Carvedilol for Cardiomyopathy in Breast Cancer Patients
(TACTIC Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Overseen byJoerg Herrmann, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
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
Prior Safety Data
Approved in 4 Jurisdictions
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.
12345How 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.
678910Eligibility 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.
+12 more
Trial 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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Active Control
Group I: Reactive StrategyExperimental Treatment1 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 StrategyExperimental Treatment1 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 CareActive Control1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo Clinic in RochesterRochester, MN
Washington University in St. LouisSaint Louis, MO
MD Anderson Cancer CenterHouston, TX
Mayo Clinic in FloridaJacksonville, FL
More Trial Locations
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Who Is Running the Clinical Trial?
Mayo ClinicLead Sponsor
Miami Heart Research InstituteCollaborator
National Cancer Institute (NCI)Collaborator
References
Are generic formulations of carvedilol of inferior pharmaceutical quality compared with the branded formulation? [2018]Carvedilol is a comprehensive beta(1)-, beta(2)-, and alpha(1)-adrenoreceptor blocker marketed as Dilatrend by F. Hoffmann-La Roche Ltd. (Roche) and as Coreg by GlaxoSmithKline for the treatment of hypertension, stable angina pectoris, post myocardial infarction with left ventricular dysfunction and all degrees of symptomatic chronic heart failure.
Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol. The Heart-Muscle Disease Study Group. [2019]The purpose of this study was to analyze whether long-term treatment with the nonselective beta-adrenergic blocking agent carvedilol may have beneficial effects in patients with dilated cardiomyopathy (DCM), who are poor responders in terms of left ventricular (LV) function and exercise tolerance to chronic treatment with the selective beta-blocker metoprolol.
Protective effect of carvedilol in cardiomyopathy caused by anthracyclines in patients suffering from breast cancer and lymphoma. [2019]Anthracyclines can damage the left ventricle, causing cardiomyopathy. This study evaluated the protective effect of carvedilol in cardiomyopathy caused by anthracyclines in patients suffering from breast cancer and lymphoma.
Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway. [2019]Carvedilol (CAR) can inhibit cell growth and induce cell apoptosis in breast cancer in vitro. But it is still not known whether CAR affects the migration and invasion of breast cancer cells.
Carvedilol: a review of its use in chronic heart failure. [2022]Carvedilol (Dilatrend) blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors, and has antioxidant and antiproliferative effects. Carvedilol improved left ventricular ejection fraction (LVEF) in patients with chronic heart failure (CHF) in numerous studies. Moreover, significantly greater increases from baseline in LVEF were seen with carvedilol than with metoprolol in a double-blind, randomised study and in a meta-analysis. Carvedilol also reversed or attenuated left ventricular remodelling in patients with CHF and in those with left ventricular dysfunction after acute myocardial infarction (MI). Combined analysis of studies in the US Carvedilol Heart Failure Trials Program (patients had varying severities of CHF; n = 1094) revealed that mortality was significantly lower in carvedilol than in placebo recipients. In addition, the risk of hospitalisation for any cardiovascular cause was significantly lower with carvedilol than with placebo. Mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF in the Carvedilol Or Metoprolol European Trial (COMET) [n = 3029]. The Carvedilol Prospective Randomised Cumulative Survival (COPERNICUS) trial (n = 2289) demonstrated that compared with placebo, carvedilol was associated with significant reductions in all-cause mortality and the combined endpoint of death or hospitalisation for any reason in severe CHF. All-cause mortality was reduced in patients who received carvedilol in addition to conventional therapy compared with those who received placebo plus conventional therapy in the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial (enrolling 1959 patients with left ventricular dysfunction following acute MI). Carvedilol was generally well tolerated in patients with CHF. Adverse events associated with the alpha- and beta-blocking effects of the drug occurred more commonly with carvedilol than with placebo, whereas placebo recipients were more likely to experience worsening heart failure. In conclusion, carvedilol blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors and has a unique pharmacological profile. It is thought that additional properties of carvedilol (e.g. antioxidant and antiproliferative effects) contribute to its beneficial effects in CHF. Carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe CHF, and should be considered a standard treatment option in this setting. Administering carvedilol in addition to conventional therapy reduces mortality and attenuates myocardial remodelling in patients with left ventricular dysfunction following acute MI. Moreover, mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF, suggesting that carvedilol may be the preferred beta-blocker.
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]Palbociclib is a cyclin-dependent kinase 4/6 inhibitor indicated for treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in combination with endocrine therapy. We investigated the efficacy and safety of palbociclib in patients enrolled in North America during two-phase 3 trials: PALOMA-2 (n = 267, data cutoff: May 31, 2017) and PALOMA-3 (n = 240, data cutoffs: April 13, 2018, for overall survival, October 23, 2015, for all other outcomes). In PALOMA-2, treatment-naïve postmenopausal patients with advanced breast cancer were randomized 2:1 to palbociclib (125 mg/d; 3 weeks on/1 week off [3/1]) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. In PALOMA-3, patients who progressed on prior endocrine therapy were randomized 2:1 to palbociclib (125 mg/d; 3/1) plus fulvestrant (500 mg, per standard of care) or placebo plus fulvestrant; pre/perimenopausal patients received ovarian suppression with goserelin. Palbociclib plus endocrine therapy prolonged median progression-free survival vs placebo plus endocrine therapy in North American patients (PALOMA-2: 25.4 vs 13.7 months, hazard ratio, 0.54 [95% CI, 0.40-0.74], P
Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer. [2023]Label="BACKGROUND">CDK4/6 inhibitors modulate immune response in breast cancer. This phase I/II trial was designed to test the safety and efficacy of palbociclib, pembrolizumab and letrozole in women with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC).
Palbociclib-letrozole as first-line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study. [2021]Palbociclib is a highly selective, reversible, oral inhibitor of cyclin-dependent kinases 4 and 6 that is approved to treat hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. An open-label, single-arm, Japanese phase 2 study was conducted to investigate the efficacy and safety of palbociclib plus letrozole as first-line treatment in 42 postmenopausal patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. The probability of progression-free survival originally reported at 1 year was 75.0% (90% confidence interval, 61.3-84.4), but median progression-free survival was not attained at the primary analysis. In this report, updated efficacy and safety results with a longer follow-up period are presented. The median duration of treatment in the updated analysis was 33.0 months (range, 1.8-49.2). The probability of progression-free survival at 1 year was 75.6% (90% confidence interval, 62.4-84.7). Median progression-free survival was 35.7 months (95% confidence interval, 21.7-46.7). Objective response rate and disease control rate were 47.6% (95% confidence interval, 32.0-63.6) and 85.7% (95% confidence interval, 71.5-94.6), respectively. Common treatment-related adverse events (all grades; grade 3/4) were neutropenia (100%; 93%), leukopenia (83%; 60%), and stomatitis (76%; 0%). Treatment-related febrile neutropenia was reported in one patient. In general, no clinically meaningful deterioration in health-related quality of life was observed. Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in this updated analysis.
A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer. [2023]Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200 mg IV every 3 weeks) with either weekly paclitaxel (80 mg/m2 weekly) or flat-dose capecitabine (2000 mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays). The secondary endpoint is efficacy (week 12 objective response). Exploratory aims are to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. The trial demonstrates that both regimens meet the pre-specified safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate is 29% for pembrolizumab/paclitaxel (n = 4/13, 95% CI: 10-61%) and 43% for pembrolizumab/capecitabine (n = 6/14, 95% CI: 18-71%). Partial responses are observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens are associated with significant peripheral leukocyte contraction over time. Response is associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor-infiltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). In conclusion, pembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens are lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted. The clinical trial registration is NCT02734290.
Advances in Oral Oncolytic Agents for Breast Cancer and Recommendations for Promoting Adherence. [2021]Hormone receptor positivity and early stage diagnosis are generally considered signs of good prognosis in breast cancer. However, breast cancer all too frequently can become resistant to hormone-based therapies, and women can experience recurrence of their breast cancer decades after the diagnosis of early stage disease. To address the therapeutic needs for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer, a number of new drugs have been tested and approved for this indication, including the class of drugs that works as cyclin-dependent kinase (CDK) 4/6 inhibitors. These drugs, often combined with other hormone-based therapy, have demonstrated considerable success in clinical trials and are now being used widely in oncology practices. Because all of the currently approved CDK4/6 inhibitor agents (palbociclib, ribociclib, and abemaciclib) are given orally, issues of patient comprehension of and adherence to prescribed regimens should be at the forefront of practitioners' concerns about these drugs. In addition, ways to support and facilitate decision-making by patients related to this class of agents and other therapies recently approved for the same indication require focused attention by health-care providers. Oncology has continued to move toward a more patient-specific, precision medicine approach. Likewise, advanced practitioners have the opportunity to identify patient characteristics, preferences, and needs that are unique to individual patients to enhance precision treatment.