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

Primary Purpose

Severe Combined Immunodeficiency (SCID), Immunodeficiency With Predominant T-cell Defect, Unspecified, Severe Chronic Neutropenia

Status
Enrolling by invitation
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
CD3/CD19 negative allogeneic hematopoietic stem cells
Sponsored by
Paul Szabolcs
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Combined Immunodeficiency (SCID) focused on measuring Lung transplantation, Bone Marrow Transplantation, Unrelated Donor, Cadaveric Donor, Deceased Donor, HLA-mismatch, BOLT, BMT, HSCT

Eligibility Criteria

5 Years - 45 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  1. Subject and/or parent guardian must be able to understand and provide informed consent.
  2. Male or female, 5 through 45 years old, inclusive, at the time of informed consent.
  3. Patients must have evidence of an underlying primary immunodeficiency for which BMT is clinically indicated.

    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 [6]
    • GATA2 Associated Immunodeficiency NOTE: A genetic diagnosis is recommended, but not required.
  4. Patients must have evidence of end-stage lung disease and be candidates for bilateral orthotopic lung transplant as determined by the lung transplant team.
  5. GFR ≥ 50 mL/min/1.73 m2.
  6. AST, ALT ≤ 4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL, normal INR.
  7. Cardiac ejection fraction ≥ 40% or shortening fraction ≥26%.
  8. Negative pregnancy test for females >10 years old or who have reached menarche, unless surgically sterilized.
  9. All females of childbearing potential and sexually active males must agree to use a FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause birth defect.
  10. Subject and/or parent guardian will also be counseled regarding the potential risks of infertility following BMT and advised to discuss sperm banking or oocyte harvesting.

Exclusion Criteria

Individuals who meet any of these criteria are not eligible for this study:

  1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol.
  2. Patients who have underlying malignant conditions.
  3. Patients who have non-malignant conditions not requiring hematopoietic stem cell transplantation.
  4. HIV positive by serology or PCR, HTLV positive by serology.
  5. Females who are pregnant or who are lactating.
  6. Allergy to DMSO or any other ingredient used in the manufacturing of the stem cell product.
  7. Uncontrolled pulmonary infection, as determined by radiographic findings and/or significant clinical deterioration. NOTE: Pulmonary colonization with multiple organisms is common, and will not be considered an exclusion criterion.
  8. Uncontrolled systemic infection, as determined by the appropriate confirmatory testing e.g. blood cultures, PCR testing, etc.
  9. Recent recipient of any licensed or investigational live attenuated vaccine(s) within 4 weeks of transplant.
  10. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

Eligibility Criteria to proceed to Bone Marrow Transplant

  1. GFR ≥ 50 mL/min/1.73 m2.
  2. AST, ALT ≤ 4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL.
  3. Cardiac ejection fraction ≥ 40% or shortening fraction of at least 26%.
  4. HIV negative by serology and PCR.
  5. HTLV serology negative.
  6. FVC and FEV1 ≥40% predicted for age and SpO2 of >90% at rest on room air AND with clearance by the lung transplant team.
  7. Absence of uncontrolled infection as determined by positive blood cultures and radiographic progression of previous sites in particular pulmonary densities during the past 2 weeks prior to chemotherapy.
  8. Absence of clinically significant Acute Cellular Rejection (A2-A4 and/or B2R rejection).

Sites / Locations

  • Children's Hospital of Pittsburgh of UPMC

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BOLT+BMT

Arm Description

All patients will receive a double lung transplant followed by a hematopoietic stem cell transplant. The lungs and stem cells are from the same partially HLA-matched cadaveric donor. Prior to transplantation, the marrow will be negatively selected for CD3/CD19 using a CliniMACS® depletion device.

Outcomes

Primary Outcome Measures

Safety: Death
How many, if any, patients die.
Safety: Engraftment syndrome
How many, if any, patients develop engraftment syndrome.
Safety: Engraftment failure
How many patients, if any, develop engraftment failure.
Safety: Rituximab
The number of grade 4 and 5 events potentially related to rituximab.
Efficacy: BOS score
Bronchiolitis Obliterans Syndrome (BOS) score for all patients who receive both lungs and stem cell transplants.
Efficacy: T-cell chimerism
The number of patients who have ≥ 25% donor T-cell chimerism.
Efficacy: Myeloid chimerism
The number of patients with myeloid disorders (e.g. CGD) who attain ≥ 10% myeloid chimerism.
Efficacy: B-cell chimerism
The number of patients with B-cell disorders who attain ≥ 10% B-cell chimerism.

Secondary Outcome Measures

Feasibility of meeting BMT eligibility critieria
The number of patients who are able to proceed to BMT within 6 months following lung transplant.
Tolerance
Development of tolerance to both the host and pulmonary graft.
Long-term complications
Long-term complications of combined solid organ and BMT.
Graft failure
The number of patients who develop graft failure.
Acute cellular rejection
The number of patients who develop acute cellular rejection.
Acute graft-versus-host disease (GVHD)
The number of patient who develop acute graft-versus-host disease (GVHD).
Chronic graft-versus-host disease (GVHD)
The number of patient who develop chronic graft-versus-host disease (GVHD).
Ability to withdraw immunosuppression
The number of patients who are able to start immunosuppression withdrawal.
Time to withdraw immunosuppression
Time from BMT to withdrawal of immunosuppression.
Pathogen-specific immunity
Time from BMT to independence from treatment dose antimicrobial drugs.
Lymphocyte count - for T-cell lymphopenias
The number of patients who are able to achieve an age adjusted, low limit normal range lymphocyte count.
Chronic lung allograft dysfunction
The number of patients who develop chronic lung allograft dysfunction post-lung transplant for all subjects, lung only and lung+stem cell transplant.
Allograft failure
The number of patients who develop allograft failure post-lung transplant for all subjects, lung only and lung+stem cell transplant.
Rituximab related adverse events
The number of grade 4 or 5 adverse events possibly related to the use of rituximab.

Full Information

First Posted
April 26, 2013
Last Updated
November 7, 2022
Sponsor
Paul Szabolcs
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1. Study Identification

Unique Protocol Identification Number
NCT01852370
Brief Title
Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
Acronym
BOLT+BMT
Official Title
Bilateral Orthotopic Lung Transplant in Tandem With CD3+ and CD19+ Cell Depleted Bone Marrow Transplant From Partially HLA-Matched Cadaveric Donors
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Enrolling by invitation
Study Start Date
June 20, 2013 (Actual)
Primary Completion Date
November 2023 (Anticipated)
Study Completion Date
November 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Paul Szabolcs

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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 5-45 years with primary immunodeficiency (PID) and end-stage lung disease.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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)
Keywords
Lung transplantation, Bone Marrow Transplantation, Unrelated Donor, Cadaveric Donor, Deceased Donor, HLA-mismatch, BOLT, BMT, HSCT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
BOLT+BMT
Arm Type
Experimental
Arm Description
All patients will receive a double lung transplant followed by a hematopoietic stem cell transplant. The lungs and stem cells are from the same partially HLA-matched cadaveric donor. Prior to transplantation, the marrow will be negatively selected for CD3/CD19 using a CliniMACS® depletion device.
Intervention Type
Biological
Intervention Name(s)
CD3/CD19 negative allogeneic hematopoietic stem cells
Intervention Description
Negative selection for CD3/CD19 will be performed on a CliniMACS® depletion device within 36 hours of collection and given at time no less than 8 weeks post lung transplant.
Primary Outcome Measure Information:
Title
Safety: Death
Description
How many, if any, patients die.
Time Frame
Up to 2 years post stem cell transplant
Title
Safety: Engraftment syndrome
Description
How many, if any, patients develop engraftment syndrome.
Time Frame
Up to 2 years post stem cell transplant
Title
Safety: Engraftment failure
Description
How many patients, if any, develop engraftment failure.
Time Frame
Up to 2 years post stem cell transplant
Title
Safety: Rituximab
Description
The number of grade 4 and 5 events potentially related to rituximab.
Time Frame
Up to 2 years post stem cell transplant
Title
Efficacy: BOS score
Description
Bronchiolitis Obliterans Syndrome (BOS) score for all patients who receive both lungs and stem cell transplants.
Time Frame
1 year post stem cell transplant
Title
Efficacy: T-cell chimerism
Description
The number of patients who have ≥ 25% donor T-cell chimerism.
Time Frame
1 year post stem cell transplant
Title
Efficacy: Myeloid chimerism
Description
The number of patients with myeloid disorders (e.g. CGD) who attain ≥ 10% myeloid chimerism.
Time Frame
1 year post stem cell transplant
Title
Efficacy: B-cell chimerism
Description
The number of patients with B-cell disorders who attain ≥ 10% B-cell chimerism.
Time Frame
1 year post stem cell transplant
Secondary Outcome Measure Information:
Title
Feasibility of meeting BMT eligibility critieria
Description
The number of patients who are able to proceed to BMT within 6 months following lung transplant.
Time Frame
Up to 2 years post stem cell transplant
Title
Tolerance
Description
Development of tolerance to both the host and pulmonary graft.
Time Frame
Up to 2 years post stem cell transplant
Title
Long-term complications
Description
Long-term complications of combined solid organ and BMT.
Time Frame
Up to 2 years post stem cell transplant
Title
Graft failure
Description
The number of patients who develop graft failure.
Time Frame
Up to 2 years post stem cell transplant
Title
Acute cellular rejection
Description
The number of patients who develop acute cellular rejection.
Time Frame
Up to 2 years post stem cell transplant
Title
Acute graft-versus-host disease (GVHD)
Description
The number of patient who develop acute graft-versus-host disease (GVHD).
Time Frame
Up to 2 years post stem cell transplant
Title
Chronic graft-versus-host disease (GVHD)
Description
The number of patient who develop chronic graft-versus-host disease (GVHD).
Time Frame
Up to 2 years post stem cell transplant
Title
Ability to withdraw immunosuppression
Description
The number of patients who are able to start immunosuppression withdrawal.
Time Frame
1 year post stem cell transplant
Title
Time to withdraw immunosuppression
Description
Time from BMT to withdrawal of immunosuppression.
Time Frame
Up to 2 years post stem cell transplant
Title
Pathogen-specific immunity
Description
Time from BMT to independence from treatment dose antimicrobial drugs.
Time Frame
Up to 2 years post stem cell transplant
Title
Lymphocyte count - for T-cell lymphopenias
Description
The number of patients who are able to achieve an age adjusted, low limit normal range lymphocyte count.
Time Frame
1 year post stem cell transplant
Title
Chronic lung allograft dysfunction
Description
The number of patients who develop chronic lung allograft dysfunction post-lung transplant for all subjects, lung only and lung+stem cell transplant.
Time Frame
1 year post lung transplant
Title
Allograft failure
Description
The number of patients who develop allograft failure post-lung transplant for all subjects, lung only and lung+stem cell transplant.
Time Frame
1 year post lung transplant
Title
Rituximab related adverse events
Description
The number of grade 4 or 5 adverse events possibly related to the use of rituximab.
Time Frame
From the time of the first dose of rituximab up to the start of BMT conditioning.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Subject and/or parent guardian must be able to understand and provide informed consent. Male or female, 5 through 45 years old, inclusive, at the time of informed consent. Patients must have evidence of an underlying primary immunodeficiency for which BMT is clinically indicated. 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 [6] GATA2 Associated Immunodeficiency NOTE: A genetic diagnosis is recommended, but not required. Patients must have evidence of end-stage lung disease and be candidates for bilateral orthotopic lung transplant as determined by the lung transplant team. GFR ≥ 50 mL/min/1.73 m2. AST, ALT ≤ 4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL, normal INR. Cardiac ejection fraction ≥ 40% or shortening fraction ≥26%. Negative pregnancy test for females >10 years old or who have reached menarche, unless surgically sterilized. All females of childbearing potential and sexually active males must agree to use a FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause birth defect. Subject and/or parent guardian will also be counseled regarding the potential risks of infertility following BMT and advised to discuss sperm banking or oocyte harvesting. Exclusion Criteria Individuals who meet any of these criteria are not eligible for this study: Inability or unwillingness of a participant to give written informed consent or comply with study protocol. Patients who have underlying malignant conditions. Patients who have non-malignant conditions not requiring hematopoietic stem cell transplantation. HIV positive by serology or PCR, HTLV positive by serology. Females who are pregnant or who are lactating. Allergy to DMSO or any other ingredient used in the manufacturing of the stem cell product. Uncontrolled pulmonary infection, as determined by radiographic findings and/or significant clinical deterioration. NOTE: Pulmonary colonization with multiple organisms is common, and will not be considered an exclusion criterion. Uncontrolled systemic infection, as determined by the appropriate confirmatory testing e.g. blood cultures, PCR testing, etc. Recent recipient of any licensed or investigational live attenuated vaccine(s) within 4 weeks of transplant. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study. Eligibility Criteria to proceed to Bone Marrow Transplant GFR ≥ 50 mL/min/1.73 m2. AST, ALT ≤ 4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL. Cardiac ejection fraction ≥ 40% or shortening fraction of at least 26%. HIV negative by serology and PCR. HTLV serology negative. FVC and FEV1 ≥40% predicted for age and SpO2 of >90% at rest on room air AND with clearance by the lung transplant team. Absence of uncontrolled infection as determined by positive blood cultures and radiographic progression of previous sites in particular pulmonary densities during the past 2 weeks prior to chemotherapy. Absence of clinically significant Acute Cellular Rejection (A2-A4 and/or B2R rejection).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Szabolcs, MD
Organizational Affiliation
Division of BMT and Cellular Therapy, Children's Hospital of Pittsburgh of UPMC
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases

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