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Lung and Bone Marrow Transplantation for Lung and Bone Marrow Failure

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03500731
Recruitment Status : Recruiting
First Posted : April 18, 2018
Last Update Posted : March 23, 2020
Sponsor:
Information provided by (Responsible Party):
Paul Szabolcs, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE March 30, 2018
First Posted Date  ICMJE April 18, 2018
Last Update Posted Date March 23, 2020
Actual Study Start Date  ICMJE April 19, 2018
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Death [ Time Frame: Up to 2 years post stem cell transplant ]
    How many, if any, patients die
  • Engraftment failure [ Time Frame: Up to 2 years post stem cell transplant ]
    How many, if any, develop engraftment failure
  • Non-hematologic events [ Time Frame: Up to 2 years post stem cell transplant ]
    Any Grade 4 event that happens at any time points
  • Hematological events [ Time Frame: after 30 days post stem cell transplant ]
    Any Grade 4 hematological events
  • BOS Score [ Time Frame: 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 [ Time Frame: at 12 months post stem cell transplant ]
    The number of patients who have ≥25% donor T-cell chimerism
  • Myeloid chimerism [ Time Frame: 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) [ Time Frame: 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Feasibility of patients able to proceed to BMT within 6 months following lung transplantation [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 2 years post stem cell transplant ]
    Development of tolerance to both the host and pulmonary graft
  • Long-term complications [ Time Frame: Up to 2 years post stem cell transplant ]
    Long-term complications of combined solid organ and BMT
  • Acute cellular rejection [ Time Frame: Up to 2 years post stem cell transplant ]
    The number of patients who develop acute cellular rejection
  • Acute graft-versus-host-disease (GVHD) [ Time Frame: 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) [ Time Frame: Up to 2 years post stem cell transplant ]
    The number of patients who develop chronic graft-versus-host-disease (GVHD)
  • Ability to withdrawal immunosuppression [ Time Frame: By 1 year post stem cell transplant ]
    The number of patients who are able to start immunosuppression withdrawal.
  • Time to withdraw immunosuppression [ Time Frame: Up to 2 years post stem cell transplant ]
    Time from BMT to withdrawal of immunosuppression
  • Prophylactic antimicrobial drugs [ Time Frame: Up to 2 years post stem cell transplant ]
    Time from BMT to independence for prophylactic antimicrobial drugs
  • Treatment antimicrobial drugs [ Time Frame: up to 2 years post stem cell transplant ]
    Time from BMT to independence from treatment antimicrobial drugs
  • Chronic lung allograft dysfunction [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 9, 2018)
  • Pace of immune reconstitution [ Time Frame: Up to 2 years post stem cell transplant ]
    The pace of immune reconstitution, systemically and in mucosal surfaces
  • Mixed chimerism [ Time Frame: 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 [ Time Frame: Up to 2 years post stem cell transplant ]
    The number of patients who have in vitro immune tolerance
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Lung and Bone Marrow Transplantation for Lung and Bone Marrow Failure
Official Title  ICMJE Lung Transplant in Tandem With Bone Marrow Transplant for Combined Lung and Bone Marrow Failure
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Idiopathic Pulmonary Fibrosis
  • Emphysema or COPD
Intervention  ICMJE
  • 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 Name: Rituxan
  • Drug: Alemtuzumab
    Transplantation Conditioning
    Other Name: Campath-1H
  • Drug: Fludarabine
    Transplantation Conditioning
    Other Name: Fludara, Oforta
  • Drug: Thiotepa
    Transplantation Conditioning
  • Drug: G-CSF
    Transplantation conditioning
    Other Name: Neupogen, Granix, Zarxio, Filgrastim
  • Drug: Hydroxyurea
    Transplantation Conditioning
Study Arms  ICMJE 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.

Interventions:
  • Biological: CD3/CD19 negative hematopoietic stem cells
  • Drug: Rituximab
  • Drug: Alemtuzumab
  • Drug: Fludarabine
  • Drug: Thiotepa
  • Drug: G-CSF
  • Drug: Hydroxyurea
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2018)
8
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2026
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

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

    • Pulmonary Fibrosis
    • COPD/Emphysema
  5. 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
  6. GFR ≥45 mL/min/1.73 m2.
  7. AST, ALT ≤4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL, normal INR, albumin >3.0 g/dL
  8. Cardiac ejection fraction ≥ 40% or shortening fraction ≥26%.
  9. Negative pregnancy test for females, unless surgically sterilized.
  10. 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.
  11. 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.

  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. HIV positive by serology or PCR, HTLV positive by serology.
  4. Females who are pregnant or who are lactating.
  5. Allergy to DMSO or any other ingredient used in the manufacturing of the stem cell product.
  6. Uncontrolled infection, as determined by the appropriate imaging and/or confirmatory testing e.g. blood cultures, PCR testing, etc.
  7. Recent recipient of any licensed or investigational live attenuated vaccine(s) within 4 weeks of transplant.
  8. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Paul Szabolcs, M.D. 412-692-5427 Paul.Szabolcs@chp.edu
Contact: Shawna H McIntyre, RN 412-692-5552 ext 4126925552 mcintyresm@upmc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03500731
Other Study ID Numbers  ICMJE PRO17110400
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Paul Szabolcs, University of Pittsburgh
Study Sponsor  ICMJE Paul Szabolcs
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University of Pittsburgh
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP