Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors

Study Overview
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Brief Summary
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This phase IIb trial studies how well low-dose carvedilol works in preventing heart failure in cancer survivors exposed to high dose anthracyclines for management of childhood cancer. Patients who received high-dose anthracycline chemotherapy are at a much greater risk for developing heart failure compared to survivors who didn't get any anthracycline chemotherapy. Heart failure happens when the heart muscle has been weakened and can't pump blood as well as it should. Carvedilol may help lower the risk of cardiovascular complications.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the impact of a two-year course of low-dose carvedilol on surrogate echocardiographic indices of heart failure (HF) risk, including: Left ventricular (LV) posterior wall thickness-dimension ratio (LV T-D); LV systolic and diastolic function, and afterload; Natriuretic peptides, troponins, and galectin-3. SECONDARY OBJECTIVES: I. To establish safety and tolerability of this two-year course of low-dose carvedilol, assessing both objective measures (hepatic function) and patient reported outcomes. II. To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year carvedilol intervention. EXPLORATORY OBJECTIVE: I. To evaluate the long-term efficacy of carvedilol in preventing cardiomyopathy and/or heart failure in high-risk childhood cancer survivors. OUTLINE: This is a dose-escalation study. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive low-dose carvedilol orally (PO) once daily (QD) or twice daily (BID) for 24 months. ARM II: Patients receive placebo PO QD or BID for 24 months. After completion of study treatment, patients are followed up for 3 years.

Official Title
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Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Heart Failure (PREVENT-HF): A Phase 2b Randomized Placebo-Controlled (Carvedilol) Trial

Conditions
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Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm

Intervention / Treatment
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* Drug: Carvedilol
* Other: Laboratory Biomarker Analysis
* Other: Pharmacogenomic Study
* Other: Pharmacological Study
* Other: Placebo Administration
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females must weigh >= 40 Kg Patient must have had a cancer diagnosis < 22 years of age, irrespective of current age Patient must have a lifetime cumulative anthracycline dose of >= 250 mg/m^2 DOXOrubicin equivalent without the protection of dexrazoxane (Zinecard) therapy; the anthracycline dose threshold must be met as part of the treatment of a cancer that was diagnosed at < 22 years of age Note: Institutional records (e.g., clinic note, treatment summary, chemotherapy roadmap) can be used to document lifetime receipt of anthracycline dose Patient must have completed cancer treatment >= 2 years prior to study enrollment Exclusion Criteria: Receiving treatment for cardiomyopathy or heart failure Ejection fraction of < 50% (by radionuclide angiogram or echocardiogram) or shortening fraction of < 25% (by echocardiogram) Note: for instances where both are reported, and one is below the threshold, the site will have the option to re-measure it centrally at the core lab Uncorrected primary obstructive or severe regurgitative valvular disease: Nondilated (restrictive); or Hypertrophic cardiomyopathy; or Significant systemic ventricular outflow obstruction Sustained or symptomatic ventricular dysrhythmias uncontrolled with drug therapy or implantable device Significant conduction defects (i.e. second or third degree atrio-ventricular block or sick sinus syndrome) Bradycardia: heart rate < 50 beats per minute (BPM) Use of an investigational drug or beta adrenergic blockers, including metoprolol, sotalol, within 30 days of enrollment History of drug sensitivity or allergic reaction to alpha or beta-blockers Low resting systolic blood pressure: < 90 mmHg Use of any other blood pressure lowering medication for treatment of hypertension within 30 days of enrollment except calcium channel blockers and diuretics History or current clinical evidence of moderate-to-severe obstructive pulmonary disease or reactive airway diseases (i.e. asthma) requiring therapy Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times upper limit of institutional normal Gastrointestinal, or biliary disorders that could impair absorption, metabolism, or excretion of orally administered medications Endocrine disorders (such as primary aldosteronism, pheochromocytoma, hyper- or hypothyroidism) not controlled with medication Uncontrolled diabetes (controlled diabetes per the American Diabetes Association and International Diabetes Center's Glycemic Target Goals is hemoglobin A1C < 7%) Anemia (hematocrit < 28%) Currently using select CYP2D6 inhibitor or inducer medications Inability to swallow pills Female patients who are pregnant are not eligible; women of childbearing potential require a negative pregnancy test prior to starting study drug Lactating females are not eligible unless they have agreed to not breastfeed their infants Sexually active female patients of reproductive potential are not eligible unless they agree to use an effective contraceptive method during study and for 2 months after stopping the study drug; abstinence is an acceptable method of birth control All patients and/or their parents or legal guardians must sign a written informed consent All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (carvedilol)<br>Patients receive low-dose carvedilol PO QD or BID for 24 months. | Drug: Carvedilol<br>* Given PO<br>* Other names: Coreg;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacogenomic Study<br>* Correlative studies<br>* Other names: PHARMACOGENOMIC;Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD or BID for 24 months. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacogenomic Study<br>* Correlative studies<br>* Other names: PHARMACOGENOMIC;Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz) | Z-score of the ratio of left ventricular (LV) posterior wall dimension of systole to internal LV dimension in diastole, calculated for each subject by subtracting the reference healthy population mean, then dividing by the standard deviation. The Z-score indicates the number of standard deviations away from the mean of the reference population. Negative Z- score indicates worse outcome. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Left Ventricular End-systolic Wall Stress | Echocardiographic measure of left ventricular (LV) afterload based on LV pressure (P), volume (V), and wall thickness (T), calculated by the formula (P x V)/T, which equals the number referred to below in the Measure Type. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Left Ventricular End-systolic Volume | The amount of blood (in ml) in the heart's left ventricle just after the heart contracts. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Left Ventricular End-diastolic Dimension | Thickness of cardiac muscle (in ml) of the left ventricle at the end of diastole. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Left Ventricular End-diastolic Dimension | The amount of blood (in ml) in the heart's left ventricle just before the heart contracts. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Left Ventricular Mass | The weight of the left ventricle adjusted for body surface area (in g/m2). The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Fractional Shortening | A measure to assess preload and afterload (in %). The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Ejection Fraction | The percentage of blood leaving the heart at the end of diastole. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Peak Early Atrial Divided by Peak Late Atrial Velocities | Ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E wave) to peak velocity flow in late diastole caused by atrial contraction (A wave). Number shown for Unit of Measure refers to this ratio. Normal: >1. Impaired: <1. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average N-terminal Pro B-type Natriuretic Peptide | B-type natriuretic peptide- a biomarker for heart failure (in pg/ml). The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Cardiac N-terminal Pro B-type Natriuretic Peptide | N-terminal pro b-type natriuretic peptide- a biomarker for heart failure (in pg/ml). The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Cardiac Troponin I | Troponin I is a biomarker for myocardial cell injury (in ng/ml). The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Galectin-3 | A protein produced by activated macrophages, and a member of a family of β-galactoside-binding lectings and promotes cardiac fibroblast proliferation and collagen synthesis following myocadial injury (in ng/ml). The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Proportion of Patients With Reportable Adverse Events as Described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). | Patients with toxicities reported via CTEP-AERS and all Grade ≥ 2 adverse events (AEs) that can be attributed probably or definitely to the study drug are considered to have AEs. The proportion of patients with AEs are reported by arm with corresponding 95% confidence intervals. | From baseline to month 24 since baseline | 
| Average Bilirubin | A liver function measurement (in mg/dL). The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Aspartate Aminotransferase | A liver function measurement (in U/L). Normal range is 14-20 for men, 10-36 for women. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Average Alanine Aminotransferase | A liver function measurement (in U/L). Normal range is 8-48 IU/L. The mean is reported by arm at each timepoint with corresponding standard errors. | Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation | 
| Proportion of Participants With Average Adherence > 90% | The number of pills taken out of the total prescribed in a 3-month period, averaged across all study time points. The proportion of participants with average adherence rate >90% is computed by arm and corresponding 95% confidence intervals are reported. | Average adherence across 6 months, 12 months, 18 months, 24 months after treatment initiation are calculated. | 
| Proportion of Patients Who Responded Moderately, Quite a Bit, or Extremely to How Bothersome the Symptom of DIARRHEA Was at Any Post-day 0 Assessment Time Point. | In a questionnaire, patients responded Yes/No to certain symptoms. If answered Yes, they selected slightly, moderately, quite a bit, or extremely regarding how bothersome the symptom was. The proportion of participants responding with any of these three categories was calculated by arm, and corresponding 95% confidence intervals are reported. | responses at days 14 to 730 were combined |