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Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Leukemia (AML/MDS/JMML)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01020539
First Posted: November 25, 2009
Last Update Posted: July 27, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Columbia University
  Purpose
Allogeneic stem cell transplantation (AlloSCT) followed by targeted immune therapy Gemtuzumab Ozogamicin patients with acute myeloid leukemia (AML)/juvenile myelomonocytic leukemia (JMML)/myelodysplastic syndromes (MDS) will be safe and well tolerated.

Condition Intervention Phase
Acute Myelogenous Leukemia Myelodysplastic Syndrome Juvenile Myelomonocytic Leukemia Drug: Fludarabine Drug: Busulfan Drug: GVHD Prophylaxis Drug: Gemtuzumab Ozogamicin Drug: Anti-Thymocyte Globulin Drug: Isotretinoin Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Acute Myelogenous Leukemia/Myelodysplastic Syndrome/Juvenile Myelomonocytic Leukemia (AML/MDS/JMML)

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • Maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO) [ Time Frame: Up to 2 years ]
    To determine the maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO) (anti CD33 immunotoxin) therapy following reduced intensity (RI) allogeneic stem cell transplantation (alloSCT) in patients with average risk AML/JMML/MDS.


Secondary Outcome Measures:
  • Change of minimal residual disease [ Time Frame: Day 60, Day 100, Day 180, 1 year, 2 years ]
    To measure the changes, if applicable, of minimal residual disease prior to and after consolidation therapy with targeted immunotherapy in average risk AML/JMML/MDS post RI AlloSCT.

  • Incidence of minor histocompatibility antigen (MHA) expression on acute myeloid leukemia (AML) tissue [ Time Frame: Up to 2 years ]
    To measure the minor histocompatibility antigen expression on AML tissue, donor and recipient, and the incidence of development of MHA specific cytotoxic T-lymphocytes (CTLs).

  • Degree of mixed/complete donor chimerism [ Time Frame: Up to 2 years ]
    To determine the degree of mixed/complete donor chimerism after RI AlloSCT in patients with average risk AML/JMML/MDS.

  • Event free survival (EFS) rate [ Time Frame: Up to 2 years ]
    To determine event free survival (EFS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS.

  • Overall survival (OS) rate [ Time Frame: Up to 2 years ]
    To determine overall survival (OS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS.


Enrollment: 18
Actual Study Start Date: September 11, 2002
Estimated Study Completion Date: March 2018
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Matched Family Donor

Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from a related family donor using bone marrow or cord blood stem cells. Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin).

During and following transplantation patients will receive methylprednisolone for immune suppression. Graft-versus-host-disease (GVHD) prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants.

Drug: Fludarabine
Conditioning Regimen
Other Name: Fludara®
Drug: Busulfan
Conditioning Regimen
Other Name: Busulfex®
Drug: GVHD Prophylaxis
Can be FK506 (Tacrolimus/Prograf®), mycophenolate mofetil ((MMF)/Cellcept®), or methotrexate (MTX, amethopterin)
Drug: Gemtuzumab Ozogamicin
Dose Escalation
Other Name: Mylotarg®
Experimental: Unrelated Donor

Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from an unrelated donor using matched bone marrow or cord blood stem cells.Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin).

During and following transplantation patients will receive methylprednisolone for immune suppression and unrelated donor transplant recipients will additionally receive Anti-Thymocyte Globulin. GVHD prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants.

Drug: Anti-Thymocyte Globulin
Unrelated Donors only
Other Name: Thymoglobulin®
Drug: Isotretinoin
JMML patients only
Other Names:
  • Accutane®
  • 13-cis-Retinoic Acid (cis-RA)

Detailed Description:
Gemtuzumab Ozogamicin (CMA-676) is a chemotherapeutic agent consisting of a recombinant humanized anti-CD33 antibody conjugated with calicheamicin, a highly potent cytotoxic antitumor antibiotic. The antibody portion of Gemtuzumab binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein expressed on the surface of leukemic blasts, normal and leukemic myeloid colony-forming cells, including leukemic clonogenic precursors, but excluding pluripotent hematopoietic stem cells and nonhematopoietic cells. This results in formation of a complex that is internalized, upon which the calicheamicin derivative is released within the lysosomes of the myeloid cell. The free calicheamicin derivative then binds to deoxyribonucleic acid (DNA), resulting in DNA double strand breaks and consequential cell death. Over 80% of AML patients possess myeloid blast cells with CD33 surface antigen expression.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Disease Status

  • AML 1st complete remission (CR) with a matched family donor (excluding Downs Syndrome, acute promyelocytic leukaemia (APL), poor cytogenetics (12p, 5q, -7 and FMS-like tyrosine kinase-3 (FLT3) mutations or duplication t(9;11) and others)) and patients consented to and registered on an upfront AML COG study with a matched family donor)
  • AML 1st CR (excluding Downs Syndrome, APL, and chromosome translocation (8;21) or inversion (16) or poor cytogenetics (12p, 5q, -7, FLT3 mutation or duplication t(9;11) and others)) with unrelated donor
  • AML 2nd CR
  • Myelodysplastic Syndrome (MDS) and ≤ 5% bone marrow myeloblasts at diagnosis (de novo patients only)
  • Juvenile Myelomonocytic Leukemia (JMML) and ≤ 5% bone marrow myeloblasts at diagnosis

In regards to disease immunophenotype, disease must express a minimum of ≥10% CD33 positivity for patients with AML

Organ Function:

Patients must have adequate organ function as defined below:

Adequate renal function defined as:

  • Serum creatinine < 1.5 x normal, or
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) 40 ml/min/m2 or > 60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range

Adequate liver function defined as total bilirubin 2.0 x upper limit of normal (ULN), or serum glutamic-oxaloacetic transaminase (SGOT)(aspartate aminotransferase (AST)) or serum glutamic-pyruvic transaminase (SGPT)(alanine aminotransferase (ALT)) < 5.0 x ULN

Adequate cardiac function defined as:

  • Shortening fraction of ≥ 25% by echocardiogram, or
  • Ejection fraction of ≥ 45% by radionuclide angiogram or echocardiogram

Adequate pulmonary function defined as:

  • Diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 40% by pulmonary function tests (PFT) (Uncorrected)
  • For children who are uncooperative, no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% on room air

Exclusion Criteria:

  • Patients with active central nervous system (CNS) AML/JMML disease at time of preparative regimen
  • Secondary MDS
  • Poor cytogenetics (12p, 5q, -7, FLT3 mutation or duplication)
  • Female patients who are pregnant (positive human chorionic gonadotropin(hCG))
  • Karnofsky <70% or Lansky <50% if 10 years or less
  • Age >30 years
  • Seropositive for Human Immunodeficiency Virus (HIV)
  • Patients consented to and registered on an upfront Children's Oncology Group (COG) AML study with a matched family donor
  Contacts and Locations
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): NCT01020539


Locations
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
Sponsors and Collaborators
Columbia University
Investigators
Principal Investigator: Monica Bhatia, MD Columbia University
  More Information

Additional Information:
Responsible Party: Columbia University
ClinicalTrials.gov Identifier: NCT01020539     History of Changes
Other Study ID Numbers: AAAA6378
CHNY-504 ( Other Identifier: CU )
First Submitted: November 23, 2009
First Posted: November 25, 2009
Last Update Posted: July 27, 2017
Last Verified: July 2017

Keywords provided by Columbia University:
Allogeneic Stem Cell Transplantation
Targeted Immune Therapy
Acute Myelogenous Leukemia
Myelodysplastic Syndrome
Juvenile Myelomonocytic Leukemia
AML
MDS
JMML

Additional relevant MeSH terms:
Syndrome
Leukemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Juvenile
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Methotrexate
Fludarabine phosphate
Tretinoin
Isotretinoin
Tacrolimus
Mycophenolate mofetil
Mycophenolic Acid
Busulfan
Antilymphocyte Serum
Fludarabine
Gemtuzumab
Methylprednisolone
Abortifacient Agents, Nonsteroidal