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Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases (BOLT+BMT)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by University of Pittsburgh
Sponsor:
Information provided by (Responsible Party):
Paul Szabolcs, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01852370
First received: April 26, 2013
Last updated: August 19, 2013
Last verified: August 2013
  Purpose

The purpose of this study is to determine whether bilateral orthotopic lung transplantation (BOLT) followed by cadaveric partially-matched hematopoietic stem cell transplantation (HSCT) is safe and effective for patients aged 5-40 years with primary immunodeficiency (PID) and end-stage lung disease.


Condition Intervention Phase
Severe Combined Immunodeficiency (SCID)
Immunodeficiency With Predominant T-cell Defect, Unspecified
Severe Chronic Neutropenia
Chronic Granulomatous Disease (CGD)
Hyper IgE Syndromes
Hyper IgM Deficiencies
Wiskott-Aldrich Syndrome
Mendelian Susceptibility to Mycobacterial Disease
Common Variable Immune Deficiency (CVID)
Biological: CD3/CD19 negative allogeneic hematopoietic stem cells
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Bilateral Orthotopic Lung Transplant in Tandem With CD3+ and CD19+ Cell Depleted Bone Marrow Transplant From Partially HLA-Matched Cadaveric Donors

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Safety: Transplant-related mortality [ Time Frame: Within 2 years of HSCT ] [ Designated as safety issue: Yes ]
    Continued enrollment without exceeding the stopping rules as determined by observing the cumulative incidence of transplant related mortality.

  • Safety: Engraftment failure [ Time Frame: Within 2 years of HSCT ] [ Designated as safety issue: Yes ]
    Continued enrollment without exceeding the stopping rules as determined by observing the cumulative incidence of engraftment failure.

  • Efficacy: Pulmonary status [ Time Frame: 6 months post HSCT ] [ Designated as safety issue: No ]
    Absence of radiographic pneumonia

  • Efficacy: Pulmonary status (late effect) [ Time Frame: 5 years post HSCT ] [ Designated as safety issue: No ]
    Continued freedom from oxygen supplementation. We will continue to follow the subjects for late effects according to clinical standards for the rest of their life

  • Efficacy: Immunologic status [ Time Frame: By 2 years post HSCT ] [ Designated as safety issue: No ]
    • Attaining independence from treatment dose or prophylactic systemic antibiotics
    • Correction of underlying immune deficiency


Secondary Outcome Measures:
  • BMT feasibility by 6 months after Lung Transplant [ Time Frame: Within 6 months of lung transplant ] [ Designated as safety issue: Yes ]
  • Incidence of mixed chimerism at day 28, 100, 180, and 1 year post-transplant [ Time Frame: Up to 1 year post transplant ] [ Designated as safety issue: Yes ]
    Mixed chimerism defined as >5% host/recipient cells

  • Incidence of acute and chronic graft-versus-host disease (GVHD) following tandem lung and bone marrow transplant. [ Time Frame: Up to 5 years post transplant ] [ Designated as safety issue: Yes ]
  • Withdrawal of immunosuppression feasibility by 1 year following hematopoietic stem cell transplant. [ Time Frame: 1 year post transplant ] [ Designated as safety issue: Yes ]
  • Removal of immunosuppression feasibility by 18 months following hematopoietic stem cell transplant [ Time Frame: Up to 18 months post transplant ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • Evaluation of Immune Reconstitution [ Time Frame: 5 years from HSCT ] [ Designated as safety issue: Yes ]
  • Evaluation of tolerance to both the host and pulmonary graft [ Time Frame: Within 5 years of HSCT ] [ Designated as safety issue: Yes ]
  • Evaluation of long term complications of solid organ transplant and hematopoietic stem cell transplant [ Time Frame: Within 5 years of HSCT ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 16
Study Start Date: June 2013
Estimated Study Completion Date: August 2022
Estimated Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BOLT+BMT

All patients will receive allogeneic hematopoietic stem cells from partially HLA-matched donors. Prior to transplantation, the marrow will be negatively selected for CD3/CD19 using a CliniMACS® depletion device.

INTERVENTION: CD3/CD19 negative allogeneic hematopoietic stem cells

Biological: CD3/CD19 negative allogeneic hematopoietic stem cells
Negative selection for CD3/CD19 will be performed on a CliniMACS® depletion device within 48 hours of collection and given at time no less that 6 weeks post lung transplant.

Detailed Description:

This is an original IND for an investigator initiated phase I/II study. The primary purpose of the study is to evaluate the safety and efficacy of performing bilateral orthotopic lung transplantation (BOLT) followed by cadaveric, partially HLA-matched CD3+/CD19+-depleted hematopoietic stem cell transplantation (HSCT) from the same donor for patients with primary immunodeficiency diseases (PID) and end-stage lung disease. For many patients with primary immunodeficiencies, HSCT is a curative, life-saving therapy, resulting in restoration of function in the immune system. Patients with primary immunodeficiencies often develop pulmonary complications as a result of chronic or recurrent infections, making them ineligible for HSCT due to the high risk of mortality and pulmonary complications. Lung transplant prior to HSCT would allow for restoration of pulmonary function prior to HSCT, allowing PID patients to proceed to HSCT, which would be curative for the patient's underlying immunodeficiency. As a secondary aim after successful engraftment with donor bone marrow, there is realistic hope for tolerating planned withdrawal of immunosuppression achieving eventual freedom from all immunosuppressive drugs and attaining a tolerant state.

  Eligibility

Ages Eligible for Study:   5 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients should be between the ages of 5 and 40 years
  • Patients should have evidence of an underlying primary immunodeficiency for which HSCT is clinically indicated.

    o Examples of such diseases include, but are not limited to:

  • Severe Combined Immunodeficiency
  • Combined immunodeficiency with defects in T-cell-mediated immunity, including Omenn syndrome and DiGeorge Syndrome
  • Severe Chronic Neutropenia
  • Chronic Granulomatous Disease
  • Hyper IgE Syndrome or Job Syndrome
  • CD40 or CD40L deficiency
  • Wiskott-Aldrich Syndrome
  • Mendelian Susceptibility to Mycobacterial Disease
  • NOTE: A genetic diagnosis is recommended, but not required.
  • Patients should have evidence of end-stage lung disease and be candidates for bilateral orthotopic lung transplant as determined by the lung transplant team.

Exclusion Criteria:

  • Patients <5 or >40 years of age
  • Patients who have underlying malignant conditions
  • Patients who have non-malignant conditions not requiring hematopoietic stem cell transplantation.
  • Patients who do not meet criteria for bilateral orthotopic lung transplant
  • GFR less than 50 mL/min/1.73 m2
  • AST, ALT >4x upper limit of normal, Bilirubin > 2.5 mg/dL
  • Cardiac ejection fraction < 40% or shortening fraction < 26%
  • HIV positive by serology or PCR, HTLV positive by serology, HepBsAg positive, or HCV RNA positive by PCR
  • Pregnancy or nursing mother
  • Allergy to DMSO or any other ingredient used in the manufacturing of the stem cell product
  • Uncontrolled infection NOTE: Pulmonary colonization with multiple organisms is common, and will not be considered an exclusion criterion.
  • Any comorbid illnesses that would otherwise preclude participation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01852370

Contacts
Contact: Paul Szabolcs, MD 412-692-6225 paul.szabolcs@chp.edu
Contact: Mark Vander Lugt, MD 412-692-7035 mark.vanderlugt@chp.edu

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Sub-Investigator: Mark Vander Lugt, MD         
Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Paul Szabolcs, MD Division of BMT and Cellular Therapy, Children's Hospital of Pittsburgh of UPMC
  More Information

No publications provided

Responsible Party: Paul Szabolcs, Chief, Division of Blood and Marrow Transplant, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01852370     History of Changes
Other Study ID Numbers: BOLT+BMT
Study First Received: April 26, 2013
Last Updated: August 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Pittsburgh:
Lung transplantation
Bone Marrow Transplantation
Unrelated Donor
Cadaveric Donor
Deceased Donor
HLA-mismatch
BOLT
BMT
HSCT

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Job Syndrome
Syndrome
Wiskott-Aldrich Syndrome
Common Variable Immunodeficiency
Disease Susceptibility
Granuloma
Granulomatous Disease, Chronic
Mycobacterium Infections
Neutropenia
Severe Combined Immunodeficiency
Actinomycetales Infections
Agranulocytosis
Bacterial Infections
Blood Coagulation Disorders
Blood Coagulation Disorders, Inherited
DNA Repair-Deficiency Disorders
Disease
Disease Attributes
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Gram-Positive Bacterial Infections
Hematologic Diseases
Hemorrhagic Disorders
Immune System Diseases
Infant, Newborn, Diseases
Leukocyte Disorders
Leukopenia
Lymphatic Diseases
Lymphopenia

ClinicalTrials.gov processed this record on November 20, 2014