Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors

Phase 2

Completed

Conditions: Malignant Solid Neoplasm
Hematopoietic and Lymphoid Cell Neoplasm

Interventions: Drug: Carvedilol
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Other: Pharmacogenomic Study
Other: Placebo Administration
Other: Quality-of-Life Assessment
Other: Questionnaire Administration

Registration Number: NCT02717507

Lead Sponsor: Children's Oncology Group

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 196

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (carvedilol)	Laboratory Biomarker Analysis	Patients receive low-dose carvedilol PO QD or BID for 24 months.
Arm II (placebo)	Placebo Administration	Patients receive placebo PO QD or BID for 24 months.
Arm II (placebo)	Pharmacological Study	Patients receive placebo PO QD or BID for 24 months.
Arm I (carvedilol)	Pharmacogenomic Study	Patients receive low-dose carvedilol PO QD or BID for 24 months.
Arm I (carvedilol)	Pharmacological Study	Patients receive low-dose carvedilol PO QD or BID for 24 months.
Arm II (placebo)	Laboratory Biomarker Analysis	Patients receive placebo PO QD or BID for 24 months.
Arm II (placebo)	Pharmacogenomic Study	Patients receive placebo PO QD or BID for 24 months.
Arm II (placebo)	Questionnaire Administration	Patients receive placebo PO QD or BID for 24 months.
Arm I (carvedilol)	Questionnaire Administration	Patients receive low-dose carvedilol PO QD or BID for 24 months.
Arm I (carvedilol)	Quality-of-Life Assessment	Patients receive low-dose carvedilol PO QD or BID for 24 months.
Arm II (placebo)	Quality-of-Life Assessment	Patients receive placebo PO QD or BID for 24 months.
Arm I (carvedilol)	Carvedilol	Patients receive low-dose carvedilol PO QD or BID for 24 months.

Primary Outcome Measures

Name	Time	Method
Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz)	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.

Secondary Outcome Measures

Name	Time	Method
Average Alanine Aminotransferase	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Left Ventricular End-systolic Wall Stress	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Left Ventricular Mass	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Fractional Shortening	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	A measure to assess preload and afterload (in %). The mean is reported by arm at each timepoint with corresponding standard errors.
Average Ejection Fraction	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Peak Early Atrial Divided by Peak Late Atrial Velocities	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Cardiac N-terminal Pro B-type Natriuretic Peptide	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Left Ventricular End-systolic Dimension	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	Thickness of cardiac muscle (in cm) of the left ventricle at the end of systole. The mean is reported by arm at each timepoint with corresponding standard errors.
Average Left Ventricular End-systolic Volume	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Left Ventricular End-diastolic Dimension	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	Thickness of cardiac muscle (in cm) of the left ventricle at the end of diastole. The mean is reported by arm at each timepoint with corresponding standard errors.
Average Left Ventricular End-diastolic Volume	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average N-terminal Pro B-type Natriuretic Peptide	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Galectin-3	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Cardiac Troponin I	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Average Aspartate Aminotransferase	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	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.
Proportion of Participants With Average Adherence > 90%	Average adherence across 6 months, 12 months, 18 months, 24 months after treatment initiation are calculated.	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.
Proportion of Patients With Reportable Adverse Events as Described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).	From baseline to month 24 since baseline	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.
Average Bilirubin	Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation	A liver function measurement (in mg/dL). The mean is reported by arm at each timepoint with corresponding standard errors.
Proportion of Patients Who Responded "Moderately", "Quite a Bit", or "Extremely" to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point.	Responses at days 14 to 730 were combined	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.

Trial Locations

Locations (91): Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
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Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States