Carvedilol for Heart Protection in Breast Cancer Patients

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: Beta-blockers, ACE inhibitors

Disqualifiers: LV dysfunction, Metastatic cancer, others

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

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: 14

Duration: 12 months

134 Participants Needed

Trial Summary

What is the purpose of this trial?

The Cardio-Oncology program at Northwestern offers care to cancer patients who develop cardiac toxicities from chemotherapy. Breast cancer patients with the tumor marker for HER2 necessitate treatment with anthracycline and/or trastuzumab and pertuzumab-based chemotherapies, which are known to cause cardiac toxicities. Breast cancer patients will undergo a "cardio-oncology echocardiogram" which incorporates advanced left ventricular assessment by utilizing deformation or strain imaging during chemotherapy treatment for surveillance of cardiac toxicities. The aims of this project are: 1. To create a registry of both clinical, and echocardiographic variables, biomarkers, and genetic analysis that will be used to develop a risk model to predict LV dysfunction in early stage breast cancer patients undergoing chemotherapy with anthracycline and/or trastuzumab and pertuzumab-based chemotherapy regimens. 2. To propose a new management algorithm for initiation of prophylactic beta-blocker therapy for early stage breast cancer patients with preclinical cardiac toxicities demonstrated by strain parameters. 3. To determine if initiation of prophylactic beta-blocker therapy in patients with early cardiac toxicity can delay or prevent a drop in LV EF and the development of clinical heart failure. 4. To explore serial measurements of a suite of novel biomarkers during ongoing anticancer treatment that are presumed but not yet proven to be predictive of cardiac dysfunction in women with breast cancer. 5. To identify DNA biomarkers of predilection to cardiotoxicity. 6. To generate hiPSC to validate markers predictive of cardiotoxicity.

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications, except if you are on beta-blockers or ACE inhibitors, which are not allowed. Other cardiac and non-cardiac medications are permitted.

What data supports the effectiveness of the drug Carvedilol for heart protection in breast cancer patients?

Carvedilol has been shown to help prevent heart damage caused by chemotherapy in cancer patients, reducing the risk of heart-related side effects. It also improves heart function and reduces mortality in patients with heart failure, suggesting it may offer protective benefits for the heart in breast cancer patients undergoing treatment. ^{1 2 3 4 5}

Is carvedilol safe for humans?

Carvedilol, also known as Coreg or Dilatrend, is generally well tolerated in humans and has been used safely for conditions like heart failure and high blood pressure. Some side effects related to its action on the heart may occur, but it is often preferred over other similar medications due to its additional benefits. ^{1 3 4 6 7}

How does carvedilol differ from other drugs for breast cancer?

Carvedilol is unique because it is primarily a heart medication used to protect the heart in breast cancer patients, rather than directly treating the cancer itself. This is different from other breast cancer drugs like CDK4/6 inhibitors, which target cancer cell growth directly. ^{8 9 10 11 12}

Eligibility Criteria

This trial is for women over 18 with early-stage HER2-positive breast cancer (Stages I-III) who are about to start treatment with specific chemotherapies known to affect the heart. They must have normal heart function and agree to use contraception. Excluded are those with severe pre-existing heart conditions, certain other health issues like severe asthma or liver dysfunction, pregnant/breastfeeding women, and anyone previously on beta-blockers.

Inclusion Criteria

Patients must have a signed informed consent prior to registration

I have a history of high blood pressure, high cholesterol, diabetes, or mild heart issues.

Women of childbearing potential and sexually active men and women should use effective contraception

Exclusion Criteria

I have never taken BB/ACE therapy.

Patients who are pregnant/lactating are not eligible

My breast cancer has spread to other parts of my body.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline echocardiogram and blood draw for biomarkers and genetic testing

1 visit

1 visit (in-person)

Treatment

Participants receive chemotherapy with anthracycline and/or trastuzumab and pertuzumab, with echocardiograms every 3 months and potential prophylactic carvedilol treatment

12 months

Every 3 weeks during titration phase, then every 3 months

Biomarker Substudy

Biomarker labs drawn at baseline and every 6 weeks for 12 months, and 1 year post-chemotherapy

12 months

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including echocardiograms and biomarker analysis

1 year post-chemotherapy

Treatment Details

Interventions

• Carvedilol

Trial Overview The study tests whether Carvedilol, a beta-blocker medication, can prevent or delay heart damage in patients receiving chemotherapy that's tough on the heart. Patients' hearts will be monitored using advanced imaging techniques to detect early signs of strain or damage during their cancer treatment.

Participant Groups

Group I: Prophylactic Carvedilol Experimental Treatment 1 Intervention

Carvedilol 3.125 mg by mouth every 12 hours, titrated to a max dose of 25 mg by mouth every 12 hours, depending on blood pressure and heart rate, until completion of study.

Group II: No Therapy Active Control 1 Intervention

Standard of care monitoring without prophylactic treatment.

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Findings from Research

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]

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]

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]

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 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]

New drugs, specifically cyclin-dependent kinase (CDK) 4/6 inhibitors like palbociclib, ribociclib, and abemaciclib, have shown significant success in treating advanced and metastatic hormone receptor-positive breast cancer, especially when combined with hormone therapies.

As these oral medications become widely used, it is crucial for healthcare providers to ensure that patients understand their treatment regimens and support them in making informed decisions about their therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Oral Oncolytic Agents for Breast Cancer and Recommendations for Promoting Adherence. Gillespie, TW.[2021]

The combination of palbociclib, pembrolizumab, and letrozole was found to be well tolerated in women with hormone receptor positive (HR+) HER2- metastatic breast cancer, with a complete response rate of 31% in the second cohort of the trial.

Patients experienced significant progression-free survival of 25.2 months and overall survival of 36.9 months, indicating promising efficacy of this treatment regimen as a front-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer. Yuan, Y., Lee, JS., Yost, SE., et al.[2023]

References

1. 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]

2. 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]

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

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

4. England pubmed.ncbi.nlm.nih.gov

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

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

Potential cardioprotective and anticancer effects of carvedilol either free or as loaded nanoparticles with or without doxorubicin in solid Ehrlich carcinoma-bearing mice. [2023]

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

Advances in Oral Oncolytic Agents for Breast Cancer and Recommendations for Promoting Adherence. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer. [2023]

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

Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial. [2019]

12. France pubmed.ncbi.nlm.nih.gov

[Targeting the cyclin-dependent kinases 4/6 in advanced breast cancers]. [2021]