BOLT-BMT: Bilateral Orthotopic Lung Transplant - Bone Marrow Transplant

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT03330795

Collaborator

University of Pittsburgh (Other), PPD (Industry)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Immunodeficiency PID	Biological: CD3/CD19 neg allogeneic BMT	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

5 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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 (RTB-003)

Actual Study Start Date :

Dec 1, 2017

Anticipated Primary Completion Date :

Nov 1, 2023

Anticipated Study Completion Date :

Nov 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CD3/CD19 neg allogeneic BMT 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 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. Other Names: CD3+/CD19+ depleted HSCT

Arm

Intervention/Treatment

Experimental: CD3/CD19 neg allogeneic BMT

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

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.

Other Names:

CD3+/CD19+ depleted HSCT

Outcome Measures

Primary Outcome Measures

Safety: Transplant-Related Mortality [Within 2 Years Post Bone Marrow Transplant (BMT)]
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.
Safety: Engraftment Failure [Within 2 Years Post Bone Marrow Transplant (BMT)]
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.
Efficacy: Count of Participants with Absence of Severe Allograft Dysfunction [1 Year Post Lung Transplant (BOLT)]
The number of participants without evidence of severe allograft dysfunction. The absence of severe allograft dysfunction using the Bronchiolitis Obliterans Syndrome (BOS) scoring system.
Efficacy: Count of Participants with T-cell Chimerism [1 Year Post Bone Marrow Transplant (BMT)]
The number of participants who have ≥ 25% donor T-cell chimerism.
Efficacy: Count of Participants with Myeloid Chimerism [1 Year Post Bone Marrow Transplant (BMT)]
The number of participants with myeloid disorders (e.g. Chronic Granulomatous Disease [CGD]) who attain ≥ 10% myeloid chimerism.
Efficacy: Count of Participants with Requirement for Supplemental Oxygen and/or Ventilatory Support [1 Year Post Lung Transplant (BOLT)]
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.
Efficacy: Count of Participants B-cell chimerism [1 Year Post Bone Marrow Transplant (BMT)]
The number of participants with B-cell disorders who attain ≥ 10% B-cell chimerism.

Secondary Outcome Measures

Count of Participants Able to Proceed to BMT [Within 6 Months Post Lung Transplant (BOLT)]
The number of participants for which it is feasible to proceed to BMT within 6 months following lung transplant.
Count of Participants Who Achieve Tolerance [Within 2 Years Post Bone Marrow Transplant (BMT)]
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.
Long Term Complications of Combined Solid Organ and Bone Marrow Transplant [Within 2 Years Post Bone Marrow Transplant (BMT)]
Summary of long-term complications of combined solid organ and bone marrow transplant (BMT).
Count of Participants Who Develop Acute Cellular Rejection [Within 2 Years Post Bone Marrow Transplant (BMT)]
The number of participants who develop acute cellular rejection.
Count of Participants Able to Initiate Withdrawal of Immunosuppression [Within 1 Year Post BMT]
The number of participants who are able to start immunosuppression withdrawal.
Time to Withdrawal of Immunosuppression [Within 2 Years Post Bone Marrow Transplant (BMT)]
Time from BMT to withdrawal of immunosuppression.
Time to Independence From Treatment Dose Antimicrobial Drug [Within 2 Years Post Bone Marrow Transplant (BMT)]
A measure of pathogen-specific immunity.
Lymphocyte Count for T-cell Lymphopenias [Within 1 Year Post BMT]
For T cell lymphopenias, achieving age adjusted, low limit normal range lymphocyte count by 1-year post-BMT.
Count of Participants Who Develop Acute Graft-Versus-Host Disease (GVHD) [Within 2 Years Post Bone Marrow Transplant (BMT)]
The number of participants who develop acute graft-versus-host disease (GVHD).
Count of Participants With Graft Failure [Within 2 Years Post Bone Marrow Transplant (BMT)]
The number of participants who develop allograft failure post-lung transplant for all participants, lung only transplant and BOLT- BMT.
Count of Participants with Chronic Graft-Versus-Host Disease (GVHD) [Within 2 Years Post Bone Marrow Transplant (BMT)]
The number of participants who develop chronic graft-versus-host disease (GVHD).
Count of Participants Who Develop Chronic Lung Allograft Dysfunction [From Lung and Bone Marrow Transplant to Month 12]
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.
Count of Participants who Develop Allograft Failure [Within 1 Year Post Lung Transplant]
The number of participants who develop allograft failure post-lung transplant for all participants, lung only transplant and BOLT-BMT.
Count of Rituximab Related Adverse Events [From the time of the first dose of rituximab up to the start of BMT conditioning]
The number of Grade 4 or 5 adverse events possibly related to the use of rituximab prior to the start of BMT conditioning.

Other Outcome Measures

EXPLORATORY: Change in Markers of Immune Reconstitution [Within 2 Years Post Bone Marrow Transplant (BMT)]
The pace of reconstitution of immunity will be explored.
EXPLORATORY: Count of Participants with Mixed Chimerism EXPLORATORY: Count of Participants with Mixed Chimerism [Months 1, 3, 6, 12, and 2 Years Post Bone Marrow Transplant (BMT)]
The number of participants with mixed chimerism, as defined by the presence of >5% host cells.
EXPLORATORY: Change in Immunologic Markers [1 Year Post Bone Marrow Transplant (BMT)]
Changes in immunological markers specific to the participant's diagnosed Primary Immunodeficiency Disease (PID) will be assessed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

10 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.