Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors

PRIMARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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