Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases

Wiskott-Aldrich Syndrome Clinical Trial

— BOLT+BMT  

Official title:

Bilateral Orthotopic Lung Transplant in Tandem With CD3+ and CD19+ Cell Depleted Bone Marrow Transplant From Partially HLA-Matched Cadaveric Donors

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT01852370
• Other study ID #: STUDY19090108
• Status: Enrolling by invitation
• Phase: Phase 1/Phase 2
• Start date: June 20, 2013
• Est. completion date: November 2026

Study information

• Verified date: November 2023
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether bilateral orthotopic lung transplantation (BOLT) followed by cadaveric partially-matched hematopoietic stem cell transplantation (HSCT) is safe and effective for patients aged 5-45 years with primary immunodeficiency (PID) and end-stage lung disease.

Description:

This is an original IND for an investigator initiated phase I/II study. The primary purpose of the 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 patients with primary immunodeficiency diseases (PID) and end-stage lung disease. For many patients with primary immunodeficiencies, HSCT 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 HSCT due to the high risk of mortality and pulmonary complications. Lung transplant prior to HSCT would allow for restoration of pulmonary function prior to HSCT, allowing PID patients to proceed to HSCT, which would be curative for the patient's underlying immunodeficiency. As a secondary aim after successful engraftment with donor bone marrow, there is realistic hope for tolerating planned withdrawal of immunosuppression achieving eventual freedom from all immunosuppressive drugs and attaining a tolerant state.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 16
• Est. completion date: November 2026
• Est. primary completion date: November 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 45 Years

Eligibility

Inclusion Criteria

1. Subject and/or parent guardian must be able to understand and provide informed consent.

2. Male or female, 5 through 45 years old, inclusive, at the time of informed consent.

3. Patients must have evidence of an underlying primary immunodeficiency for which BMT is clinically indicated.

Examples of such diseases include, but are not limited to:

• Severe Combined Immunodeficiency

• Combined immunodeficiency with defects in T-cell-mediated immunity, including Omenn syndrome and DiGeorge Syndrome

• Severe Chronic Neutropenia

• Chronic Granulomatous Disease

• Hyper IgE Syndrome or Job Syndrome

• CD40 or CD40L deficiency

• Wiskott-Aldrich Syndrome

• Mendelian Susceptibility to Mycobacterial Disease [6]

• GATA2 Associated Immunodeficiency NOTE: A genetic diagnosis is recommended, but not required.

4. Patients must have evidence of end-stage lung disease and be candidates for bilateral orthotopic lung transplant as determined by the lung transplant team.

5. GFR = 50 mL/min/1.73 m2.

6. AST, ALT = 4x upper limit of normal, total bilirubin = 2.5 mg/dL, normal INR.

7. Cardiac ejection fraction = 40% or shortening fraction =26%.

8. Negative pregnancy test for females >10 years old or who have reached menarche, unless surgically sterilized.

9. 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.

10. 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.

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 hematopoietic stem cell transplantation.

4. HIV positive by serology or PCR, HTLV positive by serology.

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 systemic infection, as determined by the appropriate 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.

Eligibility Criteria to proceed to Bone Marrow Transplant

1. GFR = 50 mL/min/1.73 m2.

2. AST, ALT = 4x upper limit of normal, total bilirubin = 2.5 mg/dL.

3. Cardiac ejection fraction = 40% or shortening fraction of at least 26%.

4. HIV negative by serology and PCR.

5. HTLV serology negative.

6. FVC and FEV1 =40% predicted for age and SpO2 of >90% at rest on room air AND with clearance by the lung transplant team.

7. Absence of uncontrolled infection as determined by positive blood cultures and radiographic progression of previous sites in particular pulmonary densities during the past 2 weeks prior to chemotherapy.

8. Absence of clinically significant Acute Cellular Rejection (A2-A4 and/or B2R rejection).

Related Conditions & MeSH terms

• Chronic Granulomatous Disease (CGD)
• Common Variable Immune Deficiency (CVID)
• Common Variable Immunodeficiency
• Granulomatous Disease, Chronic
• Hyper IgE Syndromes
• Hyper IgM Deficiencies
• Immunodeficiency With Predominant T-cell Defect, Unspecified
• Immunologic Deficiency Syndromes
• Job Syndrome
• Mendelian Susceptibility to Mycobacterial Disease
• Mycobacterium Infections
• Neutropenia
• Severe Chronic Neutropenia
• Severe Combined Immunodeficiency
• Severe Combined Immunodeficiency (SCID)
• Syndrome
• Wiskott-Aldrich Syndrome

Intervention

Biological:
• CD3/CD19 negative allogeneic hematopoietic stem cells
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.

Locations

Country	Name	City	State
United States	Children's Hospital of Pittsburgh of UPMC	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
Primary	Safety: Death	How many, if any, patients die.	Up to 2 years post stem cell transplant
Primary	Safety: Engraftment syndrome	How many, if any, patients develop engraftment syndrome.	Up to 2 years post stem cell transplant
Primary	Safety: Engraftment failure	How many patients, if any, develop engraftment failure.	Up to 2 years post stem cell transplant
Primary	Safety: Rituximab	The number of grade 4 and 5 events potentially related to rituximab.	Up to 2 years post stem cell transplant
Primary	Efficacy: BOS score	Bronchiolitis Obliterans Syndrome (BOS) score for all patients who receive both lungs and stem cell transplants.	1 year post stem cell transplant
Primary	Efficacy: T-cell chimerism	The number of patients who have = 25% donor T-cell chimerism.	1 year post stem cell transplant
Primary	Efficacy: Myeloid chimerism	The number of patients with myeloid disorders (e.g. CGD) who attain = 10% myeloid chimerism.	1 year post stem cell transplant
Primary	Efficacy: B-cell chimerism	The number of patients with B-cell disorders who attain = 10% B-cell chimerism.	1 year post stem cell transplant
Secondary	Feasibility of meeting BMT eligibility critieria	The number of patients who are able to proceed to BMT within 6 months following lung transplant.	Up to 2 years post stem cell transplant
Secondary	Tolerance	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	Graft failure	The number of patients who develop graft failure.	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 patient 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 patient who develop chronic graft-versus-host disease (GVHD).	Up to 2 years post stem cell transplant
Secondary	Ability to withdraw immunosuppression	The number of patients who are able to start immunosuppression withdrawal.	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	Pathogen-specific immunity	Time from BMT to independence from treatment dose antimicrobial drugs.	Up to 2 years post stem cell transplant
Secondary	Lymphocyte count - for T-cell lymphopenias	The number of patients who are able to achieve an age adjusted, low limit normal range lymphocyte count.	1 year 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
Secondary	Allograft failure	The number of patients who develop allograft failure post-lung transplant for all subjects, lung only and lung+stem cell transplant.	1 year post lung transplant
Secondary	Rituximab related adverse events	The number of grade 4 or 5 adverse events possibly related to the use of rituximab.	From the time of the first dose of rituximab up to the start of BMT conditioning.