Preventing Anthracycline Cardiovascular Toxicity With Statins (PREVENT)

Wake Forest University (WFU)

Status and phase: Completed; Phase 2

Conditions: Breast Cancer; Lymphoma

Treatments: Drug: Placebo; Drug: Atorvastatin

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01988571

REBACCCWFU 98213 (Other Identifier)

U10CA081851 (U.S. NIH Grant/Contract)

1R01HL118740-01 (U.S. NIH Grant/Contract)

NCI-2013-01760 (Registry Identifier)

IRB00038639

Details and patient eligibility

About

The purpose of this research study is to see if Atorvastatin (Lipitor) 40 mg by mouth daily decreases the chance of developing heart problems in individuals receiving adjuvant anthracycline-based chemotherapy for breast cancer of lymphoma.

Full description

PRIMARY OBJECTIVES:

Specific Aim 1:

To determine if Atorvastatin(Lipitor) administration preserves left ventricular ejection fraction (LVEF) 24 months after initiation of Anthracycline-based adjuvant therapy for adjuvant treatment of breast cancer or lymphoma.

Specific Aim 2:

To determine if baseline to 6-month differences in LVEF predict baseline to 24-month differences in LVEF after Anthracycline-based adjuvant therapy and concomitant atorvastatin therapy.

To achieve these aims, we will perform a double-blind, placebo-controlled, randomized clinical trial of 0 or 40 mg of atorvastatin/day in 278 individuals scheduled to receive Anthracycline-based chemotherapy for treatment of Stage I-III breast cancer or lymphoma Stage I-IV with a projected > 2 year life expectancy. We will use innovative noninvasive magnetic resonance imaging (MRI) procedures to accurately measure LVEF. In addition, we will measure left ventricle (LV) volumes, myocardial strain, fibrosis, aortic pulse wave velocity (PWV) and wall thickness, all factors that can influence LVEF by altering LV pre-load, after-load, and contractility.19,20 Advanced serum biomarkers will be measured that assess for the presence of oxidative/nitrosative stress, systemic inflammation and circulating neurohormones that also may influence LVEF.

This study will test a new clinical paradigm to manage breast cancer: primary prevention of Anthracycline-based adjuvant therapy-related LV dysfunction using pre-treatment with low-cost statins. In addition, this trial will be the first systematic collection of data regarding the mechanism(s) and time course by which LV dysfunction and subsequent chronic heart failure (CHF) evolve in individuals given Anthracycline-based chemotherapy for breast cancer or lymphoma. These data will be useful to physicians trying to determine the optimal cardiac protection strategies when administering adjuvant chemotherapeutic regimens to their breast cancer or lymphoma patients. The objective of this research is to use inexpensive medications to preserve cardiovascular (CV) health and thereby improve overall survival in the growing number of breast cancer and lymphoma patients.

SECONDARY OBJECTIVES

Specific Aim 1:

To document the effect of Atorvastatin (Lipitor) on cognitive function using a battery of neurocognitive tests (HVLT, Rey-osterrieth Figure, controlled oral word association test (COWA), Trail-making Parts A and B, Digit Span and Grooved Pegboard) in breast cancer and lymphoma patients receiving an anthracycline.

Specific Aim 2:

To document the effect of Atorvastatin(Lipitor) on self-reported quality of life using validated questionnaires (PROMIS including: General form, Cog Concerns, Cog Abilities, Fatigue, Pain intensity and interference, Sleep Disturbance, Physical Functioning and Social Functioning) in breast cancer and lymphoma patients receiving an anthracycline.

Enrollment: 279 patients

Sex: All

Ages: 21 to 100 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Stage I-III breast cancer (including inflammatory and newly diagnosed recurrent breast cancer) or lymphoma Stage I-IV. (Patients should have a > 2 year life expectancy)
• Scheduled to receive adjuvant chemotherapy with an Anthracycline (doxorubicin and epirubicin)
• 21 years of age or older
• LVEF > 50% (Most recent within the last 5 years)
• Prior administration of anthracyclines is acceptable if therapy was completed > 6 months prior to study enrollment
• Patients that are receiving or have received chemotherapy regimens are allowed
• Able to hold breath for 10 seconds
• Prior cancers allowed if no evidence of disease in last 5 years
• Eastern Cooperative Oncology Group (ECOG) 0 or 1

Exclusion criteria

• Prior use of lipid-lowering therapy within the last 6 months
• Current postmenopausal hormone-replacement therapy
• Uncontrolled hypertension (systolic blood pressure >190 mm Hg or diastolic blood pressure >100 mm Hg)
• Scheduled to receive neoadjuvant chemotherapy with an anthracycline
• No active liver disease allowed
• Uncontrolled hypothyroidism
• Recent history (within past 3 years) of alcohol or drug abuse, inflammatory conditions such as lupus or inflammatory bowel disease, use of immunosuppressant agents, or another medical condition that might compromise safety or the successful completion of the study.
• Patients with ferromagnetic cerebral aneurysm clips or other intraorbital/intracranial metal;pacemakers, defibrillators, functioning neurostimulator devices or other implanted electronic devices.
• Unstable angina; significant ventricular arrhythmias (>20 premature ventricular complexes (PVCs)/min due to gating difficulty) atrial fibrillation with uncontrolled ventricular response; coronary artery disease; acute myocardial infarction within 28 days
• Current use of Cytochrome P450 (CYP3A4) inhibitors. These include Clarithromycin, HIV protease inhibitors, Itraconazole, grapefruit juice, Cyclosporine, Rifampin or Digoxin
• Current or history of hepatic dysfunction
• Unable to provide informed consent
• Claustrophobia
• Planning to move within 24 months of trial enrollment
• Pregnant or breast-feeding

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

279 participants in 2 patient groups, including a placebo group

Arm 1 - Atorvastatin

Active Comparator group

Description:

One 40 mg Atorvastatin tablet each morning by mouth for 24 months

Treatment:

Drug: Atorvastatin

Arm 2 - Placebo

Placebo Comparator group

Description:

One placebo tablet each morning by mouth for 24 months.

Treatment:

Drug: Atorvastatin

Drug: Placebo