Safety and Tolerability Study of Allogeneic Mesenchymal Stem Cell Infusion in Adults With Cystic Fibrosis (CEASE-CF)

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

A Phase I, Single Center, Open Label, Single Dose, Dose Escalation Study Assessing the Safety and Tolerability of AllogeneiC MEsenchymAl Stem CEll Infusion in Adults With Cystic Fibrosis-CEASE CF

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.

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.

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.

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.

Number of Participants With a Dose Limiting Toxicity (DLT), Triggered by Occurrence in the First 24 Hours After Human Mesenchymal Stem Cell (hMSC) Infusion of Grade ≥3 Infusion-related Allergic Toxicities

For this study, dose limiting toxicities included the emergence of infusion-related allergic adverse events as well as regimen related toxicities in the first 24 hours after hMSC infusion of a grade ≥ 3 as scored according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. This is the number of participants who experienced a dose limiting toxicity during the study.

Participants were followed for 12 months after human mesenchymal stem cell infusion. All events from the infusion date through the end of follow-up were included. This shows the total number of adverse events or serious adverse events occurring in each dosing cohort.

Participants were followed for 12 months after human mesenchymal stem cell infusion. All events occurring from the infusion date through the end of follow-up were included. This shows the number of pulmonary exacerbations requiring intravenous antibiotics in each dosing cohort.

Forced Expiratory Volume in the First Second (FEV1) % Predicted at Baseline and 30 Minutes, 4 Hours, 24 Hours, 7 Days, 14 Days, 28 Days, 3 Months, 6 Months Post Human Mesenchymal Stem Cell Infusion.

Lung function was followed for 6 months post human mesenchymal stem cell infusion. This shows the mean forced expiratory volume in the first second (FEV1) percent predicted for each cohort throughout the study.

Baseline and 30 minutes, 4 hours, 24 hours, 7 days, 14 days, 28 days, 3 months, 6 months Post Human Mesenchymal Stem Cell Infusion

Serum inflammatory markers including Calprotectin were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for calportectin was 88.3 picogram per millilitre.

Serum Inflammatory Markers - Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Measurements at Baseline, Day 7, and Day 28

Serum inflammatory markers including Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for GM-CSF was 2.6 picograms per milliliter.

Serum inflammatory markers including interleukin -1 (IL-1) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for IL-1 was 13.1 picograms per milliliter.

Serum inflammatory markers including interleukin -17 (IL-17) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for IL-17 was 13.5 picograms per milliliter.

Serum inflammatory markers including interleukin -6 (IL-6) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for IL-6 was 13.5 picograms per milliliter.

Serum inflammatory markers including interleukin -8 (IL-8) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit for detection for IL-8 was 13.9 picograms per milliliter.

Serum inflammatory markers including myeloperoxidase (MPO) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown.

Serum Inflammatory Markers - Tumor Necrosis Factor Alpha (TNF-a) Measurements at Baseline, Day 7, and Day 28

Serum inflammatory markers including tumor necrosis factor alpha (TNF-a) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with standard deviation are shown. The lower limit of detection for TNF-a was 12.9 picograms per millilter.

Sputum Inflammatory Markers - Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Measurements at Baseline, Day 7, and Day 28

Sputum inflammatory markers including granulocyte-macrophage colony-stimulating factor (GM-CSF) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Sputum inflammatory markers including interleukin-1 (IL-1) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Sputum inflammatory markers including interleukin-10 (IL-10) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Sputum inflammatory markers including interleukin-17 (IL-17) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Sputum inflammatory markers including interleukin-6 (IL-6) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Sputum inflammatory markers including interleukin-8 (IL-8) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Sputum Inflammatory Markers - Macrophage Inflammatory Protein-3 Alpha (MIP-3a) Measurements at Baseline, Day 7, and Day 28

Sputum inflammatory markers including macrophage inflammatory protein-3 alpha (MIP-3a) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Sputum Inflammatory Markers - Tumor Necrosis Factor Alpha (TNF-a) Measurements at Baseline, Day 7, and Day 28

Sputum inflammatory markers including tumor necrosis factor alpha (TNF-a) were collected at baseline and at the visits 7 days and 28 days post human mesenchymal stem cell (hMSC) infusion. Mean values with range are shown.

Cystic Fibrosis (CF) Subject Inclusion Criteria: Male or female ≥18 years of age 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: Sweat chloride equal to or greater than 60 milliequivalents per liter (mEq/L) by quantitative pilocarpine iontophoresis test (QPIT) 2 well-characterized, disease causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene Clinically stable with no significant changes in health status within 2 weeks prior to screening. Forced expiratory volume in the first second (FEV1) ≥ 40% predicted for age based on the global lung function initiative equations at the screening visit Weight ≥ 40 kilograms at the screening visit Able to perform repeatable, consistent efforts in pulmonary function testing Written informed consent obtained from the subject. CF Subject Exclusion Criteria: Use of an investigational agent within the 4-week period prior to Visit 1 (Day -42 to -10) 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). Use of hydroxychloroquine or immunosuppressants. 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) 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 Active treatment for non-tuberculous Mycobacteria History of a sputum culture positive for a Burkholderia cepacia complex organism in the previous 12 months. Current tobacco smoker Oxygen saturation < 92% on room air at Visit 1 (Day -42 to -10) History of pulmonary hypertension Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension Total bilirubin concentration > 1.2 milligram per deciliter (mg/dL) at screening Creatinine > 1.8 mg/dL at screening 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 Screening hematology with white blood cell count < 4.5 x 109 cells/liter, hematocrit < 30%, and platelets < 150 x 109 platelets/liter History of invasive cancer requiring systemic therapy History of organ transplantation Currently listed for lung transplantation or having potential to be listed for lung transplantation in the succeeding 12 calendar months from screening Subject unlikely to complete the study as determined by the Investigator Inclusion Criteria for Healthy Volunteer Donors (NOTE: Enrollment for Healthy Volunteers is closed): Male/female age ≥ 18 years to ≤ 40 years 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 (HV) Donors and CF Donors: Fever or current illness on the day of the cell collection Evidence of communicable disease Any significant change in health status within 2 weeks prior to cell collection that the Principal Investigator/Sub-Investigator deems relevant to exclude participation Subject reported history of organ transplantation Subject reported history of human immunodeficiency virus, hepatitis B or C, or syphilis 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) Positive screening blood test result for any infectious disease. For HV donors only, positive test result for CMV or a CF gene mutation. Pregnant, planning a pregnancy, or breast-feeding at screening

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