Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent (MAINSTREAM)

Study Overview
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Brief Summary
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Breast cancer is the most commonly cancer in women in the overall global population. According to the World Cancer Research Fund International, there were more than 2.25 million new cases of breast cancer in women in 2020. Although the modern treatment strategies, based on the complex care, which consists of surgery, radiotherapy, hormone therapy, and targeted chemotherapy directed at specific cancer molecules have substantially reduced the risk of death due to breast cancer, their wide adoption results in the wider prevalence of cardiotoxicity, defined as either symptomatic heart failure, or asymptomatic contractile dysfunction. The occurrence of cardiotoxicity induced by anti-cancer therapies is estimated at 5-15%, and its development is the primary cause of therapy termination, which significantly reduces the probability of the efficacy of treatment. Several attempts have been made to determine the efficacious preventive strategy, which could diminish the risk of cancer-therapy induced cardiotoxicity. The results of the prior studies indicated a trend towards lower risk of troponin elevation, or left ventricular contractile dysfunction with the introduction of drugs interfering with the renin-angiotensin-aldosterone (RAA) axis, which constitute the primary treatment modality in heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan, the novel therapeutic agent, has been demonstrated to significantly improve prognosis in patients with HFrEF. Prior retrospective, small, single-center studies have shown that treatment with sacubitril/valsartan may reduce the risk of cancer-therapy induced cardiotoxicity, or reverse contractile dysfunction caused by anti-cancer therapy. However, no large randomized data confirmed these findings. Therefore, the Sacubitril/Valsartan in PriMAry preventIoN of the cardiotoxicity of systematic breaST canceR trEAtMent) study, has been designed to verify, whether the preventive use of sacubitril/valsartan administered in the doses recommended in patients with HFrEF in breast cancer patients undergoing adjuvant chemotherapy with anthracyclines or anthracyclines and HER-2 monoclonal antibodies, will reduce the incidence of cardiotoxicity defined as impaired left ventricular systolic function on cardiac magnetic resonance imaging (MRI). In the trial, a total of 480 patients with histologically confirmed breast cancer, who are eligible for chemotherapy with anthracyclines or anthracyclines and HER-2 monoclonal antibodies, will undergo 1:1 randomization to either preventive treatment with sacubitril/valsartan or placebo. The patients will be followed for 24 months, and will have repetitive efficacy and safety examinations, including echocardiography, MRI, electrocardiography including 24-h Holter monitoring, blood tests, functional capacity tests and quality of life assessment.

Official Title
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Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent

Conditions
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Breast Cancer, Neoplasm, Breast, Breast Diseases, Antihypertensive Agents, Sacubitril/Valsartan, Heart Failure, Angiotensin II Type 1 Receptor Blockers, Angiotensin Receptor Antagonists, Molecular Mechanisms of Pharmacological Action, Cardiac Toxicity, Cancer, Therapy-Related, Cancer Therapy-Related Cardiac Dysfunction, Cardiotoxicity

Intervention / Treatment
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* Drug: Sacubitril-valsartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Female gender, aged 18 years and over Patients with histologically confirmed breast cancer and complete assessment of tumor phenotype (ER, PR, HER2, Ki67) Ability to take oral medication and willingness to adhere to the planned regimen Tumor grade IA-IIIC or oligometastatic grade IV Radical treatment plan including surgery Plan of use of systemic treatment (preoperative, postoperative or combined) with anthracyclines and/or anti-HER2 drugs ECOG 0-2 general status LVEF ≥ 50% as assessed by echocardiography Sinus rhythm Exclusion Criteria: Prior anthracycline-based chemotherapy and/or left-sided radiotherapy (prior to diagnosis of the cancer being the present cause of therapy) Clinically relevant HF (NYHA II-IV) MI within the last < 3 months Symptomatic hypotension or SBP < 90 mmHg Significant valvular disease, symptomatic coronary artery disease (CCS>2), significant AV block, symptomatic sinus node dysfunction Expected survival <12 months GFR<30 ml/min/1.73 m2 (screening visit) K+>5.5mmol/L (screening visit) Contraindications to ACE-I/ARB or LCZ696 if not listed among criteria Active untreated liver disease Pregnancy Contraindications to cardiac MRI, including allergy to gadolinium-containing contrast agent or presence of implanted materials or devices prohibited for MRI Conditions/circumstances that may lead to non-compliance with medical staff recommendations (e.g. active drug/alcohol dependence, poorly controlled mental illness)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Sacubitril/Valsartan<br>After assessment of the tolerance of the drug during the single-blind period, during the which the starting dose of the drug of 100 mg b.i.d. should be increased after two weeks to the target dose 200 mg b.i.d, the patients will be randomized in 1:1 ratio to either intervention or placebo group. In the experimental arm, the patients after randomization will receive the dose 200 mg b.i.d of sacubitril/valsartan for the course of the study. If the patients does not tolerate the target dose of 200 mg b.i.d., the reduction of the drug dose to 100 mg b.i.d. will be possible at the discretion of the physician-in-charge. | Drug: Sacubitril-valsartan<br>* Sacubitril/valsartan (Entresto®) administered in the target dose of 200 mg b.i.d. (97/103 mg of sacubitril and valsartan respectively) for the period of 24 months. In case of target dose intolerance, the physician-in-charge will be able to reduce the dose to 100 mg b.i.d. (49/51mg of sacubitril and valsartan respectively). Physicians will be strongly encouraged to evaluate the possibility of drug dose uptitration to the target dose of 200 mg b.i.d.<br>|
| Placebo Comparator: Placebo<br>After assessment of the tolerance of the drug during the single-blind period, during the which the starting dose of the drug of 100 mg b.i.d. should be increased after two weeks to the target dose 200 mg b.i.d, the patients will be randomized in 1:1 ratio to either intervention or placebo group. In the placebo arm, the paitents will receive the matching placebo with an identical strategy of dose reduction as in the intervention group, at the discretion of the physician-in-charge. | Drug: Sacubitril-valsartan<br>* Sacubitril/valsartan (Entresto®) administered in the target dose of 200 mg b.i.d. (97/103 mg of sacubitril and valsartan respectively) for the period of 24 months. In case of target dose intolerance, the physician-in-charge will be able to reduce the dose to 100 mg b.i.d. (49/51mg of sacubitril and valsartan respectively). Physicians will be strongly encouraged to evaluate the possibility of drug dose uptitration to the target dose of 200 mg b.i.d.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decrease in left ventricular ejection fraction ≥ 5% | Reduction of LVEF assessed on magnetic resonance imaging (MRI) | At 12 months from the randomization visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death from any cause or hospitalization for heart failure | Composite clinical endpoint | From Randomization till the end of blinded therapy - at 24 months | 
| Death from any cause |  | From Randomization till the end of blinded therapy - at 24 months | 
| Death from cardiovascular causes |  | From Randomization till the end of blinded therapy - at 24 months | 
| Hospitalization for other cardiovascular causes |  | From Randomization till the end of blinded therapy - at 24 months | 
| Decrease in left ventricular ejection fraction ≥ 5% | Reduction of LVEF assessed on echocardiography | From Randomization till the end of blinded therapy - at 24 months | 
| Occurrence of diastolic dysfunction (UKG) within 24 months of randomization | Diastolic dysfunction assessed on echocardiography | From Randomization till the end of blinded therapy - at 24 months | 
| - Development of pathological pericardial fluid volume or increase in pericardial fluid volume from baseline | Assessed with any available clinical modality | From Randomization till the end of blinded therapy - at 24 months | 
| Occurrence of cardiac tamponade | Assessed with any clinical modality | From Randomization till the end of blinded therapy - at 24 months | 
| Occurrence of pericarditis | Assessed with any clinical modality | From Randomization till the end of blinded therapy - at 24 months | 
| Occurrence of myocarditis | Assessed with any clinical modality | From Randomization till the end of blinded therapy - at 24 months | 
| Development of ventricular arrhythmias | Assessed with any clinical modality | From Randomization till the end of blinded therapy - at 24 months | 
| Development of supraventricular arrhythmias | Assessed with any clinical modality | From Randomization till the end of blinded therapy - at 24 months | 
| Presence of conduction disturbances | Assessed with any clinical modality | From Randomization till the end of blinded therapy - at 24 months | 
| Changes in corrected QT interval |  | From Randomization till the end of blinded therapy - at 24 months | 
| Changes in BNP, NT pro-BNP, troponin T or troponin I levels | Assessed with serial laboratory measurements | From Randomization till the end of blinded therapy - at 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Cardiotoxicity, LCZ696, Sacubitril/Valsartan, Magnetic Resonance Imaging, Echocardiography, Cardio-oncology, Anthracyclines, Trastuzumab, Heart failure, Cardioprotection