Carvedilol for Preventing Heart Problems in HER2 Positive Breast Cancer

Recruiting at 293 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Southwest Oncology Group

Must not be taking: B2 agonists, Bosutinib

Disqualifiers: Uncontrolled asthma, Dialysis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 108 weeks

817 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial studies how well carvedilol works in preventing cardiac toxicity in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer that has spread to other places in the body. A beta-blocker, such as carvedilol, is used to treat heart failure and high blood pressure, and it may prevent the heart from side effects of chemotherapy.

Will I have to stop taking my current medications?

If you are currently taking a beta blocker, ARB, or ACE inhibitor, you cannot participate in the randomized part of the trial but may join the non-randomized observational group. Additionally, you must not take certain medications like B2 agonists, bosutinib, and others during the study.

What data supports the effectiveness of the drug Carvedilol in preventing heart problems in HER2 positive breast cancer patients?

Carvedilol has been shown to lower the risk of heart damage caused by chemotherapy in cancer patients, as it reduces the incidence of noticeable heart problems and prevents changes in heart size after treatment. ^{1 2 3 4 5}

Is carvedilol safe for humans?

Carvedilol, also known as Coreg, has been used safely in humans for conditions like heart failure and high blood pressure. It is generally well tolerated, though some people may experience side effects related to its heart and blood pressure effects. ^{1 2 3 6 7}

How does the drug carvedilol differ from other treatments for preventing heart problems in HER2 positive breast cancer?

Carvedilol is unique because it not only blocks certain receptors in the heart to improve heart function but also has antioxidant properties that may protect against heart damage caused by cancer treatments like anthracyclines. This makes it potentially effective in preventing heart problems in breast cancer patients, which is not a standard use for other heart medications. ^{1 2 3 7 8}

Research Team

Justin Floyd

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for adults with HER-2-positive metastatic breast cancer who are starting or continuing trastuzumab-based therapy. They must have normal heart function, blood pressure, and not be on certain heart medications. Pregnant or nursing individuals can't join, nor those with other recent cancers except some specific cases.

Inclusion Criteria

Your heart's pumping ability must be at least 50% as measured by a special heart ultrasound within 28 days before joining the study.

Your liver enzyme levels are within five times the normal range.

Patients must not co-enroll on other treatment trials

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive carvedilol or no intervention for up to 108 weeks, with courses repeating every 12 weeks for those on carvedilol

108 weeks

Regular visits every 12 weeks

Observation

Participants undergo observation for cardiac events and other outcomes

108 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

108 weeks

Treatment Details

Interventions

• Carvedilol

Trial Overview The study tests if carvedilol can prevent heart damage in patients receiving cancer treatment for HER-2-positive metastatic breast cancer. It involves taking the beta-blocker carvedilol alongside standard chemotherapy to see if it reduces cardiac toxicity.

Participant Groups

Group I: Arm I (carvedilol) Experimental Treatment 2 Interventions

Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive carvedilol PO BID. Courses repeat every 12 weeks for 108 weeks in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (no intervention) Active Control 1 Intervention

Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive no study intervention for up to 108 weeks.

Group III: Arm III (observation) Active Control 2 Interventions

Patients undergo observation for up to 108 weeks.

Who Is Running the Clinical Trial?

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Carvedilol significantly improves left ventricular ejection fraction (LVEF) and reduces mortality in patients with chronic heart failure (CHF), as shown in multiple studies including the US Carvedilol Heart Failure Trials Program with 1094 participants.

Compared to metoprolol, carvedilol demonstrated lower mortality rates in patients with CHF, indicating it may be the preferred beta-blocker for treatment, while also being well tolerated with fewer adverse events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carvedilol: a review of its use in chronic heart failure. Keating, GM., Jarvis, B.[2022]

Carvedilol (CAR) significantly reduces the migration and invasion of breast cancer cells, indicating its potential as an anti-metastatic agent.

The mechanism of action involves the inhibition of Src activation through different signaling pathways: the cAMP/PKA-Src pathway in MDA-MB-231 cells and the PKCδ-Src pathway in MCF-7 cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway. Dezong, G., Zhongbing, M., Qinye, F., et al.[2019]

A study assessed the pharmaceutical quality of Dilatrend (carvedilol) and 35 generic products, revealing that while all Dilatrend strengths met specifications, nearly 49% of the generics failed to meet key quality standards.

The failure of many generic products in tests for carvedilol content, tablet hardness, dissolution, and purity raises concerns about their efficacy and safety, suggesting that substituting Dilatrend with these generics could lead to unpredictable treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are generic formulations of carvedilol of inferior pharmaceutical quality compared with the branded formulation? Smith, JC., Tarocco, G., Merazzi, F., et al.[2018]

In a study of 40 breast cancer patients undergoing chemotherapy, the combination of low-dose carvedilol and candesartan significantly reduced the acute and chronic cardiotoxic effects of anthracycline drugs compared to chemotherapy alone.

Patients receiving the combination treatment maintained better left ventricular ejection fraction (LVEF) and had lower rates of cardiac abnormalities, indicating that this approach may effectively protect heart health during cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preventive effect of low-dose carvedilol combined with candesartan on the cardiotoxicity of anthracycline drugs in the adjuvant chemotherapy of breast cancer]. Liu, L., Liu, ZZ., Liu, YY., et al.[2021]

In a systematic review of six randomized controlled trials involving beta-blocker carvedilol, there was no significant difference in left ventricular ejection fraction (LVEF) after chemotherapy compared to placebo, indicating it may not prevent early asymptomatic heart function decline.

However, carvedilol was associated with a lower incidence of clinically overt cardiotoxicity and prevented increases in left ventricular end-diastolic diameter, suggesting it may help protect against more severe heart damage during cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective role of beta-blockers in chemotherapy-induced cardiotoxicity-a systematic review and meta-analysis of carvedilol. Huang, S., Zhao, Q., Yang, ZG., et al.[2020]

Carvedilol significantly reduces cardiac damage caused by severe hypertension in stroke-prone spontaneously hypertensive rats, with reductions in various histopathologic indices such as coronary artery hypertrophy and myocardial inflammation by up to 100%.

Despite not affecting systolic blood pressure, carvedilol effectively prevents cardiac remodeling and myopathies associated with a high-salt, high-fat diet, demonstrating its potential for cardioprotection without lowering systemic blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carvedilol prevents severe hypertensive cardiomyopathy and remodeling. Barone, FC., Campbell, WG., Nelson, AH., et al.[2019]

In a review of nine randomized controlled trials involving 717 patients, carvedilol showed potential benefits in preventing anthracycline-induced cardiotoxicity, particularly by improving left ventricular ejection fraction (LVEF) and possibly reducing the incidence of left ventricular systolic dysfunction (LVSD).

Despite these positive findings, the studies had significant variability in their definitions and reporting of LVSD, and there was no evidence of decreased mortality associated with carvedilol use, indicating the need for further research with larger sample sizes and longer follow-up periods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventive use of carvedilol for anthracycline-induced cardiotoxicity: a systematic review and meta-analysis of randomized controlled trials. Zhan, T., Daniyal, M., Li, J., et al.[2022]

In a study of 23 breast cancer patients undergoing anthracycline treatment, carvedilol showed a trend towards better right ventricular (RV) function compared to those receiving only chemotherapy, although the differences were not statistically significant.

The use of carvedilol was associated with a significantly higher RV S wave tissue Doppler imaging (S-TDI) measurement, suggesting a potential protective effect on RV function during cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Effect of Carvedilol in Preventing Right Ventricular Dysfunction in Breast Cancer Patients Receiving Anthracycline. Karvandi, M., Ghadyani, M., Mohebbi, N., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Carvedilol: a review of its use in chronic heart failure. [2022]

2. India pubmed.ncbi.nlm.nih.gov

Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Are generic formulations of carvedilol of inferior pharmaceutical quality compared with the branded formulation? [2018]

4. China pubmed.ncbi.nlm.nih.gov

[Preventive effect of low-dose carvedilol combined with candesartan on the cardiotoxicity of anthracycline drugs in the adjuvant chemotherapy of breast cancer]. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Protective role of beta-blockers in chemotherapy-induced cardiotoxicity-a systematic review and meta-analysis of carvedilol. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Carvedilol prevents severe hypertensive cardiomyopathy and remodeling. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Preventive use of carvedilol for anthracycline-induced cardiotoxicity: a systematic review and meta-analysis of randomized controlled trials. [2022]

8. India pubmed.ncbi.nlm.nih.gov

Evaluation of the Effect of Carvedilol in Preventing Right Ventricular Dysfunction in Breast Cancer Patients Receiving Anthracycline. [2023]