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

Primary Purpose

Acute Myelogenous Leukemia, Myelodysplastic Syndrome, Juvenile Myelomonocytic Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Fludarabine

Busulfan

GVHD Prophylaxis

Gemtuzumab Ozogamicin

Anti-Thymocyte Globulin

Isotretinoin

About this trial

This is an interventional treatment trial for Acute Myelogenous Leukemia focused on measuring Allogeneic Stem Cell Transplantation, Targeted Immune Therapy, Acute Myelogenous Leukemia, Myelodysplastic Syndrome, Juvenile Myelomonocytic Leukemia, AML, MDS, JMML

Eligibility Criteria

1 Month - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Columbia University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Matched Family Donor

Unrelated Donor

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO)

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

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

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

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

To determine event free survival (EFS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS.

Overall survival (OS) rate

To determine overall survival (OS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS.

Full Information

NCT ID

NCT01020539

First Posted

November 23, 2009

Last Updated

August 4, 2021

Sponsor

Columbia University

1. Study Identification

Unique Protocol Identification Number

NCT01020539

Brief Title

Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Leukemia

Acronym

AML/MDS/JMML

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)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Completed

Study Start Date

September 11, 2002 (Actual)

Primary Completion Date

July 20, 2011 (Actual)

Study Completion Date

December 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Columbia University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myelogenous Leukemia, Myelodysplastic Syndrome, Juvenile Myelomonocytic Leukemia

Keywords

Allogeneic Stem Cell Transplantation, Targeted Immune Therapy, Acute Myelogenous Leukemia, Myelodysplastic Syndrome, Juvenile Myelomonocytic Leukemia, AML, MDS, JMML

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Matched Family Donor

Arm Type

Experimental

Arm Description

Arm Title

Unrelated Donor

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara®

Intervention Description

Conditioning Regimen

Intervention Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

Busulfex®

Intervention Description

Conditioning Regimen

Intervention Type

Drug

Intervention Name(s)

GVHD Prophylaxis

Intervention Description

Can be FK506 (Tacrolimus/Prograf®), mycophenolate mofetil ((MMF)/Cellcept®), or methotrexate (MTX, amethopterin)

Intervention Type

Drug

Intervention Name(s)

Gemtuzumab Ozogamicin

Other Intervention Name(s)

Mylotarg®

Intervention Description

Dose Escalation

Intervention Type

Drug

Intervention Name(s)

Anti-Thymocyte Globulin

Other Intervention Name(s)

Thymoglobulin®

Intervention Description

Unrelated Donors only

Intervention Type

Drug

Intervention Name(s)

Isotretinoin

Other Intervention Name(s)

Accutane®, 13-cis-Retinoic Acid (cis-RA)

Intervention Description

JMML patients only

Primary Outcome Measure Information:

Title

Maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO)

Description

Time Frame

Up to 2 years

Secondary Outcome Measure Information:

Title

Change of minimal residual disease

Description

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.

Time Frame

Day 60, Day 100, Day 180, 1 year, 2 years

Title

Incidence of minor histocompatibility antigen (MHA) expression on acute myeloid leukemia (AML) tissue

Description

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).

Time Frame

Up to 2 years

Title

Degree of mixed/complete donor chimerism

Description

To determine the degree of mixed/complete donor chimerism after RI AlloSCT in patients with average risk AML/JMML/MDS.

Time Frame

Up to 2 years

Title

Event free survival (EFS) rate

Description

To determine event free survival (EFS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS.

Time Frame

Up to 2 years

Title

Overall survival (OS) rate

Description

To determine overall survival (OS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS.

Time Frame

Up to 2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Month

Maximum Age & Unit of Time

30 Years

Accepts Healthy Volunteers

Eligibility 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% 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Monica Bhatia, MD

Organizational Affiliation

Columbia University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Columbia University Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Leukemia

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