Clinical trial NCT02509156: Stem Cell Injection in Cancer Survivors
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cardiomyopathy Due to Anthracyclines
Keywords: Cardiomyopathy
AIC
Anthracyclines
Chemotherapy
Allogeneic
Mesenchymal stem cells
MSCs
Cancer survivors
Breast Cancer
Leukemia
Lymphoma
Sarcoma
Lead sponsor: The University of Texas Health Science Center, Houston
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2015-07-27
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: This phase I, randomized, placebo-controlled, trial will evaluate the safety and feasibility of allo-MSCs administered by transendocardial injection in thirty-seven subjects with anthracycline-induced cardiomyopathy (AIC). The first six subjects received allo-MSC therapy (open label) and were 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 was followed by a randomized, double-blind clinical trial enrolling thirty-one subjects. These subjects were randomized 1:1 to receive allo-MSCs or placebo. All subjects underwent cardiac catheterization and study product administration using the NOGA Myostar catheter injection system. Subjects are being followed at 1 day, 1 week, 1 month, 6 months, and 12 months post study product injection. All endpoints are 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 available standard-of-care medical records for cancer surveillance will be reviewed for cancer recurrence.

Eligibility criteria: Inclusion Criteria

To participate, a subject MUST:

1. Be ≥ 18 and \< 80 years of age
2. Be a cancer survivor with diagnosis of AIC
3. Have an LVEF ≤ 45% by cMRI
4. Be in 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/ARBs, and/or aldosterone antagonists for 3 months, 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 (\*exceptions to this are carcinoma in situ or fully resected basal and squamous cell cancer of the skin.)
7. Be a candidate for cardiac catheterization

Exclusion Criteria

To participate, a subject MUST NOT HAVE:

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 obstructive CAD as determined via imaging within 5 years prior to study enrollment provided there have been no symptoms or evidence of CAD since the test
4. Had a previous myocardial infarction
5. 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
6. Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe valvular (any valve) insufficiency/regurgitation within 12 months of consent.
7. Aortic stenosis with valve area ≤ 1.5cm2
8. A history of LV reduction surgery or cardiomyoplasty
9. Evidence of cardiogenic shock
10. A history of ischemic or hemorrhagic stroke within 90 days of baseline testing
11. Liver dysfunction during baseline testing, as evidenced by enzymes (e.g., AST, ALT, alkaline phosphatase) greater than 3 times upper limit of normal
12. Diabetes with poorly controlled blood glucose levels (HbA1c \> 8.5%)
13. 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 (medications will be considered on a case by case basis)
14. A baseline eGFR \<35 ml/min/1.73m2
15. A contrast allergy that cannot adequately be managed by premedication
16. Received gene or cell-based therapy from any source within the previous 12 months
17. A hematologic abnormality during baseline testing as evidenced by hemoglobin \< 9 g/dl; hematocrit \< 30%; absolute neutrophil count \< 2,000 or total WBC count more than 2 times upper limit of normal; or platelet values \< 100,000/ul
18. Evidence of active systemic infection at time of study product delivery
19. HIV and/or active HBV or HCV
20. Coagulopathy (INR \> 1.5) not due to a reversible cause (e.g., warfarin and/or Factor Xa inhibitors) (see Section 6.4 re: injection procedure and anticoagulation therapy) Note: Subjects who cannot be withdrawn from anticoagulation will be excluded.
21. Presence of LV thrombus
22. Presence of a pacemaker and/or ICD generator with any of the following limitations/conditions:

    * manufactured before the year 2000
    * leads implanted \< 6 weeks prior to consent
    * non-transvenous epicardial or abandoned leads
    * subcutaneous ICDs
    * leadless pacemakers
    * any other condition that, in the judgment of device-trained staff, would deem an MRI contraindicated
23. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded)
24. A cardiac resynchronization therapy (CRT) device implanted \< 3 months prior to consent
25. Other MRI contraindications (e.g. patient body habitus incompatible with MRI)
26. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent
27. 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
28. 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
29. Cognitive or language barriers that prohibit obtaining informed consent or any study elements (interpreter permitted)
30. Participation (currently or within the previous 30 days) in a cardiac related investigational therapeutic (including stem cell based therapies) or device trial
31. Pregnancy, lactation, plans to become pregnant in the next 12 months, or is unwilling to use acceptable forms of birth control during study participation
32. Any other condition that, in the judgment of the Investigator or Sponsor, would be a contraindication to enrollment, study product administration, or follow-up

Primary outcomes:
measure: Proportion of Major Adverse Cardiac Events (MACE)
timeFrame: Baseline to 12 months
measure: Proportion of Other Significant Clinical Events
timeFrame: Baseline to 12 months
measure: Subjects With Events Precluding Their Receipt of Product
timeFrame: Randomization to SPI
measure: Subjects Who Receive Less Than 20 Injections During SPI
timeFrame: During SPI procedure
measure: Subjects Who Did Not Receive the Study Product (Either 100 Million Cells or Placebo)
timeFrame: During SPI procedure
measure: Subjects Who Have at Least One Cardiac MRI Endpoint Measure That is Uninterpretable
timeFrame: Baseline to 12 months
measure: Subjects Who Fail to Complete Follow-up
timeFrame: Baseline to 12 months
Secondary outcomes:
measure: Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
timeFrame: Baseline to 12 months
measure: Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Global Strain (HARP MRI)
timeFrame: Baseline to 12 months
measure: Change From Baseline in Global Strain (HARP MRI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Regional Strain (HARP MRI)
timeFrame: Baseline to 12 months
measure: Change From Baseline in Regional Strain (HARP MRI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)
timeFrame: Baseline to 12 months
measure: Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)
timeFrame: Baseline to 12 months
measure: Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Left Ventricular Sphericity Index
timeFrame: Baseline to 12 months
measure: Change From Baseline in Left Ventricular Sphericity Index-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Area of Injury
timeFrame: Baseline to 12 months
measure: Change From Baseline in Area of Injury-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Exercise Tolerance (Six Minute Walk Test)
timeFrame: Baseline to 12 months
measure: Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score
timeFrame: Baseline to 12 months
measure: Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)
timeFrame: Baseline to 12 months
measure: Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory
timeFrame: Assessed as a trajectory (baseline, 6 months, and 12 months)
measure: Cumulative Days Alive and Out of Hospital for Heart Failure
timeFrame: Baseline to End of 12 Month Visit Window (i.e. 395 days after intervention)
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Gainesville
country: United States
facility: University of Florida-Department of Medicine
state: Florida
city: Miami
country: United States
facility: University of Miami-Interdiciplinary Stem Cell Institute
state: Florida
city: Indianapolis
country: United States
facility: Indiana Center for Vascular Biology and Medicine
state: Indiana
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Houston
country: United States
facility: Texas Heart Institute
state: Texas
Study officials:
affiliation: CCTRN Steering Committee Chair
name: Robert Simari, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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. No abstract available.
citation: Bolli R, Hare JM, Henry TD, Lenneman CG, March KL, Miller K, Pepine CJ, Perin EC, Traverse JH, Willerson JT, Yang PC, Gee AP, Lima JA, Moye L, Vojvodic RW, Sayre SL, Bettencourt J, Cohen M, Ebert RF, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial. Am Heart J. 2018 Jul;201:54-62. doi: 10.1016/j.ahj.2018.02.009. Epub 2018 Apr 4.