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

August 4, 2021 updated by: Monica Bhatia, Columbia University

Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Acute Myelogenous Leukemia/Myelodysplastic Syndrome/Juvenile Myelomonocytic Leukemia (AML/MDS/JMML)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 month to 30 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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% Cell Differential 33 (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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • Fludara®
Drug: Busulfan
Conditioning Regimen
Other Names:
  • Busulfex®
Drug: GVHD Prophylaxis
Can be FK506 (Tacrolimus/Prograf®), mycophenolate mofetil ((MMF)/Cellcept®), or methotrexate (MTX, amethopterin)
Drug: Gemtuzumab Ozogamicin
Dose Escalation
Other Names:
  • 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 Names:
  • Thymoglobulin®
Drug: Isotretinoin
JMML patients only
Other Names:
  • Accutane®
  • 13-cis-Retinoic Acid (cis-RA)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Up to 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Day 60, Day 100, Day 180, 1 year, 2 years
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).
Up to 2 years
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.
Up to 2 years
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.
Up to 2 years
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.
Up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Columbia University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 11, 2002

Primary Completion (Actual)

July 20, 2011

Study Completion (Actual)

December 1, 2020

Study Registration Dates

First Submitted

November 23, 2009

First Submitted That Met QC Criteria

November 23, 2009

First Posted (Estimate)

November 25, 2009

Study Record Updates

Last Update Posted (Actual)

August 6, 2021

Last Update Submitted That Met QC Criteria

August 4, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AAAA6378
  • CHNY-504 (Other Identifier: CU)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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