Donor Bone Marrow Derived Mesenchymal Stem Cells in Controlling Heart Failure in Patients With Cardiomyopathy Caused by Anthracyclines

Study Overview
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Brief Summary
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This randomized pilot phase I trial studies the side effects of donor bone marrow derived mesenchymal stem cells in controlling heart failure in patients with cardiomyopathy caused by anthracyclines. Donor bone marrow derived mesenchymal stem cells may help to control symptoms of heart failure and improve heart function.

Detailed Description
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PRIMARY OBJECTIVE: I. To demonstrate the safety of allogeneic human mesenchymal stem cells (hMSCs) administered by intravenous infusion and transendocardial injection in patients with left ventricular (LV) dysfunction and heart failure secondary to chemotherapy with anthracyclines. SECONDARY OBJECTIVE: I. To demonstrate the efficacy of allogeneic hMSCs administered by intravenous infusion and transendocardial injection in patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] < 40%) and heart failure secondary to treatment with anthracyclines. OUTLINE: Patients are randomized to 1 of 3 arms. ARM I: Patients receive hMSCs intravenously (IV) over 10-20 minutes on days 1, 14, 21, and 28 and standard of care treatment for heart failure in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive hMSCs transendocardially for a total of 15 injections and standard of care treatment for heart failure in the absence of disease progression or unacceptable toxicity. ARM III: Patients receive standard of care treatment for heart failure. After completion of study treatment, patients are followed up periodically.

Official Title
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Randomized 3-Arm Trial With Standard of Care Alone vs Either Intravenous Infusion or Transendocardial Injection of Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs) Plus Standard of Care in Patients With Anthracycline-Associated Cardiomyopathy

Conditions
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Cardiomyopathy, Heart Failure, Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm

Intervention / Treatment
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* Other: Best Practice
* Other: Laboratory Biomarker Analysis
* Drug: Mesenchymal Stem Cell Transplantation
* Drug: Mesenchymal Stem Cell Transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with LVEF </= 40% documented from treatment with anthracyclines for any malignancy at any dose at any time without evidence of other causes of cardiomyopathy. Age >/= 18 and </= 80 years of Age. Documented NYHA class I, II and III. For patients who have received trastuzumab: Persistent LV dysfunction must be present 90 days after discontinuation of trastuzumab. Able to perform 6 minute walk test. Been treated with appropriate maximal medical therapy for heart failure. Patient or legally authorized representative able to sign informed consent. Exclusion Criteria: Evidence of Ischemic Heart Disease as determined by study cardiologist. Significant Valvular Disease. (AS with AVA <1.5 and severe AR and MR) History of Familial Cardiomyopathy. Recent documented myocarditis within 2 months of enrollment. History of Infiltrative cardiomyopathy or restrictive cardiomyopathy. Presence of left ventricular thrombus as documented by echocardiography or left ventriculogram. Liver function tests > 3 x upper limit of normal. NYHA class IV heart failure. Inotropic dependence. Unstable or life-threatening arrhythmia. For patients not on anticoagulants, INR>1.5 Mechanical or Bioprosthetic heart valve. Cardiogenic shock. Breastfeeding and/or pregnant women. Autoimmune disorders on current immunosuppressive therapy. Active infection not responding to appropriate therapy as determined by Study Chair. Trastuzumab treatment within the last 3 months. Automatic implantable cardioverter defibrillator (AICD) placement within the last 30 days. AICD firing within the last 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (hMSCs IV)<br>Patients receive hMSCs IV over 10-20 minutes on days 1, 14, 21, and 28 and standard of care treatment for heart failure in the absence of disease progression or unacceptable toxicity. | Other: Best Practice<br>* Given standard of care<br>* Other names: standard therapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mesenchymal Stem Cell Transplantation<br>* Given IV<br>|
| Experimental: Arm II (hMSCs transendocardially)<br>Patients receive hMSCs transendocardially for a total of 15 injections and standard of care treatment for heart failure in the absence of disease progression or unacceptable toxicity. | Other: Best Practice<br>* Given standard of care<br>* Other names: standard therapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mesenchymal Stem Cell Transplantation<br>* Given transendocardially<br>|
| Active Comparator: Arm III (standard of care)<br>Patients receive standard of care treatment for heart failure. | Other: Best Practice<br>* Given standard of care<br>* Other names: standard therapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Statistical analyses of safety will be descriptive. | Up to 6 months | 
| Change in left ventricular ejection fraction (LVEF) | The comparison will be between the two groups of patients. | Baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in improvement of left ventricular (LV) systolic function as assessed by LVEF | As regards statistical analyses, the results of the trial will be displayed in table format. Will provide confidence intervals of the differences in change from baseline between each investigational group and the control group. If both investigation groups are significant at the p < .05 level, then the two investigational drugs can be compared using a gatekeeping procedure. These intervals and the associated p-values will be calculated using two-sample t-tests, with no adjustments for multiple comparisons. | Baseline up to 6 months | 
| LV end-systolic and end-diastolic volumes as determined by contrast-enhanced 2-dimensional(D)/3D echography | As regards statistical analyses, the results of the trial will be displayed in table format. Will provide confidence intervals of the differences in change from baseline between each investigational group and the control group. If both investigation groups are significant at the p < .05 level, then the two investigational drugs can be compared using a gatekeeping procedure. These intervals and the associated p-values will be calculated using two-sample t-tests, with no adjustments for multiple comparisons. | Up to 6 months | 
| Cardiac death | As regards statistical analyses, the results of the trial will be displayed in table format. Will provide confidence intervals of the differences in change from baseline between each investigational group and the control group. If both investigation groups are significant at the p < .05 level, then the two investigational drugs can be compared using a gatekeeping procedure. These intervals and the associated p-values will be calculated using two-sample t-tests, with no adjustments for multiple comparisons. | Up to 6 months | 
| Re-hospitalization after heart failure | As regards statistical analyses, the results of the trial will be displayed in table format. Will provide confidence intervals of the differences in change from baseline between each investigational group and the control group. If both investigation groups are significant at the p < .05 level, then the two investigational drugs can be compared using a gatekeeping procedure. These intervals and the associated p-values will be calculated using two-sample t-tests, with no adjustments for multiple comparisons. | Up to 6 months | 
| Aborted death from an automatic implantable cardioverter defibrillator (AICD) firing | As regards statistical analyses, the results of the trial will be displayed in table format. Will provide confidence intervals of the differences in change from baseline between each investigational group and the control group. If both investigation groups are significant at the p < .05 level, then the two investigational drugs can be compared using a gatekeeping procedure. These intervals and the associated p-values will be calculated using two-sample t-tests, with no adjustments for multiple comparisons. | Up to 6 months | 
| Nonfatal myocardial infarction | As regards statistical analyses, the results of the trial will be displayed in table format. Will provide confidence intervals of the differences in change from baseline between each investigational group and the control group. If both investigation groups are significant at the p < .05 level, then the two investigational drugs can be compared using a gatekeeping procedure. These intervals and the associated p-values will be calculated using two-sample t-tests, with no adjustments for multiple comparisons. | Up to 6 months | 
| Revascularization | As regards statistical analyses, the results of the trial will be displayed in table format. Will provide confidence intervals of the differences in change from baseline between each investigational group and the control group. If both investigation groups are significant at the p < .05 level, then the two investigational drugs can be compared using a gatekeeping procedure. These intervals and the associated p-values will be calculated using two-sample t-tests, with no adjustments for multiple comparisons. | Up to 6 months |