Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors

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.

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