Allogenic Stem Cell Transplantation in Patients With High Risk CD33+ AML/MDS/JMML

Study Overview
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Brief Summary
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The addition of gemtuzumab ozogamicin (GO) in combination with Busulfan/Cyclophosphamide followed by AlloSCT in patients with high risk CD33+ AML/JMML/MDS will be safe and well tolerated. This study will attempt to determine the maximum tolerated dose of the immune therapy (gemtuzumab) when given in combination with the myeloablative (high dose) drugs used in this study for allogeneic stem cell transplant. (Part A)

Detailed Description
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Gemtuzumab Ozogamicin (CMA-676) is a chemotherapeutic agent consisting of 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 leukemia 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 the complex that is internalized, upon which calicheamicin derivative is released with in the lysosomes of the myeloid cell. The free calicheamicin derivative then binds to the DNA, resulting in DNA double strand breaks and consequential cell death.

Official Title
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Gemtuzumab Ozogamicin in Combination With Busulfan and Cyclophosphamid and Allogenic Stem Cell Transplantation in Patients With High Risk CD33+ Acute Myelogenous Leukemia/Myelodysplastic Syndrome/Juvenile Myelomonocytic Leukemia

Conditions
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Acute Myeloid Leukemia, Juvenile Myelomonocytic Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Gemtuzumab Ozogamicin
* Drug: Busulfan
* Drug: Cyclophosphamide
* Drug: Thymoglobulin
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Eligibility Inclusion Criteria: Disease Status AML Induction Failure AML in 1st, 2nd, or 3rd Relapse (>10% bone marrow blasts) AML greater than or equal to 3rd CR MDS with >6% bone marrow blasts at diagnosis Secondary MDS with less than or equal to 5% bone marrow myeloblasts at diagnosis JMML with >6% bone marrow myeloblasts at diagnosis Disease Immunophenotype Patients (AML only) receiving gemtuzumab ozogamicin must express minimum of >10% or =10% CD33 positivity. Patients with <10% CD33 positivity will not receive gemtuzumab ozogamicin. 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 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 1.5 x normal, or SGOT (AST) or SGPT (ALT) <2.0 x normal or =2.0 x normal Adequate cardiac function defined as: Shortening fraction of >27% by echocardiogram, or Ejection fraction of >47% by radionuclide angiogram or echocardiogram Adequate pulmonary function defined as: DLCO >55% or =55% by PFT 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 CNS AML/JMML/MDS disease at time of conditioning therapy Female patients who are pregnant (positive HCG) Karnofsky <50% or Lansky <50% if 10 years or less Age >65 years Has received gemtuzumab in the previous 30 days or has not recovered from prior gemtuzumab therapy.

Ages Eligible for Study
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Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: study 515<br> | Drug: Gemtuzumab Ozogamicin<br>* Dose Escalation<br>* Other names: Gemtuzumab;Drug: Busulfan<br>* Conditioning Regimen<br>* Other names: Busulfex;Drug: Cyclophosphamide<br>* Conditioning Regimen<br>* Other names: Cytoxan;Drug: Thymoglobulin<br>* (Unrelated Donors only)<br>* Other names: ATG;Drug: Tacrolimus<br>* GVHD Prophylaxis<br>* Other names: FK506;Drug: Mycophenolate Mofetil<br>* GVHD Prophylaxis<br>* Other names: MMF;Drug: Methotrexate<br>* GVHD Prophylaxis<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal tolerated dose or tolerable dose of Gemtuzumab Ozogamicin (anti-CD33 immunotoxin) therapy combined with Busulfan/ Cyclophosphamide in the conditioning regimen prior to AlloSCT in patients with high risk CD33+ AML/JMML/MDS |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes, if applicable, of minimal residual disease (cytogenetics, FISH, RT-PCR) in patients with high risk CD33+ AML/JMML/MDS after AlloSCT. |  | 1 year | 
| Progression Free Survival (PFS), overall survival (OS), and disease free survival (DFS), (if applicable), following GO, Bu/CY and AlloSCT in patients with high risk CD33+ AML/JMML/MDS. |  | 1 year | 
| Quality of life before and after GO, Bu/CY conditioning and AlloSCT in patients with high risk CD33+ AML/JMML/MDS |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, JMML, MDS, Allogenic Atem Cell Transplant, Gemtuzumab Ozogamicin