Bilateral Orthotopic Lung Transplant - Bone Marrow Transplant

Study Overview
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Brief Summary
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The purpose of this study is to determine whether bilateral orthotopic lung transplantation (BOLT) followed by cadaveric partially-matched CD3+/CD19+ depleted bone marrow transplant (BMT) is safe and effective for individuals aged 10 through 45 years with the diagnosis of primary immunodeficiency (PID) and end-stage lung disease. The enrollment goal: 8 participants who receive both BOLT and BMT.

Detailed Description
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The primary purpose of this 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 participants with primary immunodeficiency diseases (PID) and end-stage lung disease. For many patients with primary immunodeficiencies, HSCT, which we refer to as Bone Marrow Transplant (BMT) 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 BMT due to the high risk of mortality and pulmonary complications. Lung transplant prior to BMT would allow for restoration of pulmonary function prior to BMT, allowing PID patients to proceed to BMT , which would be curative for the patient's underlying immunodeficiency. As a secondary aim, after successful engraftment with donor bone marrow, the feasibility of participants tolerating planned withdrawal of immunosuppression and achieving eventual freedom from all immunosuppressive drugs and attaining a tolerant state will be assessed. This is a single center study in which participants receive a cadaveric, partially Human Leukocyte Antigen (HLA)-matched lung transplant followed by a CD3+/CD19+ depleted bone marrow transplant (BMT) from the same donor. In this study, the investigators will use a ≥ 2/6 HLA-matched T cell depleted bone marrow transplant from a cadaveric organ donor with an identical ABO blood type as the recipient. Participants will undergo: Bilateral orthotopic lung transplant (BOLT) utilizing basiliximab induction or an alternate induction therapy based on their underlying disease. Rituximab may be initiated prior to the lung transplant, with tacrolimus as the ongoing maintenance immunosuppression. BMT utilizing CD3+/CD19+-depleted bone marrow with bone marrow conditioning beginning no less than 8 weeks after BOLT. The duration of participant involvement in the trial is up to 2 years post-BMT.

Official Title
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Bilateral Orthotopic Lung Transplant in Tandem With CD3+ and CD19+ Cell Depleted Bone Marrow Transplant From Partially HLA Matched Cadaveric Donors (RTB-003)

Conditions
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Primary Immunodeficiency, PID

Intervention / Treatment
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* Biological: CD3/CD19 neg allogeneic BMT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject and/or parent guardian must be able to understand and provide informed consent; Subject fulfills criteria for United Network of Organ Sharing (UNOS) listing; Subject must have evidence of an underlying primary immunodeficiency for which Bone Marrow Transplant (BMT) is clinically indicated. Examples of such diseases include, but are not limited to: Severe Combined Immunodeficiency (SCID) Combined immunodeficiency with defects in T-cell-mediated immunity, including Omenn syndrome and DiGeorge Syndrome Severe Chronic Neutropenia Chronic Granulomatous Disease (CGD) Hyper Immunoglobulin E (IgE) Syndrome or Job's Syndrome CD40 or CD40L deficiency Wiskott-Aldrich Syndrome Mendelian Susceptibility to Mycobacterial Disease GATA2-associated Immunodeficiency. Subjects must have evidence of end-stage lung disease and be candidates for bilateral orthotopic lung transplant as determined by the lung transplant team; Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2; Aspartate aminotransferase (AST), Alanine aminotransaminase (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 Food and Drug Administration (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; and 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. Eligibility for Bone Marrow Transplant*: GFR >50 mL/min/1.73 m^2; AST, ALT <4x upper limit of normal, Total bilirubin < 2.5 mg/dL; Cardiac ejection fraction ≥40% or shortening fraction of at least 26%; Human Immunodeficiency Virus (HIV) negative by serology and PCR; Human T-lymphotropic virus (HTLV) serology negative; Forced vital capacity (FVC) and Forced expiratory volume (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 blood cultures and radiographic results of previously affected sites, in particular, pulmonary densities during the past 2 weeks prior to chemotherapy; Absence of Acute Cellular Rejection (ACR); and Bone marrow processing has been completed, and an appropriate stem cell product is available for administration. Note: The decision to proceed with the BMT will be at the discretion of the lung transplant team following clearance by the bone marrow team based on the criteria below. The conditioning for the BMT will begin no less than 8 weeks following the lung transplant. Exclusion Criteria: Inability or unwillingness of a participant to give written informed consent or comply with study protocol; Subjects who have underlying malignant conditions; Subjects who have non-malignant conditions that do not require hematopoietic stem cell transplantation; Human Immunodeficiency Virus (HIV) positive by serology or polymerase chain reaction (PCR), human T-lymphotropic virus (HTLV) positive by serology; Females who are pregnant or who are lactating; Allergy to dimethyl sulfoxide (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. -- 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; or 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.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD3/CD19 neg allogeneic BMT<br>All participants will receive a double lung transplant followed by a bone marrow (hematopoietic stem cells) transplant. The lungs and allogeneic hematopoietic stem cells will be 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. | Biological: CD3/CD19 neg allogeneic BMT<br>* 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.<br>* Other names: CD3+/CD19+ depleted HSCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Transplant-Related Mortality | How many, if any, participants die. Continued enrollment without exceeding the protocol-defined stopping rules as determined by observing the cumulative incidence of transplant related mortality. | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Safety: Engraftment Failure | How many, if any, participants develop engraftment syndrome.Continued enrollment without exceeding the protocol-defined stopping rules as determined by observing the cumulative incidence of engraftment failure. | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Efficacy: Count of Participants with Absence of Severe Allograft Dysfunction | The number of participants without evidence of severe allograft dysfunction. The absence of severe allograft dysfunction using the Bronchiolitis Obliterans Syndrome (BOS) scoring system. | 1 Year Post Lung Transplant (BOLT) | 
| Efficacy: Count of Participants with T-cell Chimerism | The number of participants who have ≥ 25% donor T-cell chimerism. | 1 Year Post Bone Marrow Transplant (BMT) | 
| Efficacy: Count of Participants with Myeloid Chimerism | The number of participants with myeloid disorders (e.g. Chronic Granulomatous Disease [CGD]) who attain ≥ 10% myeloid chimerism. | 1 Year Post Bone Marrow Transplant (BMT) | 
| Efficacy: Count of Participants with Requirement for Supplemental Oxygen and/or Ventilatory Support | The number of participant(s) who need either supplemental oxygen and/or ventilator support (noninvasive/invasive) will be assessed using the Bronchiolitis Obliterans Syndrome (BOS) Classification Score for pulmonary function (e.g., the Forced Expiratory Volume in 1 Second (FEV1). FEV1 is air volume exhaled in 1 second during spirometry, a lung function test. | 1 Year Post Lung Transplant (BOLT) | 
| Efficacy: Count of Participants B-cell chimerism | The number of participants with B-cell disorders who attain ≥ 10% B-cell chimerism. | 1 Year Post Bone Marrow Transplant (BMT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Participants Able to Proceed to BMT | The number of participants for which it is feasible to proceed to BMT within 6 months following lung transplant. | Within 6 Months Post Lung Transplant (BOLT) | 
| Count of Participants Who Achieve Tolerance | The number of participants who develop tolerance to both the host and pulmonary graft. Definition of tolerance: A participant's successful withdrawal from systemic immunosuppression for 6 weeks with no increase cGVHD score and stable or improving PFTs. | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Long Term Complications of Combined Solid Organ and Bone Marrow Transplant | Summary of long-term complications of combined solid organ and bone marrow transplant (BMT). | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Count of Participants Who Develop Acute Cellular Rejection | The number of participants who develop acute cellular rejection. | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Count of Participants Able to Initiate Withdrawal of Immunosuppression | The number of participants who are able to start immunosuppression withdrawal. | Within 1 Year Post BMT | 
| Time to Withdrawal of Immunosuppression | Time from BMT to withdrawal of immunosuppression. | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Time to Independence From Treatment Dose Antimicrobial Drug | A measure of pathogen-specific immunity. | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Lymphocyte Count for T-cell Lymphopenias | For T cell lymphopenias, achieving age adjusted, low limit normal range lymphocyte count by 1-year post-BMT. | Within 1 Year Post BMT | 
| Count of Participants Who Develop Acute Graft-Versus-Host Disease (GVHD) | The number of participants who develop acute graft-versus-host disease (GVHD). | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Count of Participants With Graft Failure | The number of participants who develop allograft failure post-lung transplant for all participants, lung only transplant and BOLT- BMT. | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Count of Participants with Chronic Graft-Versus-Host Disease (GVHD) | The number of participants who develop chronic graft-versus-host disease (GVHD). | Within 2 Years Post Bone Marrow Transplant (BMT) | 
| Count of Participants Who Develop Chronic Lung Allograft Dysfunction | The number of participants who develop chronic lung allograft dysfunction post-lung transplant for all participants, lung only transplant and BOLT-BMT. Reference: Bronchiolitis Obliterans Syndrome (BOS) Classification scoring system. | From Lung and Bone Marrow Transplant to Month 12 | 
| Count of Participants who Develop Allograft Failure | The number of participants who develop allograft failure post-lung transplant for all participants, lung only transplant and BOLT-BMT. | Within 1 Year Post Lung Transplant | 
| Count of Rituximab Related Adverse Events | The number of Grade 4 or 5 adverse events possibly related to the use of rituximab prior to the start of BMT conditioning. | From the time of the first dose of rituximab up to the start of BMT conditioning | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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end-stage lung disease, Bilateral Orthotopic Lung Transplant (BOLT) candidate, CD3/CD19 negative allogeneic hematopoietic stem cells (HSCT), CD3+/CD19+ depleted Bone Marrow Transplant (BMT), Cadaveric (Deceased) Donor, Unrelated (Deceased) Donor