Lung and Bone Marrow Transplantation for Lung and Bone Marrow Failure

Idiopathic Pulmonary Fibrosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03500731
• Other study ID #: PRO17110400
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 19, 2018
• Est. completion date: December 2026

Study information

• Verified date: January 2024
• Source: University of Pittsburgh
• Contact: Paul Szabolcs, M.D.
• Phone: 412-692-5427
• Email: Paul.Szabolcs[@]chp.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 8
• Est. completion date: December 2026
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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. Patients who have non-malignant conditions not requiring BMT.

4. 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.

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 infection, as determined by the appropriate imaging and/or 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.

Related Conditions & MeSH terms

• Bone Marrow Failure Disorders
• Emphysema
• Emphysema or COPD
• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Pancytopenia
• Pulmonary Emphysema
• Pulmonary Fibrosis

Intervention

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
• Alemtuzumab
Transplantation Conditioning
• Fludarabine
Transplantation Conditioning
• Thiotepa
Transplantation Conditioning
• G-CSF
Transplantation conditioning
• Hydroxyurea
Transplantation Conditioning

Locations

Country	Name	City	State
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	UPMC Presbyterian	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Paul Szabolcs

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pace of immune reconstitution	The pace of immune reconstitution, systemically and in mucosal surfaces	Up to 2 years post stem cell transplant
Other	Mixed chimerism	The number of patients who have the incidence of mixed chimerism (.5% host cells)	at Months 1, 3, 6 and 12 post stem cell transplant
Other	In vitro immune tolerance	The number of patients who have in vitro immune tolerance	Up to 2 years post stem cell transplant
Primary	Death	How many, if any, patients die	Up to 2 years post stem cell transplant
Primary	Engraftment failure	How many, if any, develop engraftment failure	Up to 2 years post stem cell transplant
Primary	Non-hematologic events	Any Grade 4 event that happens at any time points	Up to 2 years post stem cell transplant
Primary	Hematological events	Any Grade 4 hematological events	after 30 days post stem cell transplant
Primary	BOS Score	Bronchiolitis Obliterans Syndrome (BOS) score based off patient pulmonary function testing. Graded on scale (BOS0 to BOS3), BOS0 having a better outcome then BOS3	at 1 year post lung transplant
Primary	T-cell Chimerism	The number of patients who have =25% donor T-cell chimerism	at 12 months post stem cell transplant
Primary	Myeloid chimerism	The number of patients with myeloid disorders who attain = 10% myeloid chimerism	at 12 months post stem cell transplant
Primary	Restoration of blood cell count (in absence of growth factors)	Absolute neutrophil count (ANC)=1000 per microliter of blood, platelets =50000 per microliter of blood and hematocrit =8 grams per deciliter of blood	at 12 months post stem cell transplant
Secondary	Feasibility of patients able to proceed to BMT within 6 months following lung transplantation	The number of patients who are able to proceed to BMT within 6 months following lung transplantation	Up to 2 years post stem cell transplant
Secondary	Independence	The number of patients who are able to be independent from transfusions and growth factors for at least 7 days	up to 2 years post stem cell transplant
Secondary	Independence	The number of patients who are able to be independent from transfusions and growth factors for at least 1 month	Up to 2 years post stem cell transplant
Secondary	Tolerance development to both host and pulmonary grafting	Development of tolerance to both the host and pulmonary graft	Up to 2 years post stem cell transplant
Secondary	Long-term complications	Long-term complications of combined solid organ and BMT	Up to 2 years post stem cell transplant
Secondary	Acute cellular rejection	The number of patients who develop acute cellular rejection	Up to 2 years post stem cell transplant
Secondary	Acute graft-versus-host-disease (GVHD)	The number of patients who develop acute graft-versus-host-disease (GVHD)	Up to 2 years post stem cell transplant
Secondary	Chronic graft-versus-host-disease (GVHD)	The number of patients who develop chronic graft-versus-host-disease (GVHD)	Up to 2 years post stem cell transplant
Secondary	Ability to withdrawal immunosuppression	The number of patients who are able to start immunosuppression withdrawal.	By 1 year post stem cell transplant
Secondary	Time to withdraw immunosuppression	Time from BMT to withdrawal of immunosuppression	Up to 2 years post stem cell transplant
Secondary	Prophylactic antimicrobial drugs	Time from BMT to independence for prophylactic antimicrobial drugs	Up to 2 years post stem cell transplant
Secondary	Treatment antimicrobial drugs	Time from BMT to independence from treatment antimicrobial drugs	up to 2 years post stem cell transplant
Secondary	Chronic lung allograft dysfunction	The number of patients who develop chronic lung allograft dysfunction post lung transplant for all subjects, lung only and lung +stem cell transplant.	1 year post lung transplant