Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases

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Brief Title

Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases

Official Title

Bilateral Orthotopic Lung Transplant in Tandem With CD3+ and CD19+ Cell Depleted Bone Marrow Transplant From Partially HLA-Matched Cadaveric Donors

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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Safety: Death

Secondary Outcome

 Feasibility of meeting BMT eligibility critieria

Condition

Severe Combined Immunodeficiency (SCID)

Intervention

CD3/CD19 negative allogeneic hematopoietic stem cells

Study Arms / Comparison Groups

 BOLT+BMT
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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

16

Start Date

June 20, 2013

Completion Date

November 2024

Primary Completion Date

November 2023

Eligibility Criteria

        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).
      

Gender

All

Ages

5 Years - 45 Years

Accepts Healthy Volunteers

No

Contacts

Paul Szabolcs, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01852370

Organization ID

STUDY19090108


Responsible Party

Sponsor-Investigator

Study Sponsor

Paul Szabolcs


Study Sponsor

Paul Szabolcs, MD, Principal Investigator, Division of BMT and Cellular Therapy, Children's Hospital of Pittsburgh of UPMC


Verification Date

December 2020