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

Study Phase II "Proof of Concept", National Multi-centered. Randomised 1:1, Evaluate Whether Dapagliflozin Reduces Chemotherapy Induced Cardiotoxicity in Participants With Breast Cancer Treated With (Neo-) Adjuvant Anthracycline-based Chemotherapy +/- Trastuzumab

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Dapagliflozin 10mg Tab

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)

• Study Type: Interventional
• Enrollment (Estimated): 316
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Laura Scelsi, Cardiologist; Phone Number: +390382501326; Email: l.scelsi@smatteo.pv.it

Study Locations

• Italy
  • Pavia, Italy, 27100
    • Recruiting
    • Fondazione IRCCS Policlinico San Matteo
    • Contact: Gianpiero Rizzo, Oncologist; Phone Number: +390382502094; Email: g.rizzo@smatteo.pv.it
    • Contact: Alessandra Greco, Cardiologist; Phone Number: +390382501326; Email: a.greco@smatteo.pv.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active group - Dapagliflozin 10 mg	Drug: Dapagliflozin 10mg Tab; Dapaglifloziin 10 mg 1 tab daily; Other Names: forxiga 10mg
No Intervention: Control group - Standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess whether the administration of dapagliflozin is associated with a lower rate of asymptomatic and symptomatic CTRCD during 18 months during a 18 months follow-up.	Change of Left Ventricular Ejection Fraction Global Longitudinal Strain at 3-6-12 and 18 months compared with baseline will be measured using transthoracic echocardiography.	baseline, 3 months, 6 months, 12 months and 18 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in severe, moderate and mild asymptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ and with or without the use of any of ACEi, angiotensin receptor blockers, or b-blockers	Change of Left Ventricular Ejection Fraction Global Longitudinal Strain at 3-6-12 and 18 months compared with baseline will be measured using transthoracic echocardiography.	baseline, 3 months, 6 months, 12 months and 18 months.
Difference in symptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ (subgroup analysis)	Change in Left Ventricular Ejection Fraction Global Longitudinal Strain at 3-6-12 and 18 months compared with baseline will be measured using transthoracic echocardiography.	baseline, 3 months, 6 months, 12 months and 18 months.
Change from baseline in end diastolic and systolic left ventricular volumes and in left atrial volume during 18 months	transthoracic echocardiography.	baseline, 3 months, 6 months, 12 months and 18 months.
Change from baseline of at least of one grade of diastolic disfunction (according to ESC guidelines during 18 months.	transthoracic echocardiography.	baseline, 3 months, 6 months, 12 months and 18 months.
Change in plasma levels of the bio-humoral marker NT-pro-BNP between baseline and follow-up	Change in plasma levels of the bio-humoral marker between baseline and follow-up at three, six, twelve and eighteen months: NT-pro-BNP (pg/mL).	baseline, 3 months, 6 months, 12 months and 18 months.
Change in plasma levels of the bio-humoral marker hsTNI between baseline and follow-up	Change in plasma levels of the bio-humoral marker between baseline and follow-up at three, six, twelve and eighteen months: hsTNI (ng/mL).	baseline, 3 months, 6 months, 12 months and 18 months.
Change in plasma levels of the bio-humoral marker CKD-EPI eGFR between baseline and follow-up	Change in plasma levels of the bio-humoral marker between baseline and follow-up at three, six, twelve and eighteen months: CKD-EPI eGFR (mL/min/1.7mq).	baseline, 3 months, 6 months, 12 months and 18 months.
Change in plasma levels of the bio-humoral marker hsCRP between baseline and follow-up	Change in plasma levels of the bio-humoral marker between baseline and follow-up at three, six, twelve and eighteen months: hsCRP (mg/dL).	baseline, 3 months, 6 months, 12 months and 18 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcomes: TEAE incidence	In order to detect adverse events to dapagliflozin investigators should control any difference in the rate of occurrence of Treatment Emergent Adverse Events (TEAE) between the two groups.	baseline, 3 months, 6 months, 12 months and 18 months.
Toxicity: renal failure evaluation.	Investigators should control decline in eGFR under 25 ml/min/1.7 mq.	baseline, 3 months, 6 months, 12 months and 18 months.
Toxicity: hypoglycaemia evaluation	Investigators should control the level of glycemia (mg/dL) documenting clinical hypoglycaemic events.	baseline, 3 months, 6 months, 12 months and 18 months.
Tolerability: genito-urinary tract infections	Investigators should control genito-urinary tract infections (urinalysis).	baseline, 3 months, 6 months, 12 months and 18 months.
Tolerability: symptomatic hypotension	Investigators should control symptomatic hypotension.	baseline, 3 months, 6 months, 12 months and 18 months.
Quality of Life questionaire: EQ-5D-5L	Investigators should control quality of life of the patient with a QOL questionaire (EQ-5D-5L).	baseline, 18 months.

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2023
• Primary Completion (Estimated): April 19, 2025
• Study Completion (Estimated): April 19, 2025

Study Registration Dates

• First Submitted: March 19, 2024
• First Submitted That Met QC Criteria: March 26, 2024
• First Posted (Actual): April 2, 2024

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: breast cancer; Dapagliflozin; trastuzumab; cardiotoxicity; Anthracycline-based chemotherapy; SGLT-2; Asymptomatic CTRCD; Symptomatic CTRCD; ESC Cardio-Oncology Guidelines
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Wounds and Injuries; Breast Diseases; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Breast Neoplasms; Cardiotoxicity; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: EudraCT 2022-003377-28

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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