Leukemia, Erythroblastic, Acute, Myelodysplastic Syndromes
Conditions
Brief summary
The purpose of this study is to determine whether 5-Azacytidine priming before the conditioning regimen for subjects receiving a hematopoietic stem cell transplant is an effective treatment for high risk myeloid malignancies in complete remission (CR).
Detailed description
This open label two-step phase II study is designed to determine the safety and efficacy of epigenetic priming with 5-Azacytidine immediately prior to reduced intensity conditioning for an in vivo T-cell depleted hematopoietic stem cell transplantation for high risk myeloid malignancies in complete remission (CR). Subjects will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine, melphalan and total body irradiation (TBI) prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated Human Leukocyte Antigen (HLA) matched donor. The effect of 5-azacytidine on global gene methylation will be assessed. Evaluations for safety, in particular for graft failure, transplant related mortality and acute graft versus host disease will be made on a weekly basis. Efficacy, as defined by disease free survival, will be evaluated with a bone marrow biopsy at the standard time points, which are one-, three-, six-, and twelve-months after transplant and upon clinical suspicion within regular follow-up visits - weekly for the first 3 months, then biweekly for 3 months, then monthly until one-year post-stem cell transplant. Thereafter, unless otherwise dictated by the clinical scenario, the follow up visits will be every 3 months.
Interventions
DRUG5-Azacytidine
Patients will be given a five day course of subcutaneous 5-azacytidine followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor. 5-Azacytidine 75 mg/m2 subcutaneously daily at the same time on days -11, -10, -9, -8 and -7. This will be administered on an outpatient basis if possible.
DRUGFludarabine
Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Fludarabine will be given at 40 mg/m2 intravenously daily at the same time over 30 minutes on days -6,-5,-4,-3.
DRUGMelphalan
Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Melphalan will be given at 140 mg/m2 IV on day -3.
DRUGAlemtuzumab
Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Alemtuzumab will be given at 30 mg subcutaneously on Days -4 and -2 for unrelated donors, and Day -2 for related donors.
RADIATIONTotal Body Irradiation
Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Total Body Irradiation (TBI) will be given at 2 doses of 200 cGy each on one day of the conditioning regimen (between days -6 and -3).
Sponsors
Weill Medical College of Cornell University
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
* Patients must have histologically or cytologically confirmed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) as specified below: 1. Acute myeloid leukemia with poor risk cytogenetics in complete morphologic remission. These include: del (5q)/-5, del (7q)/-7, abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) or complex karyotypes (≥ 3 unrelated abnormalities); or 2. Acute myeloid leukemia with either Flt-3, TET-2, p53, DNMT3A, or ASXL1 mutation, mutations of genes involved in the chromatin/spliceosome category (EZH2, SRSF2, U2AF1, ZRSR2), BCOR, and RUNX1, as well as MLL rearrangement, EVI1 overexpression in complete morphologic remission; or 3. Acute myeloid leukemia with a white blood cell count of greater than or equal to 50,000/mcL at presentation in first complete morphologic remission; or 4. Acute myeloid leukemia in first complete morphologic remission, having required more than one course of induction chemotherapy to attain remission status; or 5. Acute myeloid leukemia, all types, excluding M3 (Promyelocytic leukemia) in second or higher complete morphologic remission; or 6. Myelodysplastic syndromes (intermediate-2, high risk and chronic myelomonocytic leukemia (CMML) with bone marrow blasts \<5%); or 7. Secondary acute myeloid leukemia on the basis of prior MDS or prior myeloproliferative neoplasm (MPN) in complete morphologic remission * Life expectancy not severely limited by concomitant disease * Karnofsky Performance Score greater than or equal to 70%. * Adequate organ function as defined below: Serum Bilirubin:\<2.0 mg/dL; Alanine Aminotransferase (ALT) (SGPT): \<3 x upper limit of normal; Creatinine Clearance:\>60 mL/min (eGFR as estimated by the modified Modification of Diet in Renal Disease Study (MDRD) equation) \- Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Evidence of chronic active hepatitis or cirrhosis * HIV infection * Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown. * There are no prior therapies or concomitant medications that would render the patients ineligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival at 1 Year Post-transplant | 1 year post-transplant | Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 1 year post-transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival at 2 Years Post-transplant | 2 years post-transplant | Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 2 years post-transplant. |
| Overall Survival at 6 Months Post-transplant | 6 months post-transplant | Number of participants alive at 6 months post-transplant |
| Overall Survival at 1 Year Post-Transplant | 1 year post-transplant | Number of participants alive at 1 year post-transplant |
| Disease Free Survival at 6 Months Post-transplant | 6 months post-transplant | Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 6 months post-transplant |
| Graft Failure | 21 days post-transplant | Number of patients who experience graft failure, defined as the absence of neutrophil engraftment by Day +21 or a drop in the absolute neutrophil count to \<0.3 cells/microL for five consecutive days occurring after initial neutrophil engraftment within the first 3 weeks post-transplantation. |
| Acute Graft-versus-Host Disease (GVHD) | 2 years post-transplant | Number of patients who develop acute graft-versus-host disease of any grade. |
| High-Risk Extensive Chronic Graft-versus-Host-Disease | 2 years post-transplant | Number of patients who develop high-risk extensive chronic graft-versus-host disease. Extensive chronic GVHD is defined as generalized skin or multiple organ involvement. High risk chronic GVHD is defined as platelet count of less than 100k/microL |
| Overall Survival at 2 Years Post-Transplant | 2 years post-transplant | Number of participants alive at 2 years post-transplant |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 5 Azacytidine Patients will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation (TBI) prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor.
5-Azacytidine: Patients will be given a five day course of subcutaneous 5-Azacytidine followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor. AZA 75 mg/m2 subcutaneously daily at the same time on days -11, -10, -9, -8 and -7. This will be administered on an outpatient basis if possible.
Fludarabine (conditioning regimen): Fludarabine will be given at 40 mg/m2 intravenously daily at the same time over 30 minutes on days -6,-5,-4,-3.
Melphalan (conditioning regimen): Melphalan will be given at 140 mg/m2 IV on day -3.
Alemtuzumab (conditioning regimen): Alemtuzumab will be given at 30 mg subcutaneously on Days -4 and -2 for unrelated donors, and Day -2 for related donors.
TBI (conditioning regimen): TBI will be given at 2 doses of 200 cGy each on one day of the conditioning regimen (between days -6 and -3). | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | 5 Azacytidine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Disease Acute Myeloid Leukemia | 34 Participants |
| Disease Myelodysplastic Syndrome/Myeloproliferative Disease | 6 Participants |
| Donor Relationship Matched Related Donor | 17 Participants |
| Donor Relationship Matched Unrelated Donor | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 35 Participants |
| Region of Enrollment United States | 40 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 28 / 40 |
| other Total, other adverse events | 38 / 40 |
| serious Total, serious adverse events | 28 / 40 |
Outcome results
Primary
Disease Free Survival at 1 Year Post-transplant
Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 1 year post-transplant.
Time frame: 1 year post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | Disease Free Survival at 1 Year Post-transplant | 18 Participants |
95% CI: [30.1, 62.8]
Secondary
Acute Graft-versus-Host Disease (GVHD)
Number of patients who develop acute graft-versus-host disease of any grade.
Time frame: 2 years post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | Acute Graft-versus-Host Disease (GVHD) | 13 Participants |
95% CI: [19.1, 50.2]
Secondary
Disease Free Survival at 2 Years Post-transplant
Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 2 years post-transplant.
Time frame: 2 years post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | Disease Free Survival at 2 Years Post-transplant | 13 Participants |
95% CI: [19.1, 50.2]
Secondary
Disease Free Survival at 6 Months Post-transplant
Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 6 months post-transplant
Time frame: 6 months post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | Disease Free Survival at 6 Months Post-transplant | 25 Participants |
95% CI: [47.2, 78.8]
Secondary
Graft Failure
Number of patients who experience graft failure, defined as the absence of neutrophil engraftment by Day +21 or a drop in the absolute neutrophil count to \<0.3 cells/microL for five consecutive days occurring after initial neutrophil engraftment within the first 3 weeks post-transplantation.
Time frame: 21 days post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | Graft Failure | 1 Participants |
95% CI: [0.07, 13.5]
Secondary
High-Risk Extensive Chronic Graft-versus-Host-Disease
Number of patients who develop high-risk extensive chronic graft-versus-host disease. Extensive chronic GVHD is defined as generalized skin or multiple organ involvement. High risk chronic GVHD is defined as platelet count of less than 100k/microL
Time frame: 2 years post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | High-Risk Extensive Chronic Graft-versus-Host-Disease | 2 Participants |
95% CI: [0.63, 15.3]
Secondary
Overall Survival at 1 Year Post-Transplant
Number of participants alive at 1 year post-transplant
Time frame: 1 year post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | Overall Survival at 1 Year Post-Transplant | 25 Participants |
95% CI: [47.2, 78.8]
Secondary
Overall Survival at 2 Years Post-Transplant
Number of participants alive at 2 years post-transplant
Time frame: 2 years post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | Overall Survival at 2 Years Post-Transplant | 15 Participants |
Comparison: Clopper-Pearson (exact) 95% confidence interval provided for the survival proportion.95% CI: [23.4, 55.4]
Secondary
Overall Survival at 6 Months Post-transplant
Number of participants alive at 6 months post-transplant
Time frame: 6 months post-transplant
Population: 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5 Azacytidine | Overall Survival at 6 Months Post-transplant | 35 Participants |
95% CI: [75.8, 97.1]