Carvedilol for the Prevention of Anthracycline/Anti-HER2 Therapy Associated Cardiotoxicity Among Women With HER2-Positive Breast Cancer Using Myocardial Strain Imaging for Early Risk Stratification

Phase 2

Completed

• Conditions: Breast Cancer
• Interventions: Other: placebo; Drug: Carvedilol

• Registration Number: NCT02177175
• Lead Sponsor: Memorial Sloan Kettering Cancer Center

Brief Summary

The purpose of this study is to find out the effects, good and/or bad, of a beta blocker (carvedilol) on heart function during treatment with anti-HER2 medication(s) including trastuzumab (Herceptin).

Detailed Description

This phase II placebo-controlled study will evaluate the effect of carvedilol, compared to placebo, on anthracycline/anti-HER2 therapy induced left ventricular dysfunction in patients with HER2-positive breast cancer who are receiving adjuvant or neoadjuvant therapy. All patients will undergo routine cardiac surveillance with 2D echocardiograms per standard of care at multiple time points which will align as closely as possible to the following: pre-anthracycline (baseline), pre-anti-HER2 therapy, and 3, 6, 9, and 12 months (+/- 4 weeks) after initiation of anti-HER2 therapy. In the case that standard of care echocardiograms are not done at these time points, either due to a delay in anti-cancer therapy or due to the patient's medical condition, the principal investigator will determine if the standard of care echocardiogram may be used in lieu of one of the time points listed. Additional speckle tracking strain analysis will be performed on these echocardiograms, and blood specimens will be drawn at several time points for biomarker analysis.

After completion of anthracycline treatment and prior to initiation of anti-HER2 therapy, 32 patients with abnormal myocardial strain, defined as global longitudinal strain \< 19% or % change from baseline by \> 11%, will be randomized in a 1:1 ratio to carvedilol versus placebo. Carvedilol will be administered twice daily for approximately 1 year OR until the end of anti-HER2 therapy, if it is discontinued prior to 1 year. Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.

Study Timeline

• Study Start: 2014-06-24
• Study First Submitted: 2014-06-26
• Study First Submitted QC: 2014-06-26
• Study First Posted: 2014-06-27
• Status Verified: 2021-06
• Primary Completion: 2021-06-24
• Study Completion: 2021-06-24
• Results First Submitted: 2022-06-07
• Results First Submitted QC: 2022-07-11
• Last Update Submitted: 2022-07-11
• Results First Posted: 2022-07-12
• Last Update Posted: 2022-07-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 82

Inclusion Criteria

• Female
• Age ≥ 18 years
• Non-metastatic histologically confirmed primary invasive breast carcinoma
• Pathologically confirmed HER2-positive breast cancer
• Scheduled to receive anthracycline chemotherapy followed by anti-HER2 therapy at MSKCC
• Able and willing to provide informed consent
• Willing and able to comply with the requirements of the protocol
• Able to swallow capsules

For Aim 2, all patients must meet the following criteria:

• Meet all inclusion criteria above

  • LVEF > 50%

• Abnormal global longitudinal strain (<19%, or a % decrease of ≥ 11% from baseline) prior to initiation of planned anti-HER2 therapy

• Heart rate ≥ 50 beats per minute

• Sitting systolic blood pressure > 90 mmHg

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Exclusion Criteria

• Patients are to be excluded from randomization for Aim 2 of this study if they meet any of the following criteria:
• Current treatment with ACE-inhibitors or beta blockers
• Allergies or inability to tolerate beta blockers previously due to bradycardia, hypotension, or AV block.
• Known history of NCI CTCAE (Version 4.0) Grade ≥ 2 symptomatic CHF, myocardial infarction within 12 months prior to randomization, significant symptoms (Grade ≥ 3) relating to left ventricular dysfunction, significant (moderate or severe) valvular disease, or significant cardiac arrhythmia (Grade ≥ 3)
• Pre-menopausal women without a negative serum or urine pregnancy test within 4 weeks of starting treatment
• Enrollment in a therapeutic intervention trial in the Breast Medicine service

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
placebo	placebo	Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.
Carvedilol	Carvedilol	Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.

Primary Outcome Measures

Name	Time	Method
Maximum Change in LVEF at 9 Months	9 months	Value at 9 months minus value at baseline
Maximum Change in LVEF at 3 Months	3 months	Value at 3 months minus value at baseline
Maximum Change in LVEF at 6 Months	6 months	Value at 6 months minus value at baseline
Maximum Change in LVEF at 12 Months	12 months	Value at 12 months minus value at baseline

Secondary Outcome Measures

Name	Time	Method
Incidence of Abnormal LVEF at 12 Months	12 months	The study is designed to detect an intergroup difference of absolute difference of 10 percentage points (simple difference) in the change in LVEF between the experimental and control group. Ten percent is the change in LVEF that is associated with differing degrees of left ventricular dysfunction, and long-term studies among non-cancer patients have shown that outcomes differ among groups of patients who have LVEF differing by 10%.

Trial Locations

Locations (2)

Memorial Sloan Kettering West Harrison; 🇺🇸 Harrison, New York, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States