Stem Cell Injection in Cancer Survivors

Condition(s) targeted: Cardiomyopathy Due to Anthracyclines

Intervention: Allo-MSCs (Biological); Placebo (Biological)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: The University of Texas Health Science Center, Houston

Official(s) and/or principal investigator(s):
Robert Simari, MD, Study Chair, Affiliation: CCTRN Steering Committee Chair

Overall contact:
Shelly L Sayre, MPH, Phone: 713-500-9529, Email: Shelly.L.Sayre@uth.tmc.edu

The primary purpose of this study is to examine the safety and feasibility of delivering allogeneic human mesenchymal stem cells (allo-MSCs) by transendocardial injection to cancer survivors with left ventricular (LV) dysfunction secondary to anthracycline-induced cardiomyopathy (AIC). The secondary purpose of this study is to obtain preliminary evidence for therapeutic efficacy of allo-MSCs delivered by transendocardial injection to cancer survivors with LV dysfunction secondary to AIC.

Official title: A Phase I, First-in-Human, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Study of the Safety and Efficacy of Allogeneic Mesenchymal Stem Cells in Cancer Survivors With Anthracycline-Induced Cardiomyopathy

Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Change in Left Ventricular Ejection Fraction (LVEF) as measured by cMRI

Change in Global Strain (HARP MRI) as measured by cMRI

Change in Regional Strain (HARP MRI) as measured by cMRI

Change in Left Ventricular End Diastolic Volume Index (LVEDVI) as measured by cMRI

Change in Left Ventricular End Systolic Volume Index (LVESVI) as measured by cMRI

Change in Left Ventricular Sphericity Index as measured by cMRI

Change in Area of Injury as measured by cMRI

Change in Exercise Tolerance as measured by the six minute walk test

Change in Minnesota Living with Heart Failure Questionnaire (MHLFQ) Score

Incidence Rate of Major Adverse Cardiac Events (MACE)

Cumulative Days Alive and Out of the Hospital

Change in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as measured by blood draw

Secondary outcome:

Change in Left Ventricular Ejection Fraction (LVEF) as measured by cMRI

Change in Global Strain (HARP MRI) as measured by cMRI

Change in Regional Strain (HARP MRI) as measured by cMRI

Change in Left Ventricular End Diastolic Volume Index (LVEDVI)

Change in Left Ventricular End Systolic Volume Index (LVESVI)

Change in Lef Ventricular Sphericity Index as measured by cMRI

Change in Area of Injury as measured by cMRI

Change in Exercise Tolerance as measured by the six minute walk test

Change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) Score

Incidence Rate of Major Cardiac Adverse Events (MACE)

Cumulative Days Alive and Out of Hospital

Change in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as measured by blood draw

Detailed description: This phase I, randomized, placebo-controlled, trial will evaluate the safety and feasibility of allo-MSCs administered by transendocardial injection in thirty-six subjects with anthracycline-induced cardiomyopathy (AIC). The first six subjects will receive allo-MSC therapy (open label) and will be assessed for safety and feasibility of the study procedures. Following 1 month data review of each of the six subjects by the National Heart, Lung, and Blood Institute Gene and Cell Therapy Data Safety Monitoring Board; this will be followed by a randomized, double-blind clinical trial enrolling thirty subjects. These thirty subjects will be randomized 1: 1 to receive allo-MSCs or placebo. All subjects will undergo cardiac catheterization and study product administration using the NOGA Myostar catheter injection system. Subjects will be followed at 1 day, 1 week, 1 month, 6 months, and 12 months post study product injection. All endpoints will be assessed at the 6 and 12 month visits which will occur 180 ±30 days and 365 ±30 days, respectively, after the day of study product injection (Day 0). For the purpose of the safety evaluations and endpoint analysis, the Investigators will utilize an "intention-to-treat" study population. In addition, because this phase I study is the first cell therapy study in this population, at 12 months all available standard-of-care medical records for cancer surveillance will be reviewed for cancer recurrence.

Minimum age: 18 Years. Maximum age: 79 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Be ≥ 18 and < 80 years of age 2. Be a cancer survivor with diagnosis of AIC 3. Have a left ventricular ejection fraction (LVEF) < 40% by cardiac magnetic resonance imaging (cMRI) 4. Be in New York Heart Association (NYHA) class II-III 5. Have received the initial diagnosis of AIC at least six months earlier and be on stable, optimally-tolerated therapy with beta-blockers, ACE inhibitors/angiotensin receptor blocker, and/or aldosterone antagonists for 1 month, unless contraindicated 6. Have a period of at least two years of clinical cancer-free state and low likelihood of recurrence (a five-year risk of recurrence estimated at 30% or less), as determined by an oncologist, based on tumor type, response to therapy, and negative metastatic work-up at the time of diagnosis 7. Be a candidate for cardiac catheterization Exclusion Criteria: 1. A life expectancy <12 months 2. A CT scan or baseline cardiac MRI showing new tumor or suspicious lymphadenopathy raising concern of malignancy 3. Presence of coronary artery disease (CAD) as determined by one of the following: a coronary arteriogram within the last 24 months, a rest and stress nuclear scan (SPECT) within the last 12 months, or a stress echocardiogram within the last 12 months prior to enrollment in the study 4. A history of radiation therapy AND evidence of constrictive physiology and/or evidence of other patterns of non-ischemic cardiomyopathy on cardiac MRI (e. g., amyloidosis, sarcoidosis, hemochromatosis, pure radiation-induced cardiomyopathy, etc.) not consistent with AIC being the dominant etiology of heart failure 5. Severe valvular heart disease including mechanical or bioprosthetic heart valve, severe aortic, mitral, tricuspid, or pulmonic insufficiency/regurgitation (echocardiographic assessment of aortic insufficiency graded as > +4), or documented presence of aortic stenosis (aortic stenosis with orifice area of 1. 5cm2 or less) 6. A history of LV reduction surgery or cardiomyoplasty 7. Evidence of cardiogenic shock 8. A history of ischemic or hemorrhagic stroke within 90 days of baseline testing 9. Liver dysfunction during baseline testing, as evidenced by enzymes (e. g., aspartate transaminase, alanine transaminase, alkaline phosphatase) greater than 3 times upper limit of normal 10. Diabetes with poorly controlled blood glucose levels (HbA1c > 8. 5%) 11. An underlying autoimmune disorder or current immunosuppressive therapy (e. g., chronic corticosteroid, rheumatologic or immune modulating therapy) or likelihood of use of immunosuppressive therapy during participation in the trial 12. A baseline glomerular filtration rate (eGFR) <40 ml/min/1. 73m2 estimated using MDRD 13. A contrast allergy that cannot adequately be managed by premedication 14. A history of organ or cell transplantation, except for bone, skin, ligament, tendon, or cornea grafting 15. A hematologic abnormality during baseline testing as evidenced by hemoglobin < 9 g/dl; hematocrit < 30%; absolute neutrophil count < 2,000 or total white blood cell count more than 2 times upper limit of normal; or platelet values < 100,000/ul 16. Evidence of active systemic infection at time of study product delivery 17. HIV, and/or active hepatitis B (HBV) or hepatitis C (HCV) virus 18. Coagulopathy (INR > 1. 5) not due to a reversible cause (e. g., warfarin and/or Factor Xa inhibitors) Note: Subjects who cannot be withdrawn from anticoagulation will be excluded. 19. Presence of LV thrombus 20. Presence of a pacemaker and/or internal cardiac defibrillator (ICD) generator with any of the following limitations/conditions:

- manufactured before the year 2000

- leads implanted < 6 weeks prior to consent

- non-transvenous epicardial, abandoned, or no-fixation leads

- subcutaneous ICDs

- leadless pacemakers

- any other condition that, in the judgment of device-trained staff, would deem an

MRI contraindicated 21. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded) 22. A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent 23. Other MRI contraindications (e. g. patient body habitus incompatible with MRI) 24. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent 25. Ventricular tachycardia ≥ 20 consecutive beats without an ICD within 3 months of consent, or symptomatic Mobitz II or higher degree atrioventricular block without a functioning pacemaker within 3 months of consent 26. A history of drug abuse (use of illegal "street" drugs except marijuana, or prescription medications not being used appropriately for a pre-existing medical condition) or alcohol abuse (≥ 5 drinks/day for ˃ 3 months), or documented medical, occupational, or legal problems arising from the use of alcohol or drugs within the past 24 months 27. Ability to walk ≥ age/gender specified criteria on baseline six minute walk tests. 28. Cognitive or language barriers that prohibit obtaining informed consent or any study elements (interpreter permitted) 29. Participation (currently or within the previous 30 days) in a cardiac related investigational therapeutic (including stem cell based therapies) or device trial 30. Pregnancy, lactation, plans to become pregnant in the next 12 months, or is unwilling to use acceptable forms of birth control during study participation 31. Any other condition that, in the judgment of the Investigator or Sponsor, would be a contraindication to enrollment, study product administration, or follow-up

Shelly L Sayre, MPH, Phone: 713-500-9529, Email: Shelly.L.Sayre@uth.tmc.edu

Stanford University School of Medicine, Stanford, California 94305, United States; Not yet recruiting
Fouzia Khan, Phone: 650-736-1410, Email: fouziak@stanford.edu
Phil Yang, MD, Principal Investigator

University of Florida-Department of Medicine, Gainesville, Florida 32610, United States; Not yet recruiting
Dana Leach, Phone: 352-273-8930, Email: Dana.Leach@medicine.ufl.edu
Sarah Long, Phone: 352-273-8932, Email: Sarah.Long@medicine.ufl.edu
Carl Pepine, MD, Principal Investigator

University of Miami-Interdiciplinary Stem Cell Institute, Miami, Florida 33101, United States; Not yet recruiting
Darcy DiFede, Phone: 305-243-9106, Email: ddifede@med.miami.edu
Cindy Delgado, Email: cdelgado5@med.miami.edu
Josh Hare, MD, Principal Investigator

Indiana Center for Vascular Biology and Medicine, Indianapolis, Indiana 46202, United States; Not yet recruiting
Toni Lathrop, Phone: 317-278-6107, Email: lathrop@iu.edu
Adnan Malik, MD, Principal Investigator

University of Louisville, Louisville, Kentucky 40202, United States; Not yet recruiting
Anne Marie Webb, Phone: 502-587-4106, Email: anne.webb@louisville.edu
Roberto Bolli, MD, Principal Investigator

Minneapolis Heart Institute Foundation, Minneapolis, Minnesota 55407, United States; Not yet recruiting
Patti Mitchell, Phone: 612-863-6287, Email: patricia.mitchell@allina.com
Katarzyna Hryniewicz-Czeneszew, MD, Principal Investigator

Texas Heart Institute, Houston, Texas 77030, United States; Not yet recruiting
Nichole Piece, Phone: 832-355-9173, Email: npiece@texasheart.org
Sara Sampaio, Email: ssampaio@texasheart.org
James Willerson, MD, Principal Investigator

Cardiovascular Cell Therapy Research Network

National Heart, Lung, and Blood Institute

Information on stem cells from the National Institutes of Health

Related publications:

Psaltis PJ, Carbone A, Nelson AJ, Lau DH, Jantzen T, Manavis J, Williams K, Itescu S, Sanders P, Gronthos S, Zannettino AC, Worthley SG. Reparative effects of allogeneic mesenchymal precursor cells delivered transendocardially in experimental nonischemic cardiomyopathy. JACC Cardiovasc Interv. 2010 Sep;3(9):974-83. doi: 10.1016/j.jcin.2010.05.016.

Nazarian S, Halperin HR. How to perform magnetic resonance imaging on patients with implantable cardiac arrhythmia devices. Heart Rhythm. 2009 Jan;6(1):138-43. doi: 10.1016/j.hrthm.2008.10.021. Epub 2008 Oct 22. Review.

Starting date: March 2016
Last updated: July 23, 2015