Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Congestive Heart Failure (PREVENT-CHF): A Phase IIB Randomized Placebo-Controlled Trial

PRIMARY OBJECTIVES:

I. To determine the impact of a two-year course of low-dose carvedilol on surrogate
echocardiographic indices of CHF risk, including: left ventricular (LV) posterior wall
thickness-dimension ratio (LV T-D); LV systolic and diastolic function, and afterload;
natriuretic peptides, troponins, and galactin-3.

II. To establish safety and tolerability of this two-year course of low-dose carvedilol,
assessing both objective measures (hepatic function) and patients reported outcomes.

III. To examine the modifying effect of demographic, clinical, and molecular characteristics
on the risk: benefit ratio from this two-year carvedilol intervention.

IV. As an exploratory goal, to examine the relationship between carvedilol and clinical
measures of efficacy such as prevention of CHF.

SECONDARY OBJECTIVES:

I. 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 (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 5 years.

Inclusion Criteria:

- Cancer diagnosis prior to 22 years of age, irrespective of current age

- Lifetime cumulative anthracycline dose: >= 300 mg/m^2 without the protection of
dexrazoxane (Zinecard) therapy

- Time from completion of cancer treatment to study entry: >= 2 years

Exclusion Criteria:

- Receiving treatment for cardiomyopathy or congestive heart failure

- Resting ejection fraction < 50% or fractional shortening < 25%

- Uncorrected primary obstructive or severe regurgitative valvular disease, nondilated
(restrictive) or hypertrophic cardiomyopathy, or significant systemic ventricular
outflow obstruction

- Low resting systolic blood pressure: < 90 mm hemoglobin (Hg)

- Bradycardia: heart rate < 50 beats per minute (BPM)

- 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)

- History or current clinical evidence of moderate -to-severe obstructive pulmonary
disease or reactive airway diseases (i.e.: asthma) requiring therapy

- Significant hepatic (serum aspartate aminotransferase [AST] and/or alanine
aminotransferase [ALT] > 3 time upper limit of normal 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, or insulin dependent diabetes mellitus

- Females of child bearing potential who are pregnant, lactating, or sexually active and
not taking adequate contraceptive precautions (i.e.: intrauterine device [IUD] or oral
contraceptives for 3 months prior to entry into the study)

- History of drug sensitivity or allergic reaction to alpha- or beta-blockers

- Anemia (hematocrit < 28%)

- Use of an investigational drug or beta adrenergic blockers, including metoprolol,
sotalol, within 30 days of randomization

- Use of select cytochrome P450 2D6 (CYP2D6) inhibitor medications

- Inability to swallow pills

- Unwillingness or inability to cooperate, or, for the parents or guardians of minors,
to give consent, or for the child to give assent, or any condition of sufficient
severity to impair cooperation with the study

- Use of any other blood pressure lowering medication for treatment of hypertension,
within 30 days of randomization