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

Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05465031
• Other study ID #: LCZ696ABM001.001
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: February 2023
• Est. completion date: February 2028

Study information

• Verified date: July 2022
• Source: Silesian Centre for Heart Diseases
• Contact: Mateusz Tajstra, MD, PhD, Associate Professor
• Phone: +48323733860
• Email: mateusztajstra[@]wp.pl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 600
• Est. completion date: February 2028
• Est. primary completion date: December 2027
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Angiotensin II Type 1 Receptor Blockers
• Angiotensin Receptor Antagonists
• Breast Cancer
• Breast Diseases
• Breast Neoplasms
• Cancer, Therapy-Related
• Cardiac Toxicity
• Cardiotoxicity
• Heart Failure
• Molecular Mechanisms of Pharmacological Action
• Neoplasm, Breast
• Neoplasms, Second Primary
• Sacubitril/Valsartan

Intervention

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.

Locations

Country	Name	City	State
Poland	Maria Sklodowska-Curie Institute - Oncology Centre (MSCI), Gliwice Branch	Gliwice	Silesia
Poland	Holy Cross Cancer Centre, Cardio-Oncology Division	Kielce	Swietokrzyskie
Poland	Regional Cancer Centre in Opole	Opole	Opolskie
Poland	Silesian Center for Heart Diseases	Zabrze	Silesia

Sponsors (2)

Lead Sponsor	Collaborator
Silesian Centre for Heart Diseases	Medical Research Agency

Country where clinical trial is conducted

Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Decrease in left ventricular ejection fraction = 5%	Reduction of LVEF assessed on magnetic resonance imaging (MRI)	At 12 months from the randomization visit
Secondary	Death from any cause or hospitalization for heart failure	Composite clinical endpoint	From Randomization till the end of blinded therapy - at 24 months
Secondary	Death from any cause		From Randomization till the end of blinded therapy - at 24 months
Secondary	Death from cardiovascular causes		From Randomization till the end of blinded therapy - at 24 months
Secondary	Hospitalization for other cardiovascular causes		From Randomization till the end of blinded therapy - at 24 months
Secondary	Decrease in left ventricular ejection fraction = 5%	Reduction of LVEF assessed on echocardiography	From Randomization till the end of blinded therapy - at 24 months
Secondary	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
Secondary	- 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
Secondary	Occurrence of cardiac tamponade	Assessed with any clinical modality	From Randomization till the end of blinded therapy - at 24 months
Secondary	Occurrence of pericarditis	Assessed with any clinical modality	From Randomization till the end of blinded therapy - at 24 months
Secondary	Occurrence of myocarditis	Assessed with any clinical modality	From Randomization till the end of blinded therapy - at 24 months
Secondary	Development of ventricular arrhythmias	Assessed with any clinical modality	From Randomization till the end of blinded therapy - at 24 months
Secondary	Development of supraventricular arrhythmias	Assessed with any clinical modality	From Randomization till the end of blinded therapy - at 24 months
Secondary	Presence of conduction disturbances	Assessed with any clinical modality	From Randomization till the end of blinded therapy - at 24 months
Secondary	Changes in corrected QT interval		From Randomization till the end of blinded therapy - at 24 months
Secondary	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