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

This will be a prospective, single-center, dose-escalation, open-label interventional study
to evaluate the safety and tolerability of allogeneic hMSCs in 15 clinically stable subjects
with 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
10EE6 allogeneic 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, MPO, GM-CSF, IL-1β, IL-6, IL8, IL-17, and
TNF-a) and sputum markers (white cell counts and differentials, IL-1β, IL-6, IL-8, IL-10,
IL-17, GM-CSF, MIP- 3a, TNF-a, and active proteases including neutrophil elastase,
a1-anti-trypsin, and 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.

CF Subject 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 mEq/L by quantitative pilocarpine
iontophoresis test (QPIT)

2. 2 well-characterized, disease causing mutations in the CFTR gene

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

4. FEV1 ≥ 40% predicted for age based on the global lung function initiative equations at
the screening visit

5. Weight ≥ 40 kg at the screening visit

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

7. Written informed consent obtained from the subject.

CF Subject 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, IV, 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. SGOT (ALT) or SGPT (AST) > 2.5 times the upper limit of normal at screening,
documented biliary cirrhosis, or portal hypertension

12. Total bilirubin concentration > 1.2 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/L, hematocrit <
30%, and platelets < 150 x 109 platelets/L

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

Inclusion Criteria for Healthy Volunteer Donors (NOTE: Enrollment for Healthy Volunteers is
closed):

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)

Inclusion Criteria for CF Donors:

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

Exclusion Criteria for both Healthy Volunteer Donors and CF Donors:

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 PI/Sub-Investigator deems relevant to exclude participation

4. Subject reported history of organ transplantation

5. Subject reported history of HIV, 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