Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR
Sponsor
Weill Medical College of Cornell University (Other)
Overall Status
Completed
CT.gov ID
NCT02497404
Collaborator
(none)
40
1
1
76.1
0.5
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Study Type:
Interventional
Actual Enrollment
:
40 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Epigenetic Priming With 5-Azacytidine Prior to in Vivo T-cell Depleted Allogeneic Stem Cell Transplantation for Patients With High Risk Myeloid Malignancies in Morphologic Remission
Actual Study Start Date
:
Feb 13, 2015
Actual Primary Completion Date
:
Jun 17, 2020
Actual Study Completion Date
:
Jun 17, 2021
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: 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. 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.
Other Names:
Drug: Fludarabine
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.
Other Names:
Drug: Melphalan
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.
Other Names:
Drug: Alemtuzumab
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.
Other Names:
Radiation: Total 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).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
- 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
- Overall Survival at 2 Years Post-Transplant [2 years post-transplant]
Number of participants alive at 2 years 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
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) as specified below:
-
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
-
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
-
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
-
Acute myeloid leukemia in first complete morphologic remission, having required more than one course of induction chemotherapy to attain remission status; or
-
Acute myeloid leukemia, all types, excluding M3 (Promyelocytic leukemia) in second or higher complete morphologic remission; or
-
Myelodysplastic syndromes (intermediate-2, high risk and chronic myelomonocytic leukemia (CMML) with bone marrow blasts <5%); or
-
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Weill Cornell Medical College | New York | New York | United States | 10021 |
Sponsors and Collaborators
- Weill Medical College of Cornell University
Investigators
- Principal Investigator: Sebastian Mayer, MD, Weill Medical College of Cornell University
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT02497404
Other Study ID Numbers:
- 1306014009
First Posted:
Jul 14, 2015
Last Update Posted:
Sep 22, 2021
Last Verified:
Aug 1, 2021
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Period Title: Overall Study | |
| STARTED | 40 |
| COMPLETED | 39 |
| NOT COMPLETED | 1 |
Baseline Characteristics
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Overall Participants | 40 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
28
70%
|
| >=65 years |
12
30%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
21
52.5%
|
| Male |
19
47.5%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
2
5%
|
| Not Hispanic or Latino |
36
90%
|
| Unknown or Not Reported |
2
5%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
3
7.5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
1
2.5%
|
| White |
35
87.5%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
1
2.5%
|
| Region of Enrollment (participants) [Number] | |
| United States |
40
100%
|
| Disease (Count of Participants) | |
| Acute Myeloid Leukemia |
34
85%
|
| Myelodysplastic Syndrome/Myeloproliferative Disease |
6
15%
|
| Donor Relationship (Count of Participants) | |
| Matched Related Donor |
17
42.5%
|
| Matched Unrelated Donor |
22
55%
|
Outcome Measures
| Title | Disease Free Survival at 1 Year Post-transplant |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant. |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
18
45%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the survival proportion. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 46.2 | |
| Confidence Interval |
(2-Sided) 95% 30.1 to 62.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Disease Free Survival at 6 Months Post-transplant |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant. |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
25
62.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the survival proportion. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 64.1 | |
| Confidence Interval |
(2-Sided) 95% 47.2 to 78.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Disease Free Survival at 2 Years Post-transplant |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant. |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
13
32.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the survival proportion. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 33.3 | |
| Confidence Interval |
(2-Sided) 95% 19.1 to 50.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival at 6 Months Post-transplant |
|---|---|
| Description | Number of participants alive at 6 months post-transplant |
| Time Frame | 6 months post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant. |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
35
87.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the survival proportion. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 89.7 | |
| Confidence Interval |
(2-Sided) 95% 75.8 to 97.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival at 1 Year Post-Transplant |
|---|---|
| Description | Number of participants alive at 1 year post-transplant |
| Time Frame | 1 year post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
25
62.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the survival proportion. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 64.1 | |
| Confidence Interval |
(2-Sided) 95% 47.2 to 78.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival at 2 Years Post-Transplant |
|---|---|
| Description | Number of participants alive at 2 years post-transplant |
| Time Frame | 2 years post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant. |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
15
37.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the survival proportion. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 38.5 | |
| Confidence Interval |
(2-Sided) 95% 23.4 to 55.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Graft Failure |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant. |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
1
2.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the graft failure proportion. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 2.6 | |
| Confidence Interval |
(2-Sided) 95% 0.07 to 13.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Acute Graft-versus-Host Disease (GVHD) |
|---|---|
| Description | Number of patients who develop acute graft-versus-host disease of any grade. |
| Time Frame | 2 years post-transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant. |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
13
32.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the GVHD proportion. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 33.3 | |
| Confidence Interval |
(2-Sided) 95% 19.1 to 50.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | High-Risk Extensive Chronic Graft-versus-Host-Disease |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant. |
| Arm/Group Title | 5 Azacytidine |
|---|---|
| Arm/Group Description | 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). |
| Measure Participants | 39 |
| Count of Participants [Participants] |
2
5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 5 Azacytidine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Clopper-Pearson (exact) 95% confidence interval provided for the high-risk extensive chronic graft-versus-host-disease proportion. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Proportion (percent) |
| Estimated Value | 5.1 | |
| Confidence Interval |
(2-Sided) 95% 0.63 to 15.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | Adverse events were collected for all patients from start of 5-azacytidine therapy through 5 years post-transplant or when the participant was removed from the study, whichever was sooner. | |
|---|---|---|
| Adverse Event Reporting Description | All adverse events were first documented by the study transplant physicians and thereafter collated and graded by two independent reviewed according to CTCAE version 4.0. Per protocol, events reported were all infectious events and Grade 3 and higher events for non-infectious events | |
| Arm/Group Title | 5 Azacytidine | |
| Arm/Group Description | 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). | |
All Cause Mortality |
||
| 5 Azacytidine | ||
| Affected / at Risk (%) | # Events | |
| Total | 28/40 (70%) | |
Serious Adverse Events |
||
| 5 Azacytidine | ||
| Affected / at Risk (%) | # Events | |
| Total | 28/40 (70%) | |
| Blood and lymphatic system disorders | ||
| Atypical Hemolytic Uremic Syndrome | 4/40 (10%) | 4 |
| Febrile Neutropenia | 2/40 (5%) | 2 |
| Cardiac disorders | ||
| Pericardial Effusion | 4/40 (10%) | 4 |
| Gastrointestinal disorders | ||
| Diarrhea | 1/40 (2.5%) | 1 |
| Small Bowel Obstruction | 1/40 (2.5%) | 1 |
| Gastroenteritis | 1/40 (2.5%) | 1 |
| Lower Gastrointestinal Hemorrhage | 1/40 (2.5%) | 1 |
| Abdominal Pain | 1/40 (2.5%) | 1 |
| Intra-Abdominal Abscess | 1/40 (2.5%) | 1 |
| General disorders | ||
| Failure to Thrive | 1/40 (2.5%) | 1 |
| Hypervolemia | 1/40 (2.5%) | 1 |
| Fever | 3/40 (7.5%) | 3 |
| Infusion-Related Reaction | 1/40 (2.5%) | 1 |
| Hepatobiliary disorders | ||
| Cholecystitis | 1/40 (2.5%) | 1 |
| Infections and infestations | ||
| Bacteremia | 3/40 (7.5%) | 3 |
| Human Herpesvirus 6 Infection | 1/40 (2.5%) | 1 |
| Cytomegalovirus Infection | 2/40 (5%) | 2 |
| Pneumonia | 3/40 (7.5%) | 3 |
| Norovirus Infection | 1/40 (2.5%) | 1 |
| Upper Respiratory Infection - Influenza B | 1/40 (2.5%) | 1 |
| Upper Respiratory Infection - Rhinovirus | 1/40 (2.5%) | 1 |
| Fungal Pneumonia | 2/40 (5%) | 2 |
| Sepsis | 5/40 (12.5%) | 5 |
| Bronchial Infection | 1/40 (2.5%) | 1 |
| Appendicitis | 2/40 (5%) | 2 |
| Fungal Infection | 1/40 (2.5%) | 1 |
| Conjunctivitis | 1/40 (2.5%) | 1 |
| Herpes Simplex Virus Infection | 1/40 (2.5%) | 1 |
| Injury, poisoning and procedural complications | ||
| Fall | 1/40 (2.5%) | 1 |
| Investigations | ||
| Acute Graft-versus-Host Disease | 2/40 (5%) | 2 |
| Platelet Count Decreased | 1/40 (2.5%) | 1 |
| Chronic Graft-versus-Host Disease | 1/40 (2.5%) | 1 |
| Post-Transplant Lymphoproliferative Disorder | 1/40 (2.5%) | 1 |
| Musculoskeletal and connective tissue disorders | ||
| Back Pain | 1/40 (2.5%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Squamous Cell Carcinoma | 2/40 (5%) | 2 |
| Nervous system disorders | ||
| Intracranial Hemorrhage | 2/40 (5%) | 2 |
| Stroke | 1/40 (2.5%) | 1 |
| Posterior Reversible Encephalopathy Syndrome | 1/40 (2.5%) | 1 |
| Seizure | 1/40 (2.5%) | 1 |
| Renal and urinary disorders | ||
| Acute Kidney Injury | 6/40 (15%) | 6 |
| Renal Failure | 1/40 (2.5%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Respiratory Failure | 4/40 (10%) | 4 |
| Respiratory Distress | 3/40 (7.5%) | 3 |
| Pulmonary Edema | 1/40 (2.5%) | 1 |
| Pleural Effusion | 1/40 (2.5%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Rash Maculo-papular | 1/40 (2.5%) | 1 |
| Vascular disorders | ||
| Hypotension | 2/40 (5%) | 2 |
| Hypertension | 1/40 (2.5%) | 1 |
| Thromboembolic Event | 1/40 (2.5%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| 5 Azacytidine | ||
| Affected / at Risk (%) | # Events | |
| Total | 38/40 (95%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 4/40 (10%) | 4 |
| Febrile Neutropenia | 1/40 (2.5%) | 1 |
| Gastrointestinal disorders | ||
| Diarrhea | 3/40 (7.5%) | 3 |
| Nausea | 2/40 (5%) | 2 |
| Mucositis Oral | 1/40 (2.5%) | 1 |
| Small Bowel Obstruction | 1/40 (2.5%) | 1 |
| Rectal Pain | 1/40 (2.5%) | 1 |
| Periapical Abscess | 1/40 (2.5%) | 1 |
| Hepatobiliary disorders | ||
| Hepatosplenic Lesion | 1/40 (2.5%) | 1 |
| Infections and infestations | ||
| Bacteremia | 11/40 (27.5%) | 11 |
| Urinary Tract Infection | 7/40 (17.5%) | 7 |
| Upper Respiratory Infection - Parainfluenza | 8/40 (20%) | 8 |
| Clostridium difficile Colitis | 12/40 (30%) | 12 |
| Adenovirus Infection | 3/40 (7.5%) | 3 |
| Human Herpesvirus 6 Infection | 13/40 (32.5%) | 13 |
| Upper Respiratory Infection - Respiratory Synctyial Virus | 3/40 (7.5%) | 3 |
| Cytomegalovirus Infection | 11/40 (27.5%) | 11 |
| Varicella Zoster Infection | 1/40 (2.5%) | 1 |
| Upper Respiratory Infection - Influenza B | 2/40 (5%) | 2 |
| Upper Respiratory Infection - Rhinovirus | 10/40 (25%) | 10 |
| BK Virus Infection | 9/40 (22.5%) | 9 |
| Upper Respiratory Infection - Human metapneumovirus | 4/40 (10%) | 4 |
| Upper Respiratory Infection - Staphylococcus aureus | 1/40 (2.5%) | 1 |
| Fungal Pneumonia | 2/40 (5%) | 2 |
| Infectious Diarrhea | 6/40 (15%) | 6 |
| Upper Respiratory Infection - Influenza A | 5/40 (12.5%) | 5 |
| Upper Respiratory Infection - SARS-CoV-2 | 1/40 (2.5%) | 1 |
| Upper Respiratory Infection - Coronavirus | 2/40 (5%) | 2 |
| Central Line Infection | 4/40 (10%) | 4 |
| Fungal Infection | 1/40 (2.5%) | 1 |
| Epstein Barr Virus Infection | 9/40 (22.5%) | 9 |
| Investigations | ||
| Acute Graft-versus-Host Disease | 12/40 (30%) | 12 |
| Platelet count decreased | 3/40 (7.5%) | 3 |
| Neutrophil count decreased | 3/40 (7.5%) | 3 |
| Creatinine increased | 1/40 (2.5%) | 1 |
| Chronic Graft-versus-Host Disease | 5/40 (12.5%) | 5 |
| Aspartate Aminotransferase Increased | 1/40 (2.5%) | 1 |
| Metabolism and nutrition disorders | ||
| Anorexia | 3/40 (7.5%) | 3 |
| Hyponatremia | 2/40 (5%) | 2 |
| Hypocalcemia | 1/40 (2.5%) | 1 |
| Hypoalbuminemia | 1/40 (2.5%) | 1 |
| Acidosis | 1/40 (2.5%) | 1 |
| Hypomagnesemia | 1/40 (2.5%) | 1 |
| Psychiatric disorders | ||
| Delirium | 1/40 (2.5%) | 1 |
| Renal and urinary disorders | ||
| Acute Kidney Injury | 2/40 (5%) | 2 |
| Urinary Retention | 1/40 (2.5%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Respiratory Failure | 2/40 (5%) | 2 |
| Skin and subcutaneous tissue disorders | ||
| Rash Maculo-papular | 1/40 (2.5%) | 1 |
| Vascular disorders | ||
| Hypotension | 1/40 (2.5%) | 1 |
| Hypertension | 1/40 (2.5%) | 1 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Sebastian Mayer, MD |
|---|---|
| Organization | Weill Cornell Medical College |
| Phone | 646-962-7950 |
| sam2033@med.cornell.edu |
Responsible Party:
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT02497404
Other Study ID Numbers:
- 1306014009
First Posted:
Jul 14, 2015
Last Update Posted:
Sep 22, 2021
Last Verified:
Aug 1, 2021