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

NCT02866721 | Completed Phase 1 Results DMC

• 2 other identifiers: Protocol CF-MSC-01DASENB15A0
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Cystic Fibrosis

Keywords

Human Mesenchymal Stem Cells

Outcome Measures

Primary Outcomes (4)

• 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.

  24 hours post infusion

• Number of Serious Adverse Events and Number of Non-Serious Adverse Events

  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.

  1 year

• Number of Pulmonary Exacerbations Requiring Intravenous Antibiotics

  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.

  1 year

• 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

Secondary Outcomes (16)

• Serum Inflammatory Markers - Calportectin Measurements at Baseline, Day 7, and Day 28

  Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion

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

  Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion

• Serum Inflammatory Markers - Interleukin-1 (IL-1) Measurements at Baseline, Day 7, and Day 28

  Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion

• Serum Inflammatory Markers - Interleukin-17 (IL-17) Measurements at Baseline, Day 7, and Day 28

  Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion

• Serum Inflammatory Markers - Interleukin-6 (IL-6) Measurements at Baseline, Day 7, and Day 28

  Baseline, Day 7, Day 28 post human mesenchymal stem cell infusion

Study Arms (1)

Human Allogeneic Mesenchymal Stem Cells

EXPERIMENTAL

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.

Biological: Mesenchymal Stem Cells

Interventions

Mesenchymal Stem Cells 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.

Also known as: MSCs

Human Allogeneic Mesenchymal Stem Cells

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospitals Cleveland Medical Center: lead
• Case Western Reserve University: collaborator
• Cystic Fibrosis Foundation: collaborator

Study Sites (1)

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

Related Publications (10)

• Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the clinical trial design task force of the national cancer institute investigational drug steering committee. Clin Cancer Res. 2010 Mar 15;16(6):1726-36. doi: 10.1158/1078-0432.CCR-09-1961. Epub 2010 Mar 9.

  PMID: 20215542 BACKGROUND

• Inamdar AC, Inamdar AA. Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell. Exp Lung Res. 2013 Oct;39(8):315-27. doi: 10.3109/01902148.2013.816803. Epub 2013 Aug 30.

  PMID: 23992090 BACKGROUND

• Gebler A, Zabel O, Seliger B. The immunomodulatory capacity of mesenchymal stem cells. Trends Mol Med. 2012 Feb;18(2):128-34. doi: 10.1016/j.molmed.2011.10.004. Epub 2011 Nov 25.

  PMID: 22118960 BACKGROUND

• Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559. doi: 10.1371/journal.pone.0047559. Epub 2012 Oct 25.

  PMID: 23133515 BACKGROUND

• Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009 Jan;217(2):318-24. doi: 10.1002/path.2469.

  PMID: 19023885 BACKGROUND

• Bonfield TL, Caplan AI. Adult mesenchymal stem cells: an innovative therapeutic for lung diseases. Discov Med. 2010 Apr;9(47):337-45.

  PMID: 20423678 BACKGROUND

• Dimarino AM, Caplan AI, Bonfield TL. Mesenchymal stem cells in tissue repair. Front Immunol. 2013 Sep 4;4:201. doi: 10.3389/fimmu.2013.00201.

  PMID: 24027567 BACKGROUND

• Antunes MA, Laffey JG, Pelosi P, Rocco PR. Mesenchymal stem cell trials for pulmonary diseases. J Cell Biochem. 2014 Jun;115(6):1023-32. doi: 10.1002/jcb.24783.

  PMID: 24515922 BACKGROUND

• Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol. 2007 Aug 1;179(3):1855-63. doi: 10.4049/jimmunol.179.3.1855.

  PMID: 17641052 RESULT

• 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.

  PMID: 26925108 RESULT

MeSH Terms

Conditions

Cystic Fibrosis

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Limitations and Caveats

Limitations include the small sample size and short study period. The primary objective was to determine safety, therefore therapeutic exposure was limited to a single dose of human mesenchymal stem cells (hMSCs). The clinical trial was not powered to detect changes in secondary exploratory measures, thus limiting our understanding of the impact of hMSCs on inflammation in cystic fibrosis. The ability to assess efficacy was further limited by the inability of participants to produce sputum.

Results Point of Contact

• Title: Erica Roesch, MD
• Organization: University Hospitals, Rainbow Babies and Children's Hospital

Erica.Roesch@UHHospitals.org

(216) 844-3267

Study Officials

• Erica A. Roesch, MD

  University Hospitals Cleveland Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2016
• First Posted: August 15, 2016
• Study Start: August 1, 2016
• Primary Completion: August 1, 2020
• Study Completion: August 1, 2020
• Last Updated: January 30, 2023
• Results First Posted: January 30, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)