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

Sponsor

Silesian Centre for Heart Diseases (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05465031

Collaborator

Medical Research Agency, Poland (Other)

600

Enrollment

Locations

Arms

Anticipated Duration (Months)

150

Patients Per Site

2.5

Patients Per Site Per Month

Study Details

Study Description

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 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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Sacubitril-valsartan	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

600 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Double-blinded

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2027

Anticipated Study Completion Date :

Feb 1, 2028

Arms and Interventions

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.

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

Outcome Measures

Primary Outcome Measures

Decrease in left ventricular ejection fraction ≥ 5% [At 12 months from the randomization visit]
Reduction of LVEF assessed on magnetic resonance imaging (MRI)

Secondary Outcome Measures

Death from any cause or hospitalization for heart failure [From Randomization till the end of blinded therapy - at 24 months]
Composite clinical endpoint
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% [From Randomization till the end of blinded therapy - at 24 months]
Reduction of LVEF assessed on echocardiography
Occurrence of diastolic dysfunction (UKG) within 24 months of randomization [From Randomization till the end of blinded therapy - at 24 months]
Diastolic dysfunction assessed on echocardiography
- Development of pathological pericardial fluid volume or increase in pericardial fluid volume from baseline [From Randomization till the end of blinded therapy - at 24 months]
Assessed with any available clinical modality
Occurrence of cardiac tamponade [From Randomization till the end of blinded therapy - at 24 months]
Assessed with any clinical modality
Occurrence of pericarditis [From Randomization till the end of blinded therapy - at 24 months]
Assessed with any clinical modality
Occurrence of myocarditis [From Randomization till the end of blinded therapy - at 24 months]
Assessed with any clinical modality
Development of ventricular arrhythmias [From Randomization till the end of blinded therapy - at 24 months]
Assessed with any clinical modality
Development of supraventricular arrhythmias [From Randomization till the end of blinded therapy - at 24 months]
Assessed with any clinical modality
Presence of conduction disturbances [From Randomization till the end of blinded therapy - at 24 months]
Assessed with any clinical modality
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 [From Randomization till the end of blinded therapy - at 24 months]
Assessed with serial laboratory measurements

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Regional Cancer Centre in Opole	Opole	Opolskie	Poland	45-061
2	Maria Sklodowska-Curie Institute - Oncology Centre (MSCI), Gliwice Branch	Gliwice	Silesia	Poland	44102
3	Silesian Center for Heart Diseases	Zabrze	Silesia	Poland	41800
4	Holy Cross Cancer Centre, Cardio-Oncology Division	Kielce	Świętokrzyskie	Poland	25-734