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Reduced Intensity Conditioning and Familial HLA-Mismatched BMT for Non-Malignant Disorders

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03128996
Recruitment Status : Recruiting
First Posted : April 26, 2017
Last Update Posted : April 26, 2023
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Study Description
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Brief Summary:
This study is designed to estimate the efficacy and toxicity of familial HLA mismatched bone marrow transplants in patients with non-malignant disease who are less than 21 years of age and could benefit from the procedure.

Condition or disease Intervention/treatment Phase
Severe Sickle Cell Disease Bone Marrow Failure Syndromes Metabolic Disorders Immunologic Disorders Hemoglobinopathies Non-malignant Disorders Drug: RIC regimen Drug: GVHD prophylaxis regimen Phase 1 Phase 2

Detailed Description:

Patients < 21 years of age with a non-malignant disorder benefited by hematopoietic stem cell transplant will receive a reduced intensity conditioning regimen consisting of hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan.

This will be followed by a familial HLA-mismatched bone marrow transplant. The primary objective is to establish safety and donor cell engraftment at 100 days and 1 year post-transplant.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Reduced Intensity Conditioning and Familial HLA-Mismatched Bone Marrow Transplantation in Children With Non-Malignant Disorders
Actual Study Start Date : March 20, 2017
Estimated Primary Completion Date : April 2024
Estimated Study Completion Date : April 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: RIC Prep Regimen & GVHD Prophylaxis
Single arm study. All patients receive the same Reduced Intensity Conditioning (RIC) regimen and GVHD prophylaxis regimen
 Drug: RIC regimen
Days -60 to -21: hydroxyurea (30mg/kg/day po) >6hrs prior to 1st dose: alemtuzumab (3mg IV) Day -21: alemtuzumab (10mg IV or S/C) Day -20: alemtuzumab (15mg IV or S/C) (10mg if < 10kg) Day -19: alemtuzumab (20mg IV or S/C) (10mg if < 10kg) Days -8 to -4: fludarabine (30mg/m2/day IV) Day -4: thiotepa (8mg/kg IV) Day -3: melphalan (140mg/m2) Days -2 to -1: rest days/no therapy Day 0: bone marrow transplant
Other Names:
  • Transplant Preparative Regimen
  • Transplant Conditioning Regimen

Drug: GVHD prophylaxis regimen
Day +3 to +4: cyclophosphamide (50mg/kg/day IV) Day +5: Start of tacrolimus & Start of mycophenolate mofetil (MMF) Days +5, +14, +30, +60, +90: abatacept (IND) (10mg/kg/day IV) Days +120 to +390: abatacept (IND) monthly (5mg/kg/day IV)
Other Name: Graft versus Host Disease prophylaxis regimen


Outcome Measures
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Primary Outcome Measures :
  1. Donor engraftment [ Time Frame: 100 days and 1 year post-transplant ]
    as measured by chimerism


Secondary Outcome Measures :
  1. Time to neutrophil engraftment [ Time Frame: 100 days post-transplant ]
    as measured by complete blood counts

  2. Time to platelet engraftment [ Time Frame: 100 days post-transplant ]
    as measured by complete blood counts

  3. Effect of BMT on pulmonary function [ Time Frame: 90 days, 1 year, and 2 years post-transplant ]
    as measured by pulmonary function tests

  4. Effect of BMT on hepatic function [ Time Frame: 90 days, 180 days, 1 year, and 2 years post-transplant ]
    as measured by laboratory evaluations

  5. Effect of BMT on neurologic function [ Time Frame: 90 days, 1 year, and 2 years post-transplant ]
    as measured by cognitive testing and quality of life surveys

  6. Effect of BMT on cardiac function [ Time Frame: 90 days, 1 year, and 2 years post-transplant ]
    as measured by echocardiograms

  7. Effect of BMT on renal function [ Time Frame: 90 days, 180 days, 1 year, and 2 years post-transplant ]
    as measured by laboratory evaluations

  8. Pharmacokinetics of alemtuzumab [ Time Frame: days -19, day 0, day +15, and day +30 ]
    as measured by maximum plasma concentration of alemtuzumab

  9. Pharmacokinetics of abatacept [ Time Frame: days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant ]
    as measured by maximum plasma concentration of abatacept

  10. Incidence of acute graft-versus-host disease (GVHD) [ Time Frame: 1 year post-transplant ]
    as measured by protocol grading scale

  11. Incidence of chronic graft-versus-host disease (GVHD) [ Time Frame: 2 years post-transplant ]
    as measured by protocol grading scale

  12. Immune reconstitution [ Time Frame: days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant ]
    as measured by research laboratory evaluations


Eligibility Criteria
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Ages Eligible for Study:   1 Day to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Nonmalignant disorder requiring bone marrow transplant including bone marrow failure syndromes, metabolic disorders, immunologic disorders, or hemoglobinopathy

  • For patients with sickle cell disease, must have one of the following severe manifestations:

    1. Overt or silent stroke or persistently elevated transcranial doppler velocities despite transfusion therapy
    2. Recurrent acute chest syndrome with significant respiratory compromise each time
    3. Sickle nephropathy
    4. Recurrent admissions for vaso-occlusive episodes resulting in prolonged opioid use and poor quality of life with interrupted school attendance activity
    5. Red cell alloimmunization with the need for chronic transfusions
    6. Recurrent osteonecrosis or multiple joint involvement from avascular necrosis
  • Patients with sickle cell disease must have hemoglobin S < 30% within 30 days prior to beginning alemtuzumab
  • Age </= 20.99 years at the time of enrollment
  • Performance score >/= 50
  • Left ventricular ejection fraction > 40% or left ventricular shortening fraction > 26% by echocardiogram
  • DLCO > 40% (corrected for hemoglobin) or pulse oximetry with a baseline O2 saturation of >/= 90% on room air if too young to perform PFTs
  • Serum creatinine </= 1.5x upper limit of normal for age and/or GFR > 70 mL/min/1.73m2
  • Direct bilirubin < 2x upper limit of normal for age
  • ALT and AST < 5x upper limit of normal for age

  • Participants who have or are receiving >/= 8 packed red blood cell transfusions for >/= 1 year or >/= 20 packed red blood cell transfusions (lifetime cumulative) will undergo liver MRI for estimation of hepatic iron content.

    1. Liver biopsy is indicated for hepatic iron content >/= 7mg Fe/mg liver dry weight by liver MRI. Histologic examination of the liver must document for the absence of cirrhosis, bridging fibrosis, and active hepatitis

  • Female subjects of childbearing potential, must agree to practice 2 methods of contraception at the same time from the time of signing of informed consent through 12 months post transplant. Male subjects must agree to practice effective barrier contraception or practice true abstinence from the time of signing informed consent through 12 months post transplant.
  • Written informed consent must be obtained from all recipients in accordance with the guidelines of the institution's Human Studies Committee.

Exclusion Criteria:

  • Patients who have an HLA-identical sibling who is able and willing to donate bone marrow
  • Patients with cirrhosis or established bridging fibrosis of the liver or active hepatitis
  • Uncontrolled bacterial, viral, or fungal infection within 6 weeks prior to enrollment
  • Evidence of HIV infection or known HIV positive serology
  • Patients who have received a previous stem cell transplant
  • Patients who have received an investigational drug or device or off-label use of a drug or device within 3 months of enrollment
  • Females who are pregnant or breast feeding
  • Patients with active autoimmune disease (e.g. sarcoidosis, lupus, scleroderma)
Contacts and Locations
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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): NCT03128996


Contacts
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Contact: Shalini Shenoy, MD 314-454-6018 shalinishenoy@wustl.edu
Contact: Stephanie Hyde, CCRP 314-286-1180 stephanie.day@wustl.edu

Locations
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United States, Connecticut
Yale School of Medicine Recruiting
New Haven, Connecticut, United States, 06510
Contact: Niketa Shah, MD         
Principal Investigator: Niketa Shah, MD         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Shalini Shenoy, MD    314-454-6018    shalinishenoy@wustl.edu   
Contact: Lisa Murray, MA, CCRP    314-454-4240    murraylm@wustl.edu   
Principal Investigator: Shalini Shenoy, MD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Shalini Shenoy, MD Washington University School of Medicine
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03128996    
Other Study ID Numbers: 201611172
First Posted: April 26, 2017    Key Record Dates
Last Update Posted: April 26, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Washington University School of Medicine:
Bone marrow transplant
Transplant
Transplantation
Reduced Intensity
Familial HLA mismatched
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Bone Marrow Failure Disorders
Pancytopenia
Hemoglobinopathies
Metabolic Diseases
Immune System Diseases
Disease
 Pathologic Processes
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Genetic Diseases, Inborn
Bone Marrow Diseases