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Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR

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ClinicalTrials.gov Identifier: NCT02497404
Recruitment Status : Active, not recruiting
First Posted : July 14, 2015
Last Update Posted : August 29, 2019
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

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
Leukemia, Erythroblastic, Acute Myelodysplastic Syndromes Drug: 5-Azacytidine Drug: Fludarabine Drug: Melphalan Drug: Alemtuzumab Radiation: Total Body Irradiation 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
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 : February 13, 2015
Actual Primary Completion Date : June 27, 2019
Estimated Study Completion Date : July 2021


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 Name: Vidaza

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 Name: Fludara

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 Name: Alkeran

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 Name: Campath, Lemtrada

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 Name: TBI




Primary Outcome Measures :
  1. Disease free survival [ Time Frame: 2 years ]
    Evaluating disease free survival at 6 months, 1 year, 2 years, then overall survival


Secondary Outcome Measures :
  1. Incidence and severity of acute and chronic Graft-Versus-Host Disease (GVHD) [ Time Frame: 1 year ]
    To evaluate the incidence and severity of acute and chronic GVHD after 5-azacytidine priming prior to conditioning for allogeneic stem cell transplantation with Alemtuzumab-based in vivo T-cell depletion in patients with poor risk myeloid malignancies in complete morphologic remission.

  2. Engraftment and chimerism patterns [ Time Frame: 1 year ]
    To evaluate engraftment and chimerism patterns after 5-azacytidine primed conditioning for stem cell transplantation with Alemtuzumab-based in vivo T-cell depletion in patients with poor risk myeloid malignancies in complete morphologic remission.

  3. Evaluate changes in global methylation [ Time Frame: 1 year ]
    To evaluate changes in global gene methylation by 5-azacytidine prior to conditioning for stem cell transplantation with Alemtuzumab-based in vivo T-cell depletion in patients with poor risk myeloid malignancies in complete morphologic remission.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02497404


Locations
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United States, New York
Weill Cornell Medical College
New York, New York, United States, 10021
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
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Principal Investigator: Sebastian Mayer, MD Weill Medical College of Cornell University

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Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT02497404     History of Changes
Other Study ID Numbers: 1306014009
First Posted: July 14, 2015    Key Record Dates
Last Update Posted: August 29, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Erythroblastic, Acute
Myelodysplastic Syndromes
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Myeloproliferative Disorders
Fludarabine
Fludarabine phosphate
Melphalan
Azacitidine
Alemtuzumab
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Enzyme Inhibitors
Antineoplastic Agents, Immunological