Lung and Bone Marrow Transplantation for Lung and Bone Marrow Failure

Sponsor

Paul Szabolcs (Other)

Overall Status

Recruiting

CT.gov ID

NCT03500731

Collaborator

(none)

Enrollment

Locations

Arm

103.4

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether a lung transplantation prior to bone marrow transplantation (BMT) would allow for restoration of pulmonary function prior to BMT, allowing to proceed to BMT, to restore hematologic function.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis Emphysema or COPD	Biological: CD3/CD19 negative hematopoietic stem cells Drug: Rituximab Drug: Alemtuzumab Drug: Fludarabine Drug: Thiotepa Drug: G-CSF Drug: Hydroxyurea	Phase 1/Phase 2

Detailed Description

The primary purpose of the study is to evaluate the safety and efficacy of performing lung transplantation followed by cadaveric, partially HLA-matched (≥1/6 HLA-match with an identical ABO blood type) CD3+/CD19+ depleted bone marrow transplantation in bone marrow failure and end-stage lung disease. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease for which lung transplantation is the only therapy shown to prolong survival. Given the association of IPF with hematologic cytopenias and bone marrow failure, it is proposed that a tandem lung transplantation and bone marrow transplantation from a single cadaveric donor could be successful. This protocol focuses on performing combined transplantation for candidates that are unable to undergo standard lung transplantation. Lung transplantation prior to bone marrow transplantation (BMT) would allow for restoration of pulmonary function prior to BMT, and to restore hematologic function post BMT transplantation. The secondary objectives are to evaluate the feasibility and long-term complications associated with combined solid organ and BMT including the ability to initiate and successfully withdraw from immunosuppression following BMT and to attain independence from growth factors, red blood cell or platelet transfusions.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

8 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Lung Transplant in Tandem With Bone Marrow Transplant for Combined Lung and Bone Marrow Failure

Actual Study Start Date :

Apr 19, 2018

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lung and Bone Marrow Transplantation All patients will undergo a cadaveric, partially HLA-matched lung transplantation followed by a CD3+/CD19+ depleted BMT from the same donor. In this study, the investigators will use a ≥1/6 HLA-matched T cell depleted bone marrow transplantation from a cadaveric organ donor with an identical ABO blood type as the recipient. Prior to transplantation, the marrow will be negatively selected for CD3/CD19 using a CliniMACS® depletion device. Subjects will undergo lung transplantation utilizing standard induction regimens selected by the CO-PIs based on the subject's underlying comorbidities and allosensitization. Rituximab may be initiated prior to the lung transplantation with tacrolimus as the ongoing maintenance immunosuppression. Subjects will undergo BMT utilizing CD3+/CD19+-depleted bone marrow with bone marrow conditioning beginning no less than 8 weeks after lung transplantation. Bone marrow will be recovered alongside solid organs and will be processed and cryopreserved.	Biological: CD3/CD19 negative hematopoietic stem cells Negative selection for CD3/CD19 will be performed on CliniMACS® depletion device and given at time no less than 8 weeks post lung transplantation Drug: Rituximab Transplantation Conditioning Other Names: Rituxan Drug: Alemtuzumab Transplantation Conditioning Other Names: Campath-1H Drug: Fludarabine Transplantation Conditioning Other Names: Fludara, Oforta Drug: Thiotepa Transplantation Conditioning Drug: G-CSF Transplantation conditioning Other Names: Neupogen, Granix, Zarxio, Filgrastim Drug: Hydroxyurea Transplantation Conditioning

Arm

Intervention/Treatment

Experimental: Lung and Bone Marrow Transplantation

All patients will undergo a cadaveric, partially HLA-matched lung transplantation followed by a CD3+/CD19+ depleted BMT from the same donor. In this study, the investigators will use a ≥1/6 HLA-matched T cell depleted bone marrow transplantation from a cadaveric organ donor with an identical ABO blood type as the recipient. Prior to transplantation, the marrow will be negatively selected for CD3/CD19 using a CliniMACS® depletion device. Subjects will undergo lung transplantation utilizing standard induction regimens selected by the CO-PIs based on the subject's underlying comorbidities and allosensitization. Rituximab may be initiated prior to the lung transplantation with tacrolimus as the ongoing maintenance immunosuppression. Subjects will undergo BMT utilizing CD3+/CD19+-depleted bone marrow with bone marrow conditioning beginning no less than 8 weeks after lung transplantation. Bone marrow will be recovered alongside solid organs and will be processed and cryopreserved.

Biological: CD3/CD19 negative hematopoietic stem cells

Negative selection for CD3/CD19 will be performed on CliniMACS® depletion device and given at time no less than 8 weeks post lung transplantation

Drug: Rituximab

Transplantation Conditioning

Other Names:

Rituxan

Drug: Alemtuzumab

Transplantation Conditioning

Other Names:

Campath-1H

Drug: Fludarabine

Transplantation Conditioning

Other Names:

Fludara, Oforta

Drug: Thiotepa

Transplantation Conditioning

Drug: G-CSF

Transplantation conditioning

Other Names:

Neupogen, Granix, Zarxio, Filgrastim

Drug: Hydroxyurea

Transplantation Conditioning

Outcome Measures

Primary Outcome Measures

Death [Up to 2 years post stem cell transplant]
How many, if any, patients die
Engraftment failure [Up to 2 years post stem cell transplant]
How many, if any, develop engraftment failure
Non-hematologic events [Up to 2 years post stem cell transplant]
Any Grade 4 event that happens at any time points
Hematological events [after 30 days post stem cell transplant]
Any Grade 4 hematological events
BOS Score [at 1 year post lung transplant]
Bronchiolitis Obliterans Syndrome (BOS) score based off patient pulmonary function testing. Graded on scale (BOS0 to BOS3), BOS0 having a better outcome then BOS3
T-cell Chimerism [at 12 months post stem cell transplant]
The number of patients who have ≥25% donor T-cell chimerism
Myeloid chimerism [at 12 months post stem cell transplant]
The number of patients with myeloid disorders who attain ≥ 10% myeloid chimerism
Restoration of blood cell count (in absence of growth factors) [at 12 months post stem cell transplant]
Absolute neutrophil count (ANC)≥1000 per microliter of blood, platelets ≥50000 per microliter of blood and hematocrit ≥8 grams per deciliter of blood

Secondary Outcome Measures

Feasibility of patients able to proceed to BMT within 6 months following lung transplantation [Up to 2 years post stem cell transplant]
The number of patients who are able to proceed to BMT within 6 months following lung transplantation
Independence [up to 2 years post stem cell transplant]
The number of patients who are able to be independent from transfusions and growth factors for at least 7 days
Independence [Up to 2 years post stem cell transplant]
The number of patients who are able to be independent from transfusions and growth factors for at least 1 month
Tolerance development to both host and pulmonary grafting [Up to 2 years post stem cell transplant]
Development of tolerance to both the host and pulmonary graft
Long-term complications [Up to 2 years post stem cell transplant]
Long-term complications of combined solid organ and BMT
Acute cellular rejection [Up to 2 years post stem cell transplant]
The number of patients who develop acute cellular rejection
Acute graft-versus-host-disease (GVHD) [Up to 2 years post stem cell transplant]
The number of patients who develop acute graft-versus-host-disease (GVHD)
Chronic graft-versus-host-disease (GVHD) [Up to 2 years post stem cell transplant]
The number of patients who develop chronic graft-versus-host-disease (GVHD)
Ability to withdrawal immunosuppression [By 1 year post stem cell transplant]
The number of patients who are able to start immunosuppression withdrawal.
Time to withdraw immunosuppression [Up to 2 years post stem cell transplant]
Time from BMT to withdrawal of immunosuppression
Prophylactic antimicrobial drugs [Up to 2 years post stem cell transplant]
Time from BMT to independence for prophylactic antimicrobial drugs
Treatment antimicrobial drugs [up to 2 years post stem cell transplant]
Time from BMT to independence from treatment antimicrobial drugs
Chronic lung allograft dysfunction [1 year post lung transplant]
The number of patients who develop chronic lung allograft dysfunction post lung transplant for all subjects, lung only and lung +stem cell transplant.

Other Outcome Measures

Pace of immune reconstitution [Up to 2 years post stem cell transplant]
The pace of immune reconstitution, systemically and in mucosal surfaces
Mixed chimerism [at Months 1, 3, 6 and 12 post stem cell transplant]
The number of patients who have the incidence of mixed chimerism (.5% host cells)
In vitro immune tolerance [Up to 2 years post stem cell transplant]
The number of patients who have in vitro immune tolerance

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Individuals must meet all of the following criteria in order to be eligible for this study.

Subject must be able to understand and provide informed consent.
Male or female, 18 through 60 years old, inclusive, at the time of informed consent.
Meet criteria for UNOS listing for lung transplantation.
Patients must have evidence of end stage lung disease. Examples of such diseases include but are not limited to:

Pulmonary Fibrosis
COPD/Emphysema

Patients must have evidence of bone marrow failure with abnormal low cell count in at least one hematopoietic line, making the patient a poor candidate for long-term immunosuppressive therapy. Eligible patients must meet at least one of the following criteria:

Unexplained, non-drug induced neutropenia with absolute neutrophils counts of <1500/µL the previous year, confirmed by repeat testing
Unexplained, non-drug induced thrombocytopenia with mean platelets counts of <100,000/µL the previous year, confirmed by repeat testing
Unexplained, non-hemolytic anemia, with a hemoglobin level of < 12 g/dL the previous year, confirmed by repeat testing

GFR ≥45 mL/min/1.73 m2.
AST, ALT ≤4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL, normal INR, albumin

3.0 g/dL

Cardiac ejection fraction ≥ 40% or shortening fraction ≥26%.
Negative pregnancy test for females, 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 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 BMT.
HIV positive by serology or PCR, HTLV positive by serology. If HTLV serology is positive, it will be confirmed by nucleic acid testing (NAT). If HTLV NAT is negative, subject will remain eligible regardless of HTLV serology result.
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 infection, as determined by the appropriate imaging and/or 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.