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Safety Study of 5-Azacitidine and Standard Donor Lymphocyte Infusion (DLI) to Treat Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Relapsing After Allogeneic Stem Cell Transplantation

Primary Purpose

Myelodysplastic Syndrome, Acute Myeloid Leukemia

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
5-Azacitidine
Sponsored by
Heinrich-Heine University, Duesseldorf
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelodysplastic Syndrome focused on measuring Myelodysplastic syndrome (MDS), Acute myeloid leukemia (AML), Stem cell transplantation, 5-Azacitidine, Donor lymphocyte infusion, MDS or AML relapsed after stem cell transplantation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

- Primary and secondary MDS, AML after MDS, and de novo AML relapsing after allogeneic stem cell transplantation

  • Eligibility for Donor Lymphocyte Infusions
  • Performance status according to the WHO scale: 0, 1 or 2.
  • Adequate renal and liver function: bilirubin < 1.5 times the upper limit of normal and a GFR > 50 ml/min
  • Absence of severe cardiovascular disease, i.e., arrhythmias requiring chronic treatment, congestive heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease, where New-York Heart Association (NYHA)
  • HIV negative and HBs-Ag negative.
  • Absence of active uncontrolled infection (Septicaemia).
  • No prior history or current evidence of central nervous system and psychiatric disorders requiring hospitalization.
  • Age at least 18 years.
  • Negative pregnancy test for women with reproductive potential.
  • Signed written informed consent must be given according to national/local regulations.

Exclusion Criteria:

- Have malignant hepatic tumors.

  • Severe liver dysfunction CHILD B and C.
  • Renal insufficiency with a GFR < 50 ml/min
  • Radiation therapy, chemotherapy, or cytotoxic therapy, given to treat conditions other than MDS, AML or applied for conditioning prior allogeneic stemcell transplantation.
  • Psychiatric illness that would prevent granting of informed consent.
  • Treatment with androgenic hormones during the previous 14 days prior Day 1.
  • Active viral infection with known human immunodeficiency virus (HIV) or viral Hepatitis B or C.
  • Hypersensitivity to Mannitol or 5-Azacitidine.
  • Treatment with other investigational drugs following relapse after allogeneic stemcell transplantation or ongoing adverse events from previous treatment with investigational drugs regardless of time period.

Sites / Locations

  • Universitaetsklinik Heidelberg, Medizinische Klinik und Poliklinik V
  • Klinikum der Johann-Wolfgang-Goethe Universität, Medizinische Klinik II
  • Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf
  • Universitaetsklinikum Dresden, Medizinische Klinik und Poliklinik I
  • Charite´-Campus Benjamin Franklin, Medizinische Klinik III
  • Bone Marrow Transplantation Unit, University Hospital Hamburg-Eppendorf

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

5-Azacitidine

Arm Description

5-Azacitidine in addition to standard donor lymphocyte infusions.

Outcomes

Primary Outcome Measures

Best response

Secondary Outcome Measures

Safety and Toxicity of 5-Azacitidine for patients relapsing after allo-SCT
Response rate
Duration of remissions
Incidence of acute and chronic GvHD
Achievement of complete chimerism
Toxicity

Full Information

First Posted
November 20, 2008
Last Updated
January 20, 2012
Sponsor
Heinrich-Heine University, Duesseldorf
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1. Study Identification

Unique Protocol Identification Number
NCT00795548
Brief Title
Safety Study of 5-Azacitidine and Standard Donor Lymphocyte Infusion (DLI) to Treat Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Relapsing After Allogeneic Stem Cell Transplantation
Official Title
Phase-II Trial to Assess the Efficacy and Toxicity of 5-Azacitidine in Addition to Standard DLI for the Treatment of Patients With AML or MDS Relapsing After Allogeneic Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
January 2012
Overall Recruitment Status
Completed
Study Start Date
November 2008 (undefined)
Primary Completion Date
October 2010 (Actual)
Study Completion Date
August 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Heinrich-Heine University, Duesseldorf

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This open label phase-II trial evaluates hematological response of an additional treatment with 5-Azacitidine to common DLI in patients with MDS or AML relapsing after allogeneic stem cell transplantation.
Detailed Description
Relapse after allogeneic stem cell transplantation is a major problem in patients with poor prognosis AML or MDS. Donor lymphocyte infusions alone re-induce remission in a minority of these patients, which may be the result of poor differentiation of the leukemic cells. The study drug 5-Aza is effective in AML and MDS.In addition to direct cytotoxicity, it alters gene expression and induces differentiation of leukemic blast cells. Furthermore, DNA-demethylating treatment results in an induction of transcription and cell surface expression of formerly unexpressed KIRs (killer Ig-like receptors) in NK cells, which are involved in the specific recognition of leukemic target cells and who are able to generate a specific graft-versus leukemia effect. The increased expression of MHC class I and II molecules on the surface of the recipient's leukemic cells and the de novo expression of formerly silenced KIR genes in donor NK cells due to treatment with 5-Aza may result in an increased susceptibility of myeloid leukemic cells to the allogeneic graft versus leukemia effect. Therefore, the graft-versus leukemia effect by donor lymphocyte infusions and NK cells from the original donor may be supported by additional therapy with 5-Azacitidine.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndrome, Acute Myeloid Leukemia
Keywords
Myelodysplastic syndrome (MDS), Acute myeloid leukemia (AML), Stem cell transplantation, 5-Azacitidine, Donor lymphocyte infusion, MDS or AML relapsed after stem cell transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
5-Azacitidine
Arm Type
Experimental
Arm Description
5-Azacitidine in addition to standard donor lymphocyte infusions.
Intervention Type
Drug
Intervention Name(s)
5-Azacitidine
Other Intervention Name(s)
Vidaza
Intervention Description
5-Aza will be administered at doses of 100mg/m2 via subcutaneous injection over a period of 5 days. The total amount per treatment cycle, consisting of 5 days, is 500mg/m². Each treatment cycle is repeated every 28 days, with a treatment pause of 23 days between each 5-Aza cycle, to a total of 6 (optional 8 cycles) cycles. DLI will be transfused on day +34 with a total count of CD3+ cells of DLI 1-5x10E6CD3+/kg bodyweight. In absence of GvHD DLI transfusion is repeated on day +90 with DLI 1-5x10E7CD3+/kg bodyweight and on day +142 with DLI 1-5x10E8CD3+/kg bodyweight. Additional DLI may be given.
Primary Outcome Measure Information:
Title
Best response
Time Frame
within the 6 months of treatment
Secondary Outcome Measure Information:
Title
Safety and Toxicity of 5-Azacitidine for patients relapsing after allo-SCT
Time Frame
within 3 years
Title
Response rate
Time Frame
within 6 months
Title
Duration of remissions
Time Frame
within 3 years
Title
Incidence of acute and chronic GvHD
Time Frame
3 years
Title
Achievement of complete chimerism
Time Frame
6 month
Title
Toxicity
Time Frame
wtihin 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: - Primary and secondary MDS, AML after MDS, and de novo AML relapsing after allogeneic stem cell transplantation Eligibility for Donor Lymphocyte Infusions Performance status according to the WHO scale: 0, 1 or 2. Adequate renal and liver function: bilirubin < 1.5 times the upper limit of normal and a GFR > 50 ml/min Absence of severe cardiovascular disease, i.e., arrhythmias requiring chronic treatment, congestive heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease, where New-York Heart Association (NYHA) HIV negative and HBs-Ag negative. Absence of active uncontrolled infection (Septicaemia). No prior history or current evidence of central nervous system and psychiatric disorders requiring hospitalization. Age at least 18 years. Negative pregnancy test for women with reproductive potential. Signed written informed consent must be given according to national/local regulations. Exclusion Criteria: - Have malignant hepatic tumors. Severe liver dysfunction CHILD B and C. Renal insufficiency with a GFR < 50 ml/min Radiation therapy, chemotherapy, or cytotoxic therapy, given to treat conditions other than MDS, AML or applied for conditioning prior allogeneic stemcell transplantation. Psychiatric illness that would prevent granting of informed consent. Treatment with androgenic hormones during the previous 14 days prior Day 1. Active viral infection with known human immunodeficiency virus (HIV) or viral Hepatitis B or C. Hypersensitivity to Mannitol or 5-Azacitidine. Treatment with other investigational drugs following relapse after allogeneic stemcell transplantation or ongoing adverse events from previous treatment with investigational drugs regardless of time period.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guido Kobbe, PD Dr.
Organizational Affiliation
Department of Hematology, Oncology and Clinical Immunology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universitaetsklinik Heidelberg, Medizinische Klinik und Poliklinik V
City
Heidelberg
State/Province
Baden-Wuertemberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Klinikum der Johann-Wolfgang-Goethe Universität, Medizinische Klinik II
City
Frankfurt
State/Province
Hessen
ZIP/Postal Code
60590
Country
Germany
Facility Name
Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf
City
Duesseldorf
State/Province
NW
ZIP/Postal Code
40225
Country
Germany
Facility Name
Universitaetsklinikum Dresden, Medizinische Klinik und Poliklinik I
City
Dresden
State/Province
Sachsen
ZIP/Postal Code
01307
Country
Germany
Facility Name
Charite´-Campus Benjamin Franklin, Medizinische Klinik III
City
Berlin
ZIP/Postal Code
01220
Country
Germany
Facility Name
Bone Marrow Transplantation Unit, University Hospital Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany

12. IPD Sharing Statement

Learn more about this trial

Safety Study of 5-Azacitidine and Standard Donor Lymphocyte Infusion (DLI) to Treat Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Relapsing After Allogeneic Stem Cell Transplantation

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