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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure; Breast Cancer; Breast Diseases; Cardiotoxicity; Molecular Mechanisms of Pharmacological Action; Angiotensin Receptor Antagonists; Neoplasm, Breast; Cardiac Toxicity; Angiotensin II Type 1 Receptor Blockers; Cancer, Therapy-Related; Antihypertensive Agents; Sacubitril/Valsartan; Cancer Therapy-Related Cardiac Dysfunction
• Intervention / Treatment: Drug: Sacubitril-valsartan

• Study Type: Interventional
• Enrollment (Anticipated): 600
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mateusz Tajstra, MD, PhD, Associate Professor; Phone Number: +48323733860; Email: mateusztajstra@wp.pl
• Study Contact Backup: Name: Lucyna Broja; Phone Number: +48323733853; Email: l.broja@sccs.pl

Study Locations

• Poland
  • Opolskie
    • Opole, Opolskie, Poland, 45-061
      • Regional Cancer Centre in Opole
      • Contact: Barbara Radecka, MD, PhD; Phone Number: +48774416001; Email: brad@onkologia.opole.pl
  • Silesia
    • Gliwice, Silesia, Poland, 44102
      • Maria Sklodowska-Curie Institute - Oncology Centre (MSCI), Gliwice Branch
      • Contact: Michal Jarząb, MD, PhD, Associate Professor; Phone Number: +48322788886; Email: onkologia@io.gliwice.pl
    • Zabrze, Silesia, Poland, 41800
      • Silesian Center for Heart Diseases
      • Contact: Mateusz Tajstra, MD, PhD, Associate Professor; Phone Number: +48323733860; Email: mateusztajstra@wp.pl
      • Contact: Lucyna Broja; Phone Number: +48323733853; Email: l.broja@sccs.pl
  • Świętokrzyskie
    • Kielce, Świętokrzyskie, Poland, 25-734
      • Holy Cross Cancer Centre, Cardio-Oncology Division
      • Contact: Barbara Sosnowska-Pasiarska, MD, PhD; Phone Number: +48 41 34 56 882; Email: repikus@poczta.onet.pl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Experimental: Sacubitril/Valsartan; 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; 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.
PLACEBO_COMPARATOR: Placebo; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Silesian Centre for Heart Diseases
• Collaborators: Medical Research Agency, Poland

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): February 1, 2023
• Primary Completion (ANTICIPATED): December 1, 2027
• Study Completion (ANTICIPATED): February 1, 2028

Study Registration Dates

• First Submitted: July 4, 2022
• First Submitted That Met QC Criteria: July 15, 2022
• First Posted (ACTUAL): July 19, 2022

Study Record Updates

• Last Update Posted (ACTUAL): July 19, 2022
• Last Update Submitted That Met QC Criteria: July 15, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Breast Cancer; Heart failure; Magnetic Resonance Imaging; Cardiotoxicity; Cardioprotection; Echocardiography; Trastuzumab; Anthracyclines; Cardio-oncology; LCZ696; Sacubitril/Valsartan
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Wounds and Injuries; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Heart Failure; Breast Neoplasms; Breast Diseases; Cardiotoxicity; Neoplasms, Second Primary; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: LCZ696ABM001.001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No