Safety and Tolerability Study of Allogeneic Mesenchymal Stem Cell Infusion in Adults With Cystic Fibrosis

NCT ID: NCT02866721

Last Updated: 2023-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-31
• Study Completion Date: 2020-08-31

Brief Summary

This study is being done to test if it is safe to give stem cells to adult patients with Cystic Fibrosis (CF). The kind of stem cells we are studying are called allogeneic human mesenchymal stem cells or MSCs. MSCs are cells in the body that can grow into different types of cells and respond to various environmental situations. Allogeneic means the cells come from another person (a donor).

This study is only looking at whether or not it is safe to give the stem cells to adults with CF and how the infusion is tolerated. In the future, other studies may be done to see if stem cells can be a new therapeutic treatment for CF.

Stem cells, like other medical products that are intended to treat, cure or prevent disease, generally require approval from the U.S. Food and Drug Administration (FDA) before they can be marketed. The FDA has not approved any stem cell-based products for usual medical care, other than some specific blood forming stem cells for certain indications.

Detailed Description

This will be a prospective, single-center, dose-escalation, open-label interventional study to evaluate the safety and tolerability of allogeneic human mesenchymal stem cells (hMSCs) in 15 clinically stable subjects with cystic fibrosis (CF) age ≥ 18 years. After a two to six week screening period, subjects will have a Baseline visit (Days 1-2) where they will undergo a single intravenous infusion of up to 5 x 10E6 allogeneic hMSCs/kilogram (hMSCs/kg) of body weight. Infusions will be performed in the Dahms Clinical Research Unit (DCRU) of University Hospitals Cleveland Medical Center. Subjects will be monitored for any infusion related toxicities for 24 hours after the infusion. Subsequent study visits will occur on Days 7, 14, 28, Months 3 and 6 and telephone calls will occur on Days 4 (or 5), 21, 56 and Month 12. Subject safety and tolerability of a single dose of hMSCs will be evaluated at study visits by review of subject diaries, interval history, pulmonary exacerbations, physical examination, spirometry, and analysis of safety laboratories. Special attention will be placed upon detecting pulmonary exacerbations because anti-inflammatory therapies theoretically could suppress the immune system to the point where it leads to increased infectious complications, although MSC therapeutics are proposed to be antimicrobial. In addition to evaluating safety, this study will also explore efficacy end-points for future clinical trials of MSCs in CF including inflammatory biomarkers from blood and sputum. Serum markers (calprotectin, myeloperoxidase (MPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1β (IL-1β), IL-6, IL8, IL-17, and tumor necrosis factor-a (TNF-a) and sputum markers (white cell counts and differentials, IL-1β, IL-6, IL-8, IL-10, IL-17, GM-CSF, macrophage inflammatory protein-3a (MIP- 3a), TNF-a, and active proteases including neutrophil elastase, alpha-1-antitrypsin, and matrix metallopeptidase 9 (MMP-9) will be determined at Baseline and on Days 7 and 28 for with-in subject comparison. All subject samples will be archived for future projects. Finally, a diagnostic bone marrow exam will be performed on subjects with CF who consent to undergo this optional procedure. Bone marrow samples will be banked and used for future translational studies.

Conditions

Cystic Fibrosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Human Allogeneic Mesenchymal Stem Cells

One time intravenous (IV) Infusion of up to 5 x 10\^6 allogeneic human mesenchymal stem cells per kilogram of body weight (hMSCs/kg). A dose escalation using the "3+3" design will be employed. The three doses are 1 x 10\^6, 3 x 10\^6, and 5 x 10\^6 hMSCs/kg. There is no placebo group. All study participants will receive stem cells.

Group Type: EXPERIMENTAL

Mesenchymal Stem Cells

Intervention Type: BIOLOGICAL

A single dose, one time infusion (in the vein) of one of the following doses of human mesenchymal stem cells (hMSCs): 1 x 10^6, 3 x 10^6 or 5 x 10^6 human mesenchymal stem cells per kilogram body weight (hMSCs/kg) during Visit 2. A traditional 3+3 design will be utilized.

Allogeneic mesenchymal stem cells (MSCs) will be derived from bone marrow aspirates from a healthy donor whose serum tests negative for cytomegalovirus (CMV) antibodies. Healthy donors will undergo tests for infectious disease and screening for 41 common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. In addition, the MSCs will be validated for in vitro and in vivo efficacy and potency using the in vivo murine pre-clinical model of cystic fibrosis lung infection and inflammation.

Interventions

Mesenchymal Stem Cells

A single dose, one time infusion (in the vein) of one of the following doses of human mesenchymal stem cells (hMSCs): 1 x 10^6, 3 x 10^6 or 5 x 10^6 human mesenchymal stem cells per kilogram body weight (hMSCs/kg) during Visit 2. A traditional 3+3 design will be utilized.

Allogeneic mesenchymal stem cells (MSCs) will be derived from bone marrow aspirates from a healthy donor whose serum tests negative for cytomegalovirus (CMV) antibodies. Healthy donors will undergo tests for infectious disease and screening for 41 common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. In addition, the MSCs will be validated for in vitro and in vivo efficacy and potency using the in vivo murine pre-clinical model of cystic fibrosis lung infection and inflammation.

Intervention Type: BIOLOGICAL

Other Intervention Names

MSCs

Eligibility Criteria

Inclusion Criteria

1. Male or female ≥18 years of age

2. Confirmed diagnosis of CF as evidenced by 1 or more clinical features consistent with the CF phenotype and 1 or more of the following criteria:

1. Sweat chloride equal to or greater than 60 milliequivalents per liter (mEq/L) by quantitative pilocarpine iontophoresis test (QPIT)

2. 2 well-characterized, disease causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

3. Clinically stable with no significant changes in health status within 2 weeks prior to screening.

4. Forced expiratory volume in the first second (FEV1) ≥ 40% predicted for age based on the global lung function initiative equations at the screening visit

5. Weight ≥ 40 kilograms at the screening visit

6. Able to perform repeatable, consistent efforts in pulmonary function testing

7. Written informed consent obtained from the subject.

1. Male/female age ≥ 18 years to ≤ 40 years

2. Able to understand and sign consent form (a legally authorized representative will not be permitted)

1. CF subject enrolled in the main study and consented to this optional procedure

Exclusion Criteria

1. Use of an investigational agent within the 4-week period prior to Visit 1 (Day -42 to -10)

2. Chronic daily (>10 mg) or alternate daily (>20 mg on alternate days) use of systemic corticosteroids within the 4 weeks prior to Visit 1 (Day -42 to -10) or initiation of any dosage of systemic corticosteroids within 72 hours prior to Visit 2 (Day 1).

3. Use of hydroxychloroquine or immunosuppressants.

4. Initiation of a new antibiotic (oral, intravenous, and/or inhaled) that is not part of the subject's maintenance regimen for treatment of acute respiratory symptoms within 2 weeks prior to screening through Visit 2 (Day 1)

5. Initiation of any new chronic therapy (e.g., Pulmozyme®, hypertonic saline, Kalydeco®, Orkambi®, high-dose ibuprofen azithromycin, TOBI®, Cayston®, nebulized colistiin, bronchodilators, inhaled corticosteroids, etc.) within 4 weeks prior to screening

6. Active treatment for non-tuberculous Mycobacteria

7. History of a sputum culture positive for a Burkholderia cepacia complex organism in the previous 12 months.

8. Current tobacco smoker

9. Oxygen saturation < 92% on room air at Visit 1 (Day -42 to -10)

10. History of pulmonary hypertension

11. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension

12. Total bilirubin concentration > 1.2 milligram per deciliter (mg/dL) at screening

13. Creatinine > 1.8 mg/dL at screening

14. Pregnant, breastfeeding, or unwilling to practice birth control between Visit 2 (Day 1) and Telephone Call 3 (Day 56) (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent), unless surgically sterilized or postmenopausal

15. Screening hematology with white blood cell count < 4.5 x 109 cells/liter, hematocrit < 30%, and platelets < 150 x 109 platelets/liter

16. History of invasive cancer requiring systemic therapy

17. History of organ transplantation

18. Currently listed for lung transplantation or having potential to be listed for lung transplantation in the succeeding 12 calendar months from screening

19. Subject unlikely to complete the study as determined by the Investigator

1. Fever or current illness on the day of the cell collection

2. Evidence of communicable disease

3. Any significant change in health status within 2 weeks prior to cell collection that the Principal Investigator/Sub-Investigator deems relevant to exclude participation

4. Subject reported history of organ transplantation

5. Subject reported history of human immunodeficiency virus, hepatitis B or C, or syphilis

6. For HV donors only, subject-reported known history of being diagnosed with cystic fibrosis (CF) or being a CF carrier (one copy of CF gene mutation)

7. Positive screening blood test result for any infectious disease.

8. For HV donors only, positive test result for CMV or a CF gene mutation.

9. Pregnant, planning a pregnancy, or breast-feeding at screening

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Case Western Reserve University

OTHER

Sponsor Role: collaborator

Cystic Fibrosis Foundation

OTHER

Sponsor Role: collaborator

University Hospitals Cleveland Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Erica A. Roesch, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospitals Cleveland Medical Center

Locations

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

Countries

United States

References

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: RESULT

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Sutton MT, Fletcher D, Ghosh SK, Weinberg A, van Heeckeren R, Kaur S, Sadeghi Z, Hijaz A, Reese J, Lazarus HM, Lennon DP, Caplan AI, Bonfield TL. Antimicrobial Properties of Mesenchymal Stem Cells: Therapeutic Potential for Cystic Fibrosis Infection, and Treatment. Stem Cells Int. 2016;2016:5303048. doi: 10.1155/2016/5303048. Epub 2016 Jan 26.

Reference Type: RESULT

PMID: 26925108 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

DASENB15A0

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

Protocol CF-MSC-01

Identifier Type: -

Identifier Source: org_study_id