Clinical Trials /

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

NCT02497404

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 1306014009
  • NCT ID: NCT02497404

Conditions

  • Leukemia, Erythroblastic, Acute
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
5-AzacytidineVidaza5 Azacytidine
FludarabineFludara5 Azacytidine
MelphalanAlkeran5 Azacytidine
AlemtuzumabCampath, Lemtrada5 Azacytidine

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
5 AzacytidineExperimentalPatients 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
  • Fludarabine
  • Melphalan
  • Alemtuzumab

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease free survival
Time Frame:2 years
Safety Issue:
Description:Evaluating disease free survival at 6 months, 1 year, 2 years, then overall survival

Secondary Outcome Measures

Measure:Incidence and severity of acute and chronic Graft-Versus-Host Disease (GVHD)
Time Frame:1 year
Safety Issue:
Description: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.
Measure:Engraftment and chimerism patterns
Time Frame:1 year
Safety Issue:
Description: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.
Measure:Evaluate changes in global methylation
Time Frame:1 year
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Weill Medical College of Cornell University

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