Breast Cancer
Conditions
Keywords
Carvedilol, Anthracycline, HER2, 14-099
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.
Interventions
DRUGCarvedilol
OTHERplacebo
Sponsors
Memorial Sloan Kettering Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 9 Months | 9 months | Value at 9 months minus value at baseline |
| Maximum Change in LVEF at 12 Months | 12 months | Value at 12 months minus value at baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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%. |
Countries
United States
Participant flow
Pre-assignment details
11 participants were randomized to treatment. 71 participants were not randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Carvedilol | 5 |
| 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.
placebo | 6 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | stopped trastuzumab so was taken off study | 1 | 0 |
Baseline characteristics
| Characteristic | Carvedilol | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 45.6 years | 50.8 years | 55.2 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 10 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 5 Participants | 11 Participants | 6 Participants |
| Sex: Female, Male Female | 5 Participants | 11 Participants | 6 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 6 |
| other Total, other adverse events | 5 / 5 | 6 / 6 |
| serious Total, serious adverse events | 1 / 5 | 0 / 6 |
Outcome results
Primary
Maximum Change in LVEF at 12 Months
Value at 12 months minus value at baseline
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carvedilol | Maximum Change in LVEF at 12 Months | -2.5 change in percent ejection fraction |
| Placebo | Maximum Change in LVEF at 12 Months | -2 change in percent ejection fraction |
Primary
Maximum Change in LVEF at 3 Months
Value at 3 months minus value at baseline
Time frame: 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carvedilol | Maximum Change in LVEF at 3 Months | 1 change in percent ejection fraction |
| Placebo | Maximum Change in LVEF at 3 Months | -5 change in percent ejection fraction |
Primary
Maximum Change in LVEF at 6 Months
Value at 6 months minus value at baseline
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carvedilol | Maximum Change in LVEF at 6 Months | -2 change in percent ejection fraction |
| Placebo | Maximum Change in LVEF at 6 Months | -5 change in percent ejection fraction |
Primary
Maximum Change in LVEF at 9 Months
Value at 9 months minus value at baseline
Time frame: 9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carvedilol | Maximum Change in LVEF at 9 Months | -3.5 change in percent ejection fraction |
| Placebo | Maximum Change in LVEF at 9 Months | -5.5 change in percent ejection fraction |
Secondary
Incidence of Abnormal LVEF at 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%.
Time frame: 12 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carvedilol | Incidence of Abnormal LVEF at 12 Months | Abnormal LVEF | 2 Participants |
| Carvedilol | Incidence of Abnormal LVEF at 12 Months | Normal LVEF | 3 Participants |
| Placebo | Incidence of Abnormal LVEF at 12 Months | Abnormal LVEF | 1 Participants |
| Placebo | Incidence of Abnormal LVEF at 12 Months | Normal LVEF | 5 Participants |