Cardiotoxicity Prevention in Breast Cancer Patients Treated With Anthracyclines and/or Trastuzumab

Breast Cancer Clinical Trial

— SAFE  

Official title:

Role of ACE Inhibitors and Beta Blockers as Cardiotoxicity Prevention in Breast Cancer Patients Treated With (Neo)Adjuvant Anthracyclines and/or Trastuzumab: a Four Arm, Placebo Control, Randomized Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02236806
• Other study ID #: SAFE2014
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 2015
• Est. completion date: June 2022

Study information

• Verified date: January 2022
• Source: Azienda Ospedaliero-Universitaria Careggi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of the study is to analyze the protective impact on the cardiac damage of beta blockers and ACE inhibitors for breast cancer patients treated with anthracyclines-based chemotherapy with or without trastuzumab.

Description:

Over the years, due to the use of new generation therapeutic regimens, as well as the use of advanced radiation techniques, the curability of breast cancer reached an overall 10-year survival rate of approximately 80%.

Anthracyclines have a key role in the treatment of breast cancer. Many published studies showed a benefit of disease-free survival in patients with positive lymph nodes treated with anthracyclines-based regimens. Many anthracyclines and taxanes-based regimens are currently used in clinical practice in the treatment of breast cancer. Numerous randomized trials have confirmed the benefit of the addition of taxanes to anthracyclines.

Trastuzumab is a recombinant humanized monoclonal antibody with specificity for the extracellular domain of human epidermal growth factor receptor 2 (HER2). The use of trastuzumab administered sequentially or concurrently with adjuvant chemotherapy compared to chemotherapy in patients with HER2 positive was evaluated in several randomized trials. Many data concerning the incidence of adverse cardiovascular events acute, subacute and late are now available. The cardiac toxicity of anthracyclines may be acute, subacute and chronic. The acute toxicity occurs during or shortly after the infusion of the drug with arrhythmias, which in some cases leads to heart failure, pericarditis-myocarditis and electrocardiographic abnormalities. The acute toxicity is usually reversible in a dose-dependent manner. The acute and subacute toxicity are rare (1-4%). Data are available concerning clinically relevant cardiac toxicity with a chronic progressive deterioration of ventricular function up to heart failure.

Beside the cumulative dose risk factor, other unfavourable features such as advanced age, female sex, and the combination of anthracyclines and trastuzumab should be evaluated. In most cases, the late toxicity occurs within the first year following completion of chemotherapy but nevertheless the clinical manifestations can occur even after 10-20 years. This fact suggests that in women treated in (neo)adjuvant setting is strongly necessary an echocardiographic monitoring even after a longer time.

The aim of the study is to analyze the protective impact on the cardiac damage of beta blockers and ACE inhibitors for breast cancer patients treated with anthracyclines-based chemotherapy with or without trastuzumab, using myocardial strain imaging monitoring.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 262
• Est. completion date: June 2022
• Est. primary completion date: June 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Female

• Age >18 years

• Non-metastatic histologically confirmed primary invasive breast cancer

• Scheduled to receive neoadjuvant and/or adjuvant anthracyclines with or without anti-HER2 therapy

• Provided informed consent

• Able to swallow capsules

• LVEF > 50%

Exclusion Criteria:

• Pregnant or lactating women

• Treatment with ACE-inhibitors or beta blockers at diagnosis

• History of NCI Common Toxicity Criteria for Adverse Effects (CTCAE) (version 4.0) Grade >2 symptomatic congestive heart failure (CHF), previous myocardial infarction, significant symptoms (Grade>2) relating to LVEF dysfunction, valvular disease, cardiac arrhythmia (Grade>3)

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Cardiotoxicity

Intervention

Drug:
• Bisoprolol
5 mg daily
• Ramipril
5 mg daily
• Placebo
1 capsule daily

Locations

Country	Name	City	State
Italy	Azienda Ospedaliero-Universitaria Careggi, Florence University	Florence

Sponsors (2)

Lead Sponsor	Collaborator
Azienda Ospedaliero-Universitaria Careggi	University of Florence

Country where clinical trial is conducted

Italy, 

References & Publications (3)

Francolini G, Desideri I, Meattini I, Becherini C, Terziani F, Olmetto E, Delli Paoli C, Pezzulla D, Loi M, Bonomo P, Greto D, Calusi S, Casati M, Pallotta S, Livi L. Assessment of a guideline-based heart substructures delineation in left-sided breast cancer patients undergoing adjuvant radiotherapy : Quality assessment within a randomized phase III trial testing a cardioprotective treatment strategy (SAFE-2014). Strahlenther Onkol. 2019 Jan;195(1):43-51. doi: 10.1007/s00066-018-1388-x. Epub 2018 Nov 7. — View Citation

Livi L, Barletta G, Martella F, Saieva C, Desideri I, Bacci C, Del Bene MR, Airoldi M, Amoroso D, Coltelli L, Scotti V, Becherini C, Visani L, Salvestrini V, Mariotti M, Pedani F, Bernini M, Sanchez L, Orzalesi L, Nori J, Bianchi S, Olivotto I, Meattini I — View Citation

Meattini I, Curigliano G, Terziani F, Becherini C, Airoldi M, Allegrini G, Amoroso D, Barni S, Bengala C, Guarneri V, Marchetti P, Martella F, Piovano P, Vannini A, Desideri I, Tarquini R, Galanti G, Barletta G, Livi L. SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab. Med Oncol. 2017 May;34(5):75. doi: 10.1007/s12032-017-0938-x. Epub 2017 Mar 31. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Left ventricular ejection fraction (LVEF)	Change in LVEF (3-dimensional and 2-dimensional) at time-frame	at months 6,9,12,24
Primary	Global longitudinal strain (GLS)	Change in GLS at time-frame	at months 6,9,12,24
Secondary	Indexed left ventricular end diastolic volume (EDVI)	Change in EDVI at time-frame	at months 6,9,12,24
Secondary	Indexed left ventricular end systolic volume (ESVI)	Change in ESVI at time-frame	at months 6,9,12,24