Carvedilol for Cardiomyopathy in Breast Cancer Patients

(TACTIC Trial)

Recruiting at 4 trial locations

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must be taking: HER2-directed therapy

Must not be taking: Beta-blockers, ACE inhibitors, ARBs, Antiarrhythmics

Disqualifiers: Heart failure, Cardiomyopathy, Asthma, 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: Unknown

450 Participants Needed

Trial Summary

What is the purpose of this trial?

Breast cancer patients undergoing trastuzumab-based HER2-directed therapy are at risk of heart function decline or heart failure symptoms, but it is unknown if, when, and for how long cardiovascular protective strategies, e.g. with a beta-blocker, could help. This study randomly assigns those taking curative-intent trastuzumab-based HER2-directed therapy to the beta-blocker carvedilol-either when significant heart function decline or subtle early signs of heart injury (either by elevation of a cardiac blood biomarker, i.e. cardiac troponin, or by an abnormal heart ultrasound marker, i.e. global longitudinal strain) are noted, or preventatively before beginning trastuzumab-based HER2-directed therapy. This study will further randomly assign those patients on carvedilol to either discontinuation at the end of trastuzumab-based HER2-directed therapy or continuation for another year, providing much needed clinical trial data on what the best strategy ("tactic") for those at risk of cardiotoxicity with trastuzumab-based HER2-directed therapy is.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using certain medications like beta-blockers, ACE inhibitors, ARBs, or antiarrhythmics. It's best to discuss your specific medications with the trial team.

Is carvedilol safe for use in humans?

Carvedilol has been generally well tolerated in patients with chronic heart failure, with some side effects related to its action on the heart. It has been used safely in various heart conditions, and studies have shown it can reduce mortality and hospitalizations compared to placebo. ^{1 2 3 4 5}

How does the drug Carvedilol differ from other treatments for cardiomyopathy in breast cancer patients?

Carvedilol is unique because it is a beta-blocker, which means it works by slowing down the heart rate and reducing blood pressure, helping to protect the heart from damage. This is different from other treatments for cardiomyopathy in breast cancer patients, which may not specifically target heart rate and blood pressure in the same way. ^{6 7 8 9 10}

Research Team

Joerg Herrmann, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for adults over 18 with a new or recurring HER2+ breast cancer, treated with curative intent and planned HER2-directed therapy. It's not for those with past heart failure/cardiomyopathy, low heart function at screening, certain blood pressure/heart rhythm issues, severe liver dysfunction, pregnancy, metastatic breast cancer or intolerance to beta-blockers.

Inclusion Criteria

I am 18 years old or older.

I am scheduled for a treatment targeting HER2, excluding Nerantinib and Lapatinib.

I have a new or returning HER2+ breast cancer and plan to treat it to cure.

Exclusion Criteria

I am taking ACE inhibitors or ARBs for high blood pressure, diabetes, or kidney disease.

Your heart's pumping ability is less than 50%.

I am currently taking medication for heart rhythm problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Emptive Treatment

Carvedilol titrated to maximally tolerated doses initiated one week before start of trastuzumab-based therapy and continued until end of therapy

Duration of trastuzumab therapy

Reactive Treatment

Carvedilol initiated after documentation of subclinical cardiotoxicity and continued until end of therapy

Duration of trastuzumab therapy

Standard of Care

Carvedilol initiated after documentation of a drop in LVEF and continued until end of therapy

Duration of trastuzumab therapy

Follow-up

Participants are monitored for cardiac function changes after completion of HER2-directed therapy

1 year

Treatment Details

Interventions

• Carvedilol

Trial Overview The study tests if the beta-blocker carvedilol can protect the heart when given during trastuzumab-based HER2-directed therapy for breast cancer. Participants are randomly assigned to start carvedilol either after early signs of heart injury or preventatively before treatment. They may continue or stop taking it after completing trastuzumab therapy.

Participant Groups

Group I: Reactive Strategy Experimental Treatment 1 Intervention

Carvedilol titrated to maximally tolerated doses (3.125 mg to 25 mg twice a day) initiated after documentation of subclinical cardiotoxicity, defined by an abnormal global longitudinal strain (GLS) or high-sensitive cardiac troponin (hsTnI) elevation and continued until end of therapy

Group II: Pre-Emptive Strategy Experimental Treatment 1 Intervention

Carvedilol titrated to maximally tolerated doses (3.125 mg to 25 mg twice a day) initiated one week before start of therapy and continued until end of therapy

Group III: Standard of Care Active Control 1 Intervention

Carvedilol titrated to maximally tolerated doses (3.125 mg to 25 mg twice a day) initiated after documentation of a drop in LVEF by \>10% to a value less than 53% and continued until end of therapy

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Miami Heart Research Institute

Collaborator

Trials

2

Recruited

650+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 30 patients with dilated cardiomyopathy who were not responding well to metoprolol, switching to carvedilol for 12 months led to significant improvements in left ventricular function, including a better ejection fraction and reduced heart size.

While carvedilol showed benefits in heart function and reduced arrhythmias, it negatively impacted exercise capacity, indicating that while it can be effective for heart remodeling, it may not improve overall exercise tolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol. The Heart-Muscle Disease Study Group. Di Lenarda, A., Sabbadini, G., Salvatore, L., et al.[2019]

In a clinical trial involving 66 patients with breast cancer and lymphoma, carvedilol was evaluated for its protective effects against cardiomyopathy caused by anthracycline chemotherapy.

The study found that a daily dose of 12.5mg of carvedilol provided protection against diastolic dysfunction, while a higher dose of 25mg offered protection against both systolic and diastolic dysfunction, suggesting its potential as a cardioprotective agent during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective effect of carvedilol in cardiomyopathy caused by anthracyclines in patients suffering from breast cancer and lymphoma. Salehi, R., Zamani, B., Esfehani, A., et al.[2019]

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]

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]

In two phase 3 trials (PALOMA-2 with 267 participants and PALOMA-3 with 240 participants), palbociclib combined with endocrine therapy significantly prolonged progression-free survival in women with advanced hormone receptor-positive breast cancer, with median survival times of 25.4 months versus 13.7 months in PALOMA-2 and 9.9 months versus 3.5 months in PALOMA-3 compared to placebo.

The safety profile of palbociclib was consistent with previous studies, with neutropenia being the most common side effect, and no new safety concerns were identified, indicating it is a safe treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of palbociclib plus endocrine therapy in North American women with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Gelmon, KA., Cristofanilli, M., Rugo, HS., et al.[2022]

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]

In a phase 2 study of 42 postmenopausal patients with advanced breast cancer, palbociclib combined with letrozole showed a median progression-free survival of 35.7 months, indicating its effectiveness as a first-line treatment.

The treatment was generally well-tolerated, with common side effects including neutropenia and leukopenia, but no significant decline in quality of life was observed, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib-letrozole as first-line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study. Takahashi, M., Masuda, N., Nishimura, R., et al.[2021]

In a phase Ib trial involving women with triple-negative breast cancer, both pembrolizumab combined with weekly paclitaxel and with capecitabine were found to be safe, meeting the safety endpoint with 87% and 100% of patients respectively not experiencing severe toxicities.

The efficacy results showed an objective response rate of 29% for the pembrolizumab/paclitaxel combination and 43% for the pembrolizumab/capecitabine combination, indicating that both regimens are clinically active, particularly in patients with specific biomarkers like PD-L1 scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer. Page, DB., Pucilowska, J., Chun, B., et al.[2023]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol. The Heart-Muscle Disease Study Group. [2019]

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

Protective effect of carvedilol in cardiomyopathy caused by anthracyclines in patients suffering from breast cancer and lymphoma. [2019]

4. 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]

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

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

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

Efficacy and safety of palbociclib plus endocrine therapy in North American women with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. [2022]

7. 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]

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

Palbociclib-letrozole as first-line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study. [2021]

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

A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer. [2023]

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

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