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

NCT05465031 | Recruiting Phase 4 DMC

• 1 other identifier: LCZ696ABM001.001
• Study Type: interventional
• Target: 600
• Locations: 1 country
• Sites: 4

Brief Summary

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 transthoracic echocardiography (TTE). 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 (optionally), electrocardiography including 24-h Holter monitoring, blood tests, functional capacity tests and quality of life assessment.

Conditions

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

Keywords

LCZ696; Sacubitril/Valsartan; Magnetic Resonance Imaging; Echocardiography; Cardio-oncology; Breast Cancer; Cardiotoxicity; Anthracyclines; Trastuzumab; Heart failure; Cardioprotection

Outcome Measures

Primary Outcomes (1)

• Change in left ventricular ejection fraction (LVEF) by ≥5%

  Reduction of LVEF assessed on transthoracic echocardiography (TTE)

  Within 24 months from the randomization visit

Secondary Outcomes (16)

• Death from any cause or hospitalization for heart failure

  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

• Change in left ventricular ejection fraction by ≥ 5%

  From Randomization till the end of blinded therapy - within 24 months

Study Arms (2)

Experimental: Sacubitril/Valsartan

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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 patients 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: Placebo

Interventions

Sacubitril-valsartan DRUG

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.

Experimental: Sacubitril/Valsartan

Placebo DRUG

Placebo matching the sacubitril/valsartan (Entresto®) administered in the target dose matching the dosing of 200 mg b.i.d. (97/103 mg) for the period of 24 months. In case of intolerance of target dose of placebo, the physician-in-charge will be able to reduce the dose to placebo matching the dose of 100 mg b.i.d. (49/51mg). Physicians will be strongly encouraged to evaluate the possibility of drug dose uptitration to the target dose of placebo matching the dose of 200 mg b.i.d.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: As breast cancer is primarily the female malignancy, the studied population will be limited to female patients
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent
• Female gender, aged 18 years and over
• Patients with histologically confirmed breast cancer and complete assessment of tumor phenotype (Estrogen receptor - ER, Progesterone receptor - PR, Human epidermal growth factor receptor 2 - HER2, Kiel - 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
• Eastern Cooperative Oncology Group (ECOG) 0-2 general status
• LVEF ≥ 50% as assessed by echocardiography
• Sinus rhythm

You may not qualify if:

• Prior anthracycline-based chemotherapy and/or thoracic radiotherapy (prior to diagnosis of the cancer being the present cause of therapy)
• Clinically relevant HF (NYHA II-IV)
• Myocardial infarction (MI) within the last \< 3 months
• Symptomatic hypotension or systolic blood pressure (SBP) \< 90 mmHg
• Significant valvular disease, symptomatic coronary artery disease (CCS\>2), significant atrioventricular (AV) block, symptomatic sinus node dysfunction
• Expected survival \<12 months
• Glomerular filtration rate (GFR) \<30 ml/min/1.73 m2 (screening visit)
• K+\>5.5mmol/L (screening visit)
• Contraindications to angiotensin converting enzyme inhibitor (ACE-I)/angiotensin II receptor blocker (ARB) or LCZ696 if not listed among criteria
• Active untreated liver disease
• Pregnancy
• Conditions/circumstances that may lead to non-compliance with medical staff recommendations (e.g. active drug/alcohol dependence, poorly controlled mental illness)

Sponsors & Collaborators

• Silesian Centre for Heart Diseases: lead
• Medical Research Agency, Poland: collaborator

Study Sites (4)

Regional Cancer Centre in Opole

Opole, Opole Voivodeship, 45-061, Poland

RECRUITING

Maria Sklodowska-Curie Institute - Oncology Centre (MSCI), Gliwice Branch

Gliwice, Silesian Voivodeship, 44102, Poland

RECRUITING

Silesian Center for Heart Diseases

Zabrze, Silesian Voivodeship, 41800, Poland

ACTIVE NOT RECRUITING

Holy Cross Cancer Centre, Cardio-Oncology Division

Kielce, Świętokrzyskie Voivodeship, 25-734, Poland

RECRUITING

Related Publications (1)

• Tajstra M, Dyrbus M, Rutkowski T, Skladowski K, Sosnowska-Pasiarska B, Gozdz S, Radecka B, Staszewski M, Majsnerowska A, Myrda K, Nowowiejska-Wiewiora A, Skoczylas I, Rymkiewicz I, Niklewski T, Nowak J, Przybylowski P, Gasior M, Jarzab M. Sacubitril/valsartan for cardioprotection in breast cancer (MAINSTREAM): design and rationale of the randomized trial. ESC Heart Fail. 2023 Oct;10(5):3174-3183. doi: 10.1002/ehf2.14466. Epub 2023 Jul 14.

  PMID: 37449716 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Breast Diseases; Heart Failure; Cardiotoxicity; Neoplasms, Second Primary

Interventions

sacubitril and valsartan sodium hydrate drug combination

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries

Study Officials

• Mateusz Tajstra

  3rd Department of Cardiology, School of Medical Sciences in Zabrze, Medical University of Silesia, Katowice; Silesian Center for Heart Diseases

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mateusz Tajstra, MD, PhD, Assoc Prof

CONTACT

+48323733860; mateusztajstra@wp.pl

Lucyna Broja

CONTACT

+48323733853; l.broja@sccs.pl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double-blinded
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 4, 2022
• First Posted: July 19, 2022
• Study Start: April 17, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): February 1, 2029
• Last Updated: March 14, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

PL (4)