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Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases

Primary Purpose

Bone Marrow Failure, Osteopetrosis, Fanconi Anemia

Status
Unknown status
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Fludarabine
Cyclophosphamide
Cyclophosphamide 40
Cyclophosphamide 30
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bone Marrow Failure focused on measuring Bone marrow Failure, Fanconi, SCID

Eligibility Criteria

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

Inclusion Criteria

  • Patients must meet the eligibility criteria for organ function regardless of diagnosis:

    • Age < 30 or = 30 years of age
    • Adequate renal function defined as serum creatinine < or = 1.5 x normal, or creatinine clearance or radioisotope GFR > or =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 SGOT (AST) or SGPT (ALT) < 5.0 x normal
  • Adequate cardiac function defined as shortening fraction of > or = 28% by echocardiogram, or ejection fraction of > or = 48% by radionuclide angiogram or echocardiogram
  • Adequate pulmonary function defined as asymptomatic or, if symptomatic, DLCO >45% of predicted (corrected for hemoglobin level). If unable to obtain pulmonary function test, O2 saturation >85% in room air.

Bone Marrow Failure Syndromes

Patients with the following diagnoses are eligible:

Severe Aplastic Anemia:

  • Hypocellular bone marrow biopsy (<25% cellularity) and 2/3 of the following (at diagnosis or nadir):
  • Absolute Neutrophil Count (ANC) <200/mm3,
  • Platelets <20,000/mm3
  • Reticulocyte count <60,000/mm3

Fanconi Anemia:

  • Abnormal clastogenic studies (all patients)
  • Severe Congenital Neutropenia (Kostmann's Syndrome)
  • Amegakaryocytic Thrombocytopenia
  • Severe thrombocytopenia (< or =20,000/mm3) at diagnosis
  • Severe depletion of megakaryocytes on bone marrow aspirate (< or =25% normal)

Diamond-Blackfan Anemia:

  • Corticosteroid dependent for > 6 months OR Transfusion dependent OR refractory acquired pure red cell aplasia.
  • Infantile Osteopetrosis
  • Schwachman-Diamond Syndrome
  • Dyskeratosis Congenita

Other bone marrow failure syndromes at discretion of co-principal investigators

  • Immunodeficiencies
  • SCIDS, all subtypes
  • Combined Immunodeficiency Syndrome
  • Wiskott-Aldrich Syndrome
  • Chronic Granulomatous Disease
  • Chediak-Higashi Syndrome
  • Leukocyte Adhesion Deficiency
  • Other immunodeficiencies at discretion of co-principal investigators
  • Inborn Errors of Metabolism (IEOM)

Transplant is recommended for the following disorders:

  • Hurler syndrome (alpha-L-iduronidase deficiency, MPS-I), preferably before age 24 months
  • Maroteaux-Lamy syndrome (galactosamine-4-sulfatase deficiency,MPSVI)
  • Sly syndrome (beta-glucuronidase deficiency, MPS-VII)
  • Globoid cell leukodystrophy (galactocerebrosidase deficiency), with careful attention to neurologic status in the infantile form
  • Metachromatic leukodystrophy (arylsulfatase A deficiency),juvenile or adult onset form; late infantile MLD only if pre-symptomatic
  • Childhood-onset X-linked adrenoleukodystrophy (X-ALD), at initial signs of neuropsychological deterioration, with dietary modification prior to transplant
  • Fucosidosis (fucosidase deficiency)
  • Mannosidosis
  • Aspartylglucosaminuria
  • Niemann-Pick Disease Type B (acid sphingomyelinase deficiency) Other diagnoses may be considered at the discretion of the co-principal investigators
  • For X-ALD patients greater than 5 years of age, IQ >80 is required. For other patients greater than 5 years of age, IQ > 70 is required.
  • For Gaucher disease (glucocerebrosidase deficiency) Type I (non-neuropathic), the primary therapy is enzyme replacement, but allogeneic stem cell transplant has been used effectively.
  • Histiocytoses

    • Hemophagocytic Lymphohistiocytosis (HLH)
    • Familial Erythrophagocytic Lymphohistiocytosis
    • Langerhans Cell Histiocytosis Patients with multi-system disease whose initial disease is stable or progressive after minimum 6 weeks of appropriate therapy, OR Patients with recurrent multi-system disease.
    • Malignant Histiocytosis
  • Other non-malignant diseases not listed above may be eligible if deemed appropriate by the co-principal investigators.

Sites / Locations

  • Columbia University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Fludarabine

Cyclohosphamide 200

Cyclophosphamide 40

Cyclophosphamide 30

Arm Description

Outcomes

Primary Outcome Measures

This study is to determine the toxicity of administering a fludarabine/cyclophosphamide (Flu/CY) or busulfan (Bu)/Flu based conditioning regimen followed by allogeneic stem cell transplant.

Secondary Outcome Measures

To determine the risk of disease progression (including neuropsychological deterioration in patients with metabolic non-malignant diseases) following a Flu/CY or Bu/Flu based conditioning regimen.
To measure immune reconstitution following a Flu/CY or Bu/Flu based conditioning regimen and AlloSCT in patients with selected non-malignant diseases.
To estimate the incidence and severity of GVHD following a Flu/Cy or Bu/Flu based conditioning regimen
To determine metabolic/immune (gene/protein) reconstitution by standard biochemical/PCR assays in patients

Full Information

First Posted
November 23, 2009
Last Updated
October 18, 2011
Sponsor
Columbia University
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1. Study Identification

Unique Protocol Identification Number
NCT01019876
Brief Title
Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
Official Title
Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Selected Non-Malignant Diseases
Study Type
Interventional

2. Study Status

Record Verification Date
October 2011
Overall Recruitment Status
Unknown status
Study Start Date
June 2002 (undefined)
Primary Completion Date
May 2012 (Anticipated)
Study Completion Date
May 2013 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Columbia University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Reduced intensity conditioning followed by allogeneic stem cell transplantation will result in mixed/complete donor chimerism and potentially alter the natural history and outcome of patients with non-malignant diseases.
Detailed Description
This study is to determine the toxicity of administering a fludarabine/cyclophosphamide (Flu/CY) or busulfan (Bu)/Flu based conditioning regimen followed by allogeneic stem cell transplant (AlloSCT) in patients with non-malignant diseases.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bone Marrow Failure, Osteopetrosis, Fanconi Anemia, Severe Combined Immunodeficiency
Keywords
Bone marrow Failure, Fanconi, SCID

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Fludarabine
Arm Type
Experimental
Arm Title
Cyclohosphamide 200
Arm Type
Experimental
Arm Title
Cyclophosphamide 40
Arm Type
Experimental
Arm Title
Cyclophosphamide 30
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
Fludarabine/Busulfan/Alemtuzumab
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide/Fludarabine/TMG
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide 40
Other Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide/Fludarabine/ATG/TBI
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide 30
Other Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide /Fludarabine/TMG
Primary Outcome Measure Information:
Title
This study is to determine the toxicity of administering a fludarabine/cyclophosphamide (Flu/CY) or busulfan (Bu)/Flu based conditioning regimen followed by allogeneic stem cell transplant.
Time Frame
Day 30, Day 60, Day 100, 1 year, 2 years
Secondary Outcome Measure Information:
Title
To determine the risk of disease progression (including neuropsychological deterioration in patients with metabolic non-malignant diseases) following a Flu/CY or Bu/Flu based conditioning regimen.
Time Frame
Day 30, Day 60, Day 100, 1 year
Title
To measure immune reconstitution following a Flu/CY or Bu/Flu based conditioning regimen and AlloSCT in patients with selected non-malignant diseases.
Time Frame
Day 30, Day 60, Day 100, 1 year
Title
To estimate the incidence and severity of GVHD following a Flu/Cy or Bu/Flu based conditioning regimen
Time Frame
Day 30, Day 60, Day 100, 1 year
Title
To determine metabolic/immune (gene/protein) reconstitution by standard biochemical/PCR assays in patients
Time Frame
Day 30, Day 60, Day 100, 1 year

10. Eligibility

Sex
All
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Patients must meet the eligibility criteria for organ function regardless of diagnosis: Age < 30 or = 30 years of age Adequate renal function defined as serum creatinine < or = 1.5 x normal, or creatinine clearance or radioisotope GFR > or =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 SGOT (AST) or SGPT (ALT) < 5.0 x normal Adequate cardiac function defined as shortening fraction of > or = 28% by echocardiogram, or ejection fraction of > or = 48% by radionuclide angiogram or echocardiogram Adequate pulmonary function defined as asymptomatic or, if symptomatic, DLCO >45% of predicted (corrected for hemoglobin level). If unable to obtain pulmonary function test, O2 saturation >85% in room air. Bone Marrow Failure Syndromes Patients with the following diagnoses are eligible: Severe Aplastic Anemia: Hypocellular bone marrow biopsy (<25% cellularity) and 2/3 of the following (at diagnosis or nadir): Absolute Neutrophil Count (ANC) <200/mm3, Platelets <20,000/mm3 Reticulocyte count <60,000/mm3 Fanconi Anemia: Abnormal clastogenic studies (all patients) Severe Congenital Neutropenia (Kostmann's Syndrome) Amegakaryocytic Thrombocytopenia Severe thrombocytopenia (< or =20,000/mm3) at diagnosis Severe depletion of megakaryocytes on bone marrow aspirate (< or =25% normal) Diamond-Blackfan Anemia: Corticosteroid dependent for > 6 months OR Transfusion dependent OR refractory acquired pure red cell aplasia. Infantile Osteopetrosis Schwachman-Diamond Syndrome Dyskeratosis Congenita Other bone marrow failure syndromes at discretion of co-principal investigators Immunodeficiencies SCIDS, all subtypes Combined Immunodeficiency Syndrome Wiskott-Aldrich Syndrome Chronic Granulomatous Disease Chediak-Higashi Syndrome Leukocyte Adhesion Deficiency Other immunodeficiencies at discretion of co-principal investigators Inborn Errors of Metabolism (IEOM) Transplant is recommended for the following disorders: Hurler syndrome (alpha-L-iduronidase deficiency, MPS-I), preferably before age 24 months Maroteaux-Lamy syndrome (galactosamine-4-sulfatase deficiency,MPSVI) Sly syndrome (beta-glucuronidase deficiency, MPS-VII) Globoid cell leukodystrophy (galactocerebrosidase deficiency), with careful attention to neurologic status in the infantile form Metachromatic leukodystrophy (arylsulfatase A deficiency),juvenile or adult onset form; late infantile MLD only if pre-symptomatic Childhood-onset X-linked adrenoleukodystrophy (X-ALD), at initial signs of neuropsychological deterioration, with dietary modification prior to transplant Fucosidosis (fucosidase deficiency) Mannosidosis Aspartylglucosaminuria Niemann-Pick Disease Type B (acid sphingomyelinase deficiency) Other diagnoses may be considered at the discretion of the co-principal investigators For X-ALD patients greater than 5 years of age, IQ >80 is required. For other patients greater than 5 years of age, IQ > 70 is required. For Gaucher disease (glucocerebrosidase deficiency) Type I (non-neuropathic), the primary therapy is enzyme replacement, but allogeneic stem cell transplant has been used effectively. Histiocytoses Hemophagocytic Lymphohistiocytosis (HLH) Familial Erythrophagocytic Lymphohistiocytosis Langerhans Cell Histiocytosis Patients with multi-system disease whose initial disease is stable or progressive after minimum 6 weeks of appropriate therapy, OR Patients with recurrent multi-system disease. Malignant Histiocytosis Other non-malignant diseases not listed above may be eligible if deemed appropriate by the co-principal investigators.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
James Garvin, MD, PhD
Phone
212 305 5872
Email
jhg1@columbia.edu
First Name & Middle Initial & Last Name or Official Title & Degree
William A Kim, Ph.D.
Phone
212-305-7213
Email
billkim@columbia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James Garvin, MD. PhD
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
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
James Garvin, MD, PhD
Phone
212-305-5872
Email
jhg1@columbia.edu
First Name & Middle Initial & Last Name & Degree
William A Kim, PhD
Phone
212-305-7213
Email
billkim@columbia.edu
First Name & Middle Initial & Last Name & Degree
James Garvin, MD, PhD

12. IPD Sharing Statement

Links:
URL
http://www.childrensnyp.org/
Description
Click on "Morgan Stanley Children's Hospital" and then "Clinical Services" and then "Blood & Marrow Transplantation"

Learn more about this trial

Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases

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