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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 14
- 主要终点
- Subjects Who Receive Less Than 20 Injections During SPI
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •To participate, a subject MUST:
- •Be ≥ 18 and < 80 years of age
- •Be a cancer survivor with diagnosis of AIC
- •Have an LVEF ≤ 45% by cMRI
- •Be in NYHA class II-III
- •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
- •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.)
- •Be a candidate for cardiac catheterization
排除标准
- •To participate, a subject MUST NOT HAVE:
- •A life expectancy <12 months
- •A CT scan or baseline cardiac MRI showing new tumor or suspicious lymphadenopathy raising concern of malignancy
- •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
- •Had a previous myocardial infarction
- •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
- •Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe valvular (any valve) insufficiency/regurgitation within 12 months of consent.
- •Aortic stenosis with valve area ≤ 1.5cm2
- •A history of LV reduction surgery or cardiomyoplasty
- •Evidence of cardiogenic shock
- •A history of ischemic or hemorrhagic stroke within 90 days of baseline testing
- •Liver dysfunction during baseline testing, as evidenced by enzymes (e.g., AST, ALT, alkaline phosphatase) greater than 3 times upper limit of normal
- •Diabetes with poorly controlled blood glucose levels (HbA1c > 8.5%)
- •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)
- •A baseline eGFR <35 ml/min/1.73m2
- •A contrast allergy that cannot adequately be managed by premedication
- •Received gene or cell-based therapy from any source within the previous 12 months
- •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
- •Evidence of active systemic infection at time of study product delivery
- •HIV and/or active HBV or HCV
- •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.
- •Presence of LV thrombus
- •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
- •Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded)
- •A cardiac resynchronization therapy (CRT) device implanted < 3 months prior to consent
- •Other MRI contraindications (e.g. patient body habitus incompatible with MRI)
- •An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent
- •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
- •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
- •Cognitive or language barriers that prohibit obtaining informed consent or any study elements (interpreter permitted)
- •Participation (currently or within the previous 30 days) in a cardiac related investigational therapeutic (including stem cell based therapies) or device trial
- •Pregnancy, lactation, plans to become pregnant in the next 12 months, or is unwilling to use acceptable forms of birth control during study participation
- •Any other condition that, in the judgment of the Investigator or Sponsor, would be a contraindication to enrollment, study product administration, or follow-up
结局指标
主要结局
Subjects Who Receive Less Than 20 Injections During SPI
时间窗: During SPI procedure
Number and percent of subjects who receive less than 20 injections during SPI
Subjects Who Did Not Receive the Study Product (Either 100 Million Cells or Placebo)
时间窗: During SPI procedure
Number and percent of subjects who did not receive the study product (either 100 million cells or placebo)
Subjects Who Have at Least One Cardiac MRI Endpoint Measure That is Uninterpretable
时间窗: Baseline to 12 months
Number and percent of subjects who have at least one cardiac MRI endpoint measure that is uninterpretable due to issues related to the device, including, but not limited to, inability to undergo the procedure.
Proportion of Other Significant Clinical Events
时间窗: Baseline to 12 months
Proportion of other significant adjudicated clinical events including: non-fatal stroke, non-fatal MI, coronary artery revascularization, ventricular tachycardia/fibrillation, pericardial tamponade, infectious myocarditis, hypersensitivity reaction, neoplasm, and/or other potential deleterious late effects.
Proportion of Major Adverse Cardiac Events (MACE)
时间窗: Baseline to 12 months
Proportion of adjudicated events including death, hospitalization for worsening heart failure, and/or other exacerbation of heart failure (non-hospitalization).
Subjects With Events Precluding Their Receipt of Product
时间窗: Randomization to SPI
Number and percent of subjects with events between randomization and study product injection (SPI) that preclude the subject from receiving product.
Subjects Who Fail to Complete Follow-up
时间窗: Baseline to 12 months
Number and percent of subjects who fail to complete follow up
次要结局
- Change From Baseline in Global Strain (HARP MRI)(Baseline to 12 months)
- Change From Baseline in Left Ventricular Ejection Fraction (LVEF)(Baseline to 12 months)
- Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)(Baseline to 12 months)
- Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score(Baseline to 12 months)
- Change From Baseline in Global Strain (HARP MRI)-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in Regional Strain (HARP MRI)(Baseline to 12 months)
- Change From Baseline in Exercise Tolerance (Six Minute Walk Test)(Baseline to 12 months)
- Change From Baseline in Left Ventricular Sphericity Index(Baseline to 12 months)
- Change From Baseline in Area of Injury(Baseline to 12 months)
- Change From Baseline in Area of Injury-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in Left Ventricular Sphericity Index-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Cumulative Days Alive and Out of Hospital for Heart Failure(Baseline to End of 12 Month Visit Window (i.e. 395 days after intervention))
- Change From Baseline in Regional Strain (HARP MRI)-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)(Baseline to 12 months)
- Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score-Trajectory(Assessed as a trajectory (baseline, 6 months, and 12 months))
- Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)(Baseline to 12 months)
研究者
Barry R Davis
Professor of Biostatistics
The University of Texas Health Science Center, Houston