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 - Full Text View

Sponsored by:	Heinrich-Heine University, Duesseldorf
Information provided by:	Heinrich-Heine University, Duesseldorf
ClinicalTrials.gov Identifier:	NCT00795548

Purpose

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.

Condition	Intervention	Phase
Myelodysplastic Syndrome Acute Myeloid Leukemia	Drug: 5-Azacitidine	Phase II

MedlinePlus related topics: Leukemia, Adult Acute Leukemia, Adult Chronic

Drug Information available for: Azacitidine

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
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

Further study details as provided by Heinrich-Heine University, Duesseldorf:

Primary Outcome Measures:

Best response [ Time Frame: within the 6 months of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Safety and Toxicity of 5-Azacitidine for patients relapsing after allo-SCT [ Time Frame: within 3 years ] [ Designated as safety issue: Yes ]
Response rate [ Time Frame: within 6 months ] [ Designated as safety issue: No ]
Duration of remissions [ Time Frame: within 3 years ] [ Designated as safety issue: No ]
Incidence of acute and chronic GvHD [ Designated as safety issue: Yes ]
Achievement of complete chimerism [ Designated as safety issue: No ]
Toxicity [ Time Frame: wtihin 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	30
Study Start Date:	November 2008
Estimated Study Completion Date:	December 2013
Estimated Primary Completion Date:	November 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
5-Azacitidine: Experimental 5-Azacitidine in addition to standard donor lymphocyte infusions.	Drug: 5-Azacitidine 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.

Arms

Assigned Interventions

5-Azacitidine: Experimental

5-Azacitidine in addition to standard donor lymphocyte infusions.

Drug: 5-Azacitidine

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.

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00795548

Contacts

Contact: Guido Kobbe, PD Dr.	0049-211-8117720	Kobbe@med.uni-duesseldorf.de
Contact: Akos Czibere, Dr.	0049-211-8117720	Akos.Czibere@med.uni-duesseldorf.de

Locations

Germany
Bone Marrow Transplantation Unit, University Hospital Hamburg-Eppendorf	Not yet recruiting
Hamburg, Germany, 20246
Contact: Nikolaus Kroeger, Prof.Dr. 0049-40-428035864
Principal Investigator: Nikolaus Kroeger, Prof. Dr.
Germany, NW
Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf	Recruiting
Duesseldorf, NW, Germany, 40225
Contact: Guido Kobbe, PD Dr. 0049-211-8117720 Kobbe@med.uni-duesseldorf.de
Contact: Akos Czibere, Dr. 0049-211-8117720 Akos.Czibere@med.uni-duesseldorf.de
Principal Investigator: Guido Kobbe, PD Dr.
Sub-Investigator: Akos Czibere, Dr.

Sponsors and Collaborators

Heinrich-Heine University, Duesseldorf

Investigators

Principal Investigator:

Guido Kobbe, PD Dr.

Department of Hematology, Oncology and Clinical Immunology

More Information

Responsible Party:	Heinrich-Heine University, Duesseldorf, Dep.of Hematology, Oncology, Clinical Immunology ( Heinrich-Heine University represented by Coordinating Investigator PD Dr. Guido Kobbe )
Study ID Numbers:	AZARELA_HHU_2007
Study First Received:	November 20, 2008
Last Updated:	November 20, 2008
ClinicalTrials.gov Identifier:	NCT00795548
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Heinrich-Heine University, Duesseldorf:

Myelodysplastic syndrome (MDS)
Acute myeloid leukemia (AML)
Stem cell transplantation

5-Azacitidine
Donor lymphocyte infusion
MDS or AML relapsed after stem cell transplantation

Study placed in the following topic categories:

Myelodysplastic syndromes
Precancerous Conditions
Hematologic Diseases
Myelodysplastic Syndromes
Myelodysplasia
Acute myelogenous leukemia
Leukemia, Myeloid

Leukemia, Myeloid, Acute
Leukemia
Preleukemia
Azacitidine
Bone Marrow Diseases
Acute myelocytic leukemia

Additional relevant MeSH terms:

Antimetabolites
Neoplasms
Antimetabolites, Antineoplastic
Pathologic Processes
Disease
Neoplasms by Histologic Type

Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Syndrome
Enzyme Inhibitors
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 10, 2009