily for 5 days.
Sponsors
Eisai Inc.
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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 CMML; patients with AML who are age 60 or older. No prior intensive chemotherapy or high-dose ara-C (\> 1g/m2). No prior azacytidine for 3 cycles or more or prior decitabine for 2 cycles or more. Prior biologic therapies, targeted therapies, or single agent chemotherapy allowed.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. 2. Continued from #1: Hydroxyurea is permitted for control of counts prior to treatment. Procrit, granulocyte colony-stimulating factor (GCSF) are allowed before therapy. Procrit, GCSF or other growth factors are permitted on therapy. Use of hydroxyurea with rapidly proliferative disease is allowed for the first two weeks on therapy. 3. Performance 0-2 (ECOG). Adequate liver function (bilirubin of \< 2mg/dl) and renal function (creatinine \< 2mg/dl). Adequate cardiac functions (NYHA cardiac III-IV excluded). ALT \< 2.5x institutional upper limit of normal. 4. Signed informed consent.
Exclusion criteria
1. Nursing and pregnant females. Patients of childbearing potential should practice effective methods of contraception. 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. Known ornithine transcarbamylase disorder. 5. Patients requiring continuous valproic acid treatment for the control of seizure disorders.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participant Response Rates to Decitabine With or Without Valproic Acid in MDS and AML | 1 Year | Complete Remission (CR): CR defined as normalization of peripheral blood and bone marrow with \< 5% bone marrow blasts, a peripheral blood granulocyte count \> (1.0 x 10\^9/ L, and a platelet count \> 100 x 10\^9/L). CRi or complete remission with incomplete platelet recovery is defined as above, but platelets \<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. Clinical Benefit: In MDS/CMML, as per International Working Group (IWG) criteria, platelets increase by 50% and to above 30 x 10\^9/L untransfused (if lower than that pretherapy); or granulocytes increase by 100% and to above 10\^9/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 10\^9/L. In addition to IWG criteria, in AML, a decrease in bone marrow blasts to \<5% also considered clinical benefit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Duration | Up to 60 months | The date of Response to the date of loss of response or last follow-up. |
| Overall Survival Rate | Up to 7 years | Time from date of treatment start until date of death due to any cause or last Follow-up. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: 12/13/2006 to 07/05/2010. All recruitment done at The University of Texas MD Anderson Cancer Center.
Pre-assignment details
Of the 153 participants registered on the study for Decitabine (DAC) with or without Valproic Acid (VPA) in Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML), three were screen failures therefore 150 patients were randomized with 149 participants treated.
Participants by arm
| Arm | Count |
|---|---|
| Decitabine Decitabine 20 mg/m\^2 intravenous (IV) over 1 hour daily for 5 days. | 71 |
| Decitabine + Valproic Acid Decitabine 20 mg/m\^2 IV over 1 hour daily for 5 days. Valproic Acid 50 mg/kg orally daily for 7 days. | 79 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Not treated | 1 | 0 |
Baseline characteristics
| Characteristic | Decitabine | Decitabine + Valproic Acid | Total |
|---|---|---|---|
| Age, Continuous | 71 years | 66 years | 69 years |
| Region of Enrollment United States | 71 participants | 79 participants | 150 participants |
| Sex: Female, Male Female | 21 Participants | 37 Participants | 58 Participants |
| Sex: Female, Male Male | 50 Participants | 42 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 71 | 36 / 79 |
| serious Total, serious adverse events | 43 / 71 | 49 / 79 |
Outcome results
Primary
Participant Response Rates to Decitabine With or Without Valproic Acid in MDS and AML
Complete Remission (CR): CR defined as normalization of peripheral blood and bone marrow with \< 5% bone marrow blasts, a peripheral blood granulocyte count \> (1.0 x 10\^9/ L, and a platelet count \> 100 x 10\^9/L). CRi or complete remission with incomplete platelet recovery is defined as above, but platelets \<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. Clinical Benefit: In MDS/CMML, as per International Working Group (IWG) criteria, platelets increase by 50% and to above 30 x 10\^9/L untransfused (if lower than that pretherapy); or granulocytes increase by 100% and to above 10\^9/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 10\^9/L. In addition to IWG criteria, in AML, a decrease in bone marrow blasts to \<5% also considered clinical benefit.
Time frame: 1 Year
Population: One enrolled participant on the Decitabine arm was not treated, therefore not evaluable for response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Decitabine | Participant Response Rates to Decitabine With or Without Valproic Acid in MDS and AML | Complete Remission (CR) | 22 Percentage of Participants |
| Decitabine | Participant Response Rates to Decitabine With or Without Valproic Acid in MDS and AML | Partial Remission (PD) | 0 Percentage of Participants |
| Decitabine | Participant Response Rates to Decitabine With or Without Valproic Acid in MDS and AML | Complete Remission Without Platelet Recovery (CRi) | 6 Percentage of Participants |
| Decitabine + Valproic Acid | Participant Response Rates to Decitabine With or Without Valproic Acid in MDS and AML | Complete Remission (CR) | 29 Percentage of Participants |
| Decitabine + Valproic Acid | Participant Response Rates to Decitabine With or Without Valproic Acid in MDS and AML | Complete Remission Without Platelet Recovery (CRi) | 9 Percentage of Participants |
| Decitabine + Valproic Acid | Participant Response Rates to Decitabine With or Without Valproic Acid in MDS and AML | Partial Remission (PD) | 1 Percentage of Participants |
Secondary
Overall Survival Rate
Time from date of treatment start until date of death due to any cause or last Follow-up.
Time frame: Up to 7 years
Population: One enrolled participant on the Decitabine arm was not treated, therefore not evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Decitabine | Overall Survival Rate | 11.2 months |
| Decitabine + Valproic Acid | Overall Survival Rate | 11.9 months |
Secondary
Response Duration
The date of Response to the date of loss of response or last follow-up.
Time frame: Up to 60 months
Population: One enrolled participant on the Decitabine arm was not treated, therefore not evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Decitabine | Response Duration | 12.9 Months |
| Decitabine + Valproic Acid | Response Duration | 6.3 Months |