Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
Conditions
Brief summary
This clinical trial studies potential genetic markers which might be used to predict which patients with acute myeloid leukemia or myelodysplastic syndromes respond to decitabine. This study will contribute to the efforts to find effective and less toxic therapies to provide durable remissions in a significant proportion of elderly AML patients.
Interventions
DRUGdecitabine
Sponsors
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All of the following: * Patient must have non-M3 AML or MDS * An adverse risk karyotype defined by: * Complex karyotype by cytogenetics, or * Deletion of all or part of chromosome 5, 7, 12, or 17 defined by FISH or cytogenetics, or * Somatic TP53 mutation All of the following: 1. Patient must have an ECOG performance status ≤ 2. 2. Patient must have \>10% disease burden measured by cytomorphology, flow cytometry, or cytogenetics. 3. Patient must have peripheral white blood cell count \< 50,000/mcl. 4. Patient must have adequate organ function, defined as: 1. Total bilirubin \< 1.5 x ULN 2. AST/ALT \< 2.5 x ULN 3. Serum creatinine \< 2.0 x ULN 5. Patient must have undergone ≤ 2 cycles of prior hypomethylating agent (decitabine or azacitidine). 6. Patient must be enrolled in HRPO# 201011766 (Tissue Acquisition for Analysis of Genetic Progression Factors in Hematologic Diseases). 7. Patient must be \> 18 years of age. 8. Patient must be able to understand and willing to sign an IRB-approved written informed consent document.
Exclusion criteria
* Patient must not be pregnant or nursing * Patient must not have acute promyelocytic leukemia or t(15;17) observed by FISH. * Patient must not have known central nervous system (CNS) leukemia * Patient must not have a history of positive human immunodeficiency virus (HIV) serology * Patient must not have a history of positive hepatitis C serology * Patient must not have undergone prior allogeneic stem cell transplant * Patient must not have any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, ongoing or active graft-versus-host disease (GVHD), congestive heart failure of New York Heart Association (NYHA) class 3 or 4, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements * Patient must not have had radiation therapy within 14 days of enrollment * Patient must not have received any chemotherapy within 21 days of enrollment and any acute treatment-related toxicities must have returned to baseline. Patients may be receiving hydrea at time of enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of Patient Specific Mutations With Overall Response Rate | 4 months (4 treatment cycles) | -Best response after 4 treatment cycles as assessed according to International Working Group (IWG) criteria; bone marrow for gene sequencing will be collected at baseline; mutations will be correlated with overall response rate --Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Marrow complete remission (mCR), Partial remission (PR), Stable disease (SD), Progressive disease (PD) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Mutation Clearance During Treatment | Up to Day 56 | Samples collected at baseline and after 10, 28 and 56 days of therapy; the rate of mutation clearance was measured as mean VAF change per day of treatment and was estimated using linear mixed model for repeated measurement data . |
| Compare Outcomes of a 10-day Decitabine Per Cycle Regimen to a 5-day Regimen (Historical Controls) | 4 months (4 treatment cycles) | The overall response rate (CR/CRi/mCR/PR) and complete response rate (CR/CRi/mCR) will be compared with historical controls. Response assessed according to IWG criteria. |
| Peripheral Blood Decitabine Plasma Levels | Day 4 | * To determine whether steady state serum concentrations of decitabine correlated with responses * Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Partial remission (PR), Stable disease (SD), Progressive disease (PD), Not applicable (NA) - assessed according to International Working Group (IWG) criteria |
| Change in Bone Marrow Methylcytosine | Baseline and Day 10 | -Change of total bone marrow deoxyribonucleic acid (DNA) methylcytosine from baseline to Day 10 |
Countries
United States
Participant flow
Recruitment details
The study opened to participant enrollment on 02/12/2013 and closed to participant enrollment on 06/19/2017.
Participants by arm
| Arm | Count |
|---|---|
| Decitabine Patients receive decitabine IV over 1 hour on days 1-10 of a 28-day cycle. Treatment continues for 2 cycles. Patients then receive decitabine IV over 1 hour on days 1-10, 1-5, or 1-3 (depending on response). Treatment continues in the absence of disease progression or unacceptable toxicity. | 114 |
| Total | 114 |
Baseline characteristics
| Characteristic | Decitabine |
|---|---|
| Age, Continuous | 73 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 90 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 105 Participants |
| Region of Enrollment United States | 114 participants |
| Sex: Female, Male Female | 48 Participants |
| Sex: Female, Male Male | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 38 / 50 | 43 / 64 |
| other Total, other adverse events | 50 / 50 | 64 / 64 |
| serious Total, serious adverse events | 42 / 50 | 47 / 64 |
Outcome results
Primary
Correlation of Patient Specific Mutations With Overall Response Rate
-Best response after 4 treatment cycles as assessed according to International Working Group (IWG) criteria; bone marrow for gene sequencing will be collected at baseline; mutations will be correlated with overall response rate --Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Marrow complete remission (mCR), Partial remission (PR), Stable disease (SD), Progressive disease (PD)
Time frame: 4 months (4 treatment cycles)
Population: -Some participants were not evaluable for this outcome measure due to sample collection quality issues and if they had repeat bone marrow biopsies and could be evaluated for responses.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | RUNX1 | 5 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | NRAS | 3 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | TET2 | 4 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | IDH2 | 6 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | IDH1 | 2 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | ASXL1 | 9 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | NPM1 | 4 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | DNMT3A | 8 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | U2AF1 | 4 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | TP53 | 26 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | MY05B | 3 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | SF3B1 | 7 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | WT1 | 5 Participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Correlation of Patient Specific Mutations With Overall Response Rate | SRSF2 | 7 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | WT1 | 1 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | TP53 | 3 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | ASXL1 | 2 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | SRSF2 | 5 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | IDH2 | 5 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | DNMT3A | 5 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | SF3B1 | 0 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | RUNX1 | 3 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | TET2 | 3 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | IDH1 | 3 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | NRAS | 3 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | U2AF1 | 1 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | MY05B | 2 Participants |
| Decitabine (Participants With Response of SD/PD) | Correlation of Patient Specific Mutations With Overall Response Rate | NPM1 | 1 Participants |
Comparison: Statistical analysis #1 is for the genetic mutation TP53.p-value: 0.035Fisher Exact
Comparison: Statistical analysis #2 is for ASXL1 genetic mutationp-value: 0.72Fisher Exact
Comparison: Statistical analysis #3 is for SRSF2 genetic mutationp-value: 0.28Fisher Exact
Comparison: Statistical analysis #4 is for IDH2 genetic mutationp-value: 0.14Fisher Exact
Comparison: Statistical analysis #5 is for DNMT3A genetic mutationp-value: 0.3Fisher Exact
Comparison: Statistical analysis #6 is for SF3B1 genetic mutationp-value: 0.183Fisher Exact
Comparison: Statistical analysis #7 is for RUNX1 genetic mutationp-value: 0.42Fisher Exact
Comparison: Statistical analysis #8 is for TET2 genetic mutationp-value: 0.36Fisher Exact
Comparison: Statistical analysis #9 is for IDH1 genetic mutationp-value: 0.1Fisher Exact
Comparison: Statistical analysis #10 is for NPM1 genetic mutationp-value: 1Fisher Exact
Comparison: Statistical analysis #11 is for NRAS genetic mutationp-value: 0.17Fisher Exact
Comparison: -Statistical analysis #12 is for U2AF1 genetic mutationp-value: 1Fisher Exact
Comparison: Statistical analysis #13 is for MY05B genetic mutationp-value: 0.6Fisher Exact
Comparison: Statistical analysis #14 is for WT1 genetic mutationp-value: 1Fisher Exact
Secondary
Change in Bone Marrow Methylcytosine
-Change of total bone marrow deoxyribonucleic acid (DNA) methylcytosine from baseline to Day 10
Time frame: Baseline and Day 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Change in Bone Marrow Methylcytosine | Day 0 | 0.53 proportion of methylcytosine | Standard Deviation 0 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Change in Bone Marrow Methylcytosine | Day 10 | 0.4416 proportion of methylcytosine | Standard Deviation 0.0247 |
| Decitabine (Participants With Response of SD/PD) | Change in Bone Marrow Methylcytosine | Day 0 | 0.5374 proportion of methylcytosine | Standard Deviation 0 |
| Decitabine (Participants With Response of SD/PD) | Change in Bone Marrow Methylcytosine | Day 10 | 0.4639 proportion of methylcytosine | Standard Deviation 0.035 |
Secondary
Compare Outcomes of a 10-day Decitabine Per Cycle Regimen to a 5-day Regimen (Historical Controls)
The overall response rate (CR/CRi/mCR/PR) and complete response rate (CR/CRi/mCR) will be compared with historical controls. Response assessed according to IWG criteria.
Time frame: 4 months (4 treatment cycles)
Population: -Participants were evaluable for this outcome measure if they completed at least one cycle of treatment and the cycle 1 day 28 bone marrow biopsy to assess response
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Compare Outcomes of a 10-day Decitabine Per Cycle Regimen to a 5-day Regimen (Historical Controls) | Overall response rate (CR, CRi/mCR/PR) | 74.42 percentage of participants |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Compare Outcomes of a 10-day Decitabine Per Cycle Regimen to a 5-day Regimen (Historical Controls) | Complete response rate (CR, CRi, mCR) | 63.95 percentage of participants |
Comparison: -The historical control of a 5-day regimen (Cashen et al 2010 JCO = NCT00358644) showed 25% (14 out of 55 participants) in overall response ratep-value: <0.000195% CI: [0.652, 0.836]Chi-squared
Comparison: -The historical control of a 5-day regimen (Cashen et al 2010 JCO = NCT00358644) showed 24% (13 out of 55 participants) in complete response rate.p-value: <0.000195% CI: [0.538, 0.741]Chi-squared
Secondary
Peripheral Blood Decitabine Plasma Levels
* To determine whether steady state serum concentrations of decitabine correlated with responses * Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Partial remission (PR), Stable disease (SD), Progressive disease (PD), Not applicable (NA) - assessed according to International Working Group (IWG) criteria
Time frame: Day 4
Population: The first 45 participants enrolled with adequate samples were analyzed using GC-MS quantification of serum decitabine levels. Sufficient funds were lacking to complete the analysis of additional participants and all participants with data analyzed are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Peripheral Blood Decitabine Plasma Levels | CR | 140.5 ng/ml | Standard Deviation 53.41 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Peripheral Blood Decitabine Plasma Levels | CRi | 117.2 ng/ml | Standard Deviation 54.6 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Peripheral Blood Decitabine Plasma Levels | PR | 67.71 ng/ml | Standard Deviation 56.18 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Peripheral Blood Decitabine Plasma Levels | SD | 145 ng/ml | Standard Deviation 73.06 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Peripheral Blood Decitabine Plasma Levels | PD | 298.5 ng/ml | Standard Deviation 213.3 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Peripheral Blood Decitabine Plasma Levels | NA | 99.64 ng/ml | Standard Deviation 58.4 |
Secondary
Rate of Mutation Clearance During Treatment
Samples collected at baseline and after 10, 28 and 56 days of therapy; the rate of mutation clearance was measured as mean VAF change per day of treatment and was estimated using linear mixed model for repeated measurement data .
Time frame: Up to Day 56
Population: -The first 39 cases with adequate samples were serially evaluated with enhanced exome sequencing. The investigators evaluated 15 additional cases using gene panel sequencing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | TP53 | -0.781 proportion of variant alleles per day | Standard Deviation 0.4423 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | SRSF2 | -0.2214 proportion of variant alleles per day | Standard Deviation 0.2705 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | DNMT3A | -0.2122 proportion of variant alleles per day | Standard Deviation 0.2817 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | IDH2 | -0.08344 proportion of variant alleles per day | Standard Deviation 0.2841 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | RUNX1 | -0.2641 proportion of variant alleles per day | Standard Deviation 0.6536 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | TET2 | -0.07478 proportion of variant alleles per day | Standard Deviation 0.3164 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | ASXL1 | -0.3898 proportion of variant alleles per day | Standard Deviation 0.3791 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | IDH1 | -0.1103 proportion of variant alleles per day | Standard Deviation 0.196 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | NRAS | 0.04544 proportion of variant alleles per day | Standard Deviation 0.2554 |
| Decitabine (Participants With Response of CR/CRi/mCR/PR) | Rate of Mutation Clearance During Treatment | SF3B1 | -0.719 proportion of variant alleles per day | Standard Deviation 0.3481 |