Potential Protective Role of SGLT-2 Inhibitors for Chemotherapy-induced Cardiotoxicity

NCT ID: NCT06341842

Last Updated: 2024-04-02

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 316 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-19
• Study Completion Date: 2025-04-19

Brief Summary

The purpose of this study is to evaluate whether dapagliflozin reduces chemotherapy-induced cardiotoxicity in participants with breast cancer treated with (neo-)adjuvant Anthracycline-based chemotherapy +/- trastuzumab. The study aims to describe the efficacy for dapagliflozin as compared to standard of care. Participants will be recruited in participating centers, where they are planning on starting (neo-) adjuvant ACT-based chemotherapy and/or trastuzumab for stage I-III breast cancer.

Detailed Description

Anthracyclines (AC) are among the most widely used chemotherapeutic agents and have been shown to be effective in a wide range of tumors, in particular breast cancer. Their clinical effectiveness, however, may be thwarted by the development of cardiotoxicity that negatively affects patients' outcomes and seriously limits their oncological therapeutic opportunities. A subgroup of breast cancer with overexpressed human epidermal growth factor receptor type 2 (HER2), associated with poor prognosis, is now treated with highly effective targeted therapies such Trastuzumab, Pertuzumab, trastuzumab Emtansine (T-DM1), Trastuzumab Deruxtecan. Based on several large-scale trials of adjuvant therapy in breast cancer, the rate of cardiac dysfunction ranged from 7 to 34%, with HF (NYHA class III or IV) rates between 0 and 4%. In the last twenty years several randomized and observational trials tried to study a prophylactic intervention in order to avoid drug-induced cardiotoxicity and the onset of heart failure. A meta-analysis published in 2019 showed a significant, but small, benefit of neurohormonal therapies in reducing decline in LV systolic function among patients undergoing chemotherapy. SGLT-2 inhibitors are a class of drugs primary developed as oral hypoglycemic medications for diabetic patients. In several trials SGLT-2 inhibitors (also known as gliflozins) have reduced HF hospitalization, CV mortality and all-cause mortality to a different extent, suggesting a pleiotropic effect which goes beyond glycemic control since some RCTs have employed these medications in non-diabetic patients. Currently there is a lack of human evidence in the role of these medications to prevent heart failure induced by chemotherapies. Quagliarello et al performed a preliminary cellular studies on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to empaglifozin. In preclinical study, empaglifozin increased left ventricle ejection fraction and fraction shortening compared to doxorubicin groups (p < 0.05), prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin. Recently, Gongora et al conduct a retrospective study to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines. The authors conclude that SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the conducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracycline.

The PROTECT trial seeks primarily to assess whether the administration of dapagliflozin is associated with a lower rate of asymptomatic and symptomatic CTRCD during 18 months . The key secondary is to assess whether the administration of dapagliflozin is associated with a lower rate of asymptomatic CTRCD during 18 months. Patients will be recruited in participating centers, where they are planning on starting (neo-) adjuvant ACT-based chemotherapy and/or trastuzumab for stage I-III breast cancer. The enrollment will be ongoing for 1 year until the needed number of patients are recruited.

After screening for inclusion and exclusion criteria, patients will be randomized using a web-based system stratified by the use of trastuzumab to: Active group: chemotherapy regimen plus standard of care plus dapagliflozin (10 mg/die) during 18 months; Control group: chemotherapy regimen plus standard of care during 18 months.During follow-up period, if a patient develops asymptomatic or symptomatic systolic disfunction should be treated according to good clinical practice in both arms.

The sample size is computed based on the primary endpoint and makes use of the data reported in the literature. At 18 months, we expect a cumulative incidence of CTRCD of 35% in the control arm, corresponding to an event-free survival rate of 65%. With 316 patients (158 per arm) we will be able to elicit an increase in event-free survival in the dapaglifozin arm up to 80% (hazard ratio, HR 0.52, 78 events) with a power of 80 and type I error (2-tailed) of 5%. This sample size accounts for a 10% dropout rate and is based on the logrank test to compare event-free survivals. For calculation we used the Stata command: power logrank .65 .80, wdprob(.1) power(.80) alpha(0.05)

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Active group - Dapagliflozin 10 mg

Group Type: EXPERIMENTAL

Dapagliflozin 10mg Tab

Intervention Type: DRUG

Dapaglifloziin 10 mg 1 tab daily

Control group - Standard of care

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Dapagliflozin 10mg Tab

Dapaglifloziin 10 mg 1 tab daily

Intervention Type: DRUG

Other Intervention Names

forxiga 10mg

Eligibility Criteria

Inclusion Criteria

• Chemotherapy-naive patients, scheduled for antracycline +/- trastuzumab treatment in the (neo-)adjuvant setting for stage I-III breast cancer.
• Adult women between 18 and 70 years of age
• eGFR>25 ml/min/1.7 mq
• ECOG score 0-2Consent form signed. Female patients of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a negative result from a serum pregnancy test performed within 7 days of randomization and on the day of first study treatment prior to the initiation of study treatment. Women of childbearing potential must agree to use highly effective contraceptive measures from the time of informed consent through 7 months after last dose of study drug. Women of childbearing potential willing to use highly effective contraceptive measures from the time of informed consent through 7 months after last dose of study drug .

Exclusion Criteria

• Left ventricular ejection fraction (LVEF) <53%*
• Valvular heart disease.
• Previous malignancy requiring treatment with anthracyclines or chest radiotherapy.
• A life expectancy of ≤12 weeks.
• Currently pregnant (confirmed with positive pregnancy test performed from -7 to -1 days prior to start study drug) or unwilling to adopt highly effective contraceptive method.
• Currently breast-feeding women
• History of hypersensitivity to dapagliflozin or any of the excipients of the product.
• History of Diabetic Ketoacidosis (DKA) requiring medical intervention (e.g. emergency room visit and/or hospitalization) within 1 month prior to enrolment visit.
• Type 1 diabetes mellitus

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Fondazione IRCCS Policlinico San Matteo di Pavia

OTHER

Sponsor Role: lead

Responsible Party

Laura Scelsi

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Fondazione IRCCS Policlinico San Matteo

Pavia, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Laura Scelsi, Cardiologist

Role: CONTACT

l.scelsi@smatteo.pv.it

+390382501326

Facility Contacts

Gianpiero Rizzo, Oncologist

Role: primary

g.rizzo@smatteo.pv.it

+390382502094

Alessandra Greco, Cardiologist

Role: backup

a.greco@smatteo.pv.it

+390382501326

References

Greco A, Quagliariello V, Rizzo G, Tedeschi A, Schirinzi S, Turco A, Galiazzo M, Acquaro M, De Amicis M, Klersy C, Ghio S, Perrone L, Paccone A, Uccello G, Canale ML, Oliva S, Guerra F, De Luca L, Maurea N, Scelsi L. SGLT2i Dapagliflozin in primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy +/- trastuzumab: rationale and design of the multicenter PROTECT trial. Cardiooncology. 2025 Sep 1;11(1):79. doi: 10.1186/s40959-025-00368-9.

Reference Type: DERIVED

PMID: 40890873 (View on PubMed)

Other Identifiers

EudraCT 2022-003377-28

Identifier Type: -

Identifier Source: org_study_id