Evaluation of Dapagliflozin in Reducing Chemotherapy-Induced Cardiotoxicity in Breast Cancer Patients Receiving Anthracycline-Based Therapy

The primary objective of this Phase II study is to evaluate whether the administration of **dapagliflozin** is associated with a lower rate of asymptomatic and symptomatic chemotherapy-induced cardiotoxicity (CTRCD) in patients with breast cancer undergoing (neo-) adjuvant Anthracycline-based chemotherapy, with or without trastuzumab, over an 18-month period. This is clinically relevant as reducing CTRCD can significantly improve the cardiac health and overall prognosis of breast cancer patients receiving chemotherapy.

Secondary objectives include:

• Demonstrating whether dapagliflozin reduces the excess risk associated with trastuzumab.
• Demonstrating the reduction of the rate of asymptomatic mild, moderate, and severe CTRCD in the dapagliflozin group during 18 months.
• Demonstrating the reduction of the rate of symptomatic CTRCD in the dapagliflozin group during 18 months.
• Assessing the efficacy of dapagliflozin on the improvement of diastolic function, end systolic and diastolic left ventricular volumes, and plasma levels of bio-humoral markers, compared to standard care during 18 months.

The clinical trial focuses on **chemotherapy-induced cardiotoxicity in breast cancer** and involves a study population of adult women aged between 18 and 70 years. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants are chemotherapy-naive patients scheduled for anthracycline with or without trastuzumab treatment in the (neo-)adjuvant setting for stage I-III breast cancer. The trial includes women with an estimated glomerular filtration rate (eGFR) greater than 25 ml/min/1.7 m² and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. Female participants of childbearing potential must have a negative serum pregnancy test and agree to use highly effective contraceptive measures from the time of informed consent through seven months after the last dose of the study drug. The trial does not involve a vulnerable population, and both male and female subjects are considered, although the primary focus is on female participants. Lifestyle considerations such as diet and physical activity are not specified in the provided data.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy of **dapagliflozin** in reducing chemotherapy-induced cardiotoxicity in patients with breast cancer undergoing anthracycline-based chemotherapy, with or without trastuzumab. The trial will be conducted over an estimated duration of 18 months, with participant recruitment starting on October 19, 2023, and the study expected to conclude by December 31, 2026. Participants will be randomly assigned in a 1:1 ratio to receive either dapagliflozin or a placebo, administered orally in the form of 10 mg film-coated tablets.

The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the **screening** visit, eligibility will be assessed based on criteria such as being chemotherapy-naive, scheduled for anthracycline ± trastuzumab treatment, and having an eGFR > 25 ml/min/1.7 m². Participants must be adult women aged 18 to 70 years with an ECOG score of 0-2. A negative serum pregnancy test is required for women of childbearing potential, who must also agree to use effective contraception during the study and for seven months after the last dose.

Follow-up visits will occur at regular intervals to monitor the participants' health and assess the primary endpoint, which is the rate of asymptomatic and symptomatic chemotherapy-related cardiac dysfunction (CTRCD) over the 18-month period. Secondary endpoints include the rate of asymptomatic CTRCD. The end-of-study visit will involve a comprehensive evaluation of the participants' health status and the collection of final data for analysis.

Participant involvement is expected to last for the entire 18-month duration unless early termination is warranted. Conditions that may lead to early withdrawal include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The study aims to provide valuable insights into the potential cardioprotective effects of dapagliflozin in this patient population.

The clinical trial involves the administration of **dapagliflozin**, marketed under the name Forxiga, as the experimental medication. Forxiga is provided in the form of **film-coated tablets**, each containing 10 mg of dapagliflozin. The tablets are administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 5.4 grams over the course of the study. The treatment period is set for a maximum of 18 months. Dapagliflozin is a chemical substance, and its use in this trial is for an indication different from its marketing authorization. The trial aims to evaluate the potential of dapagliflozin in reducing chemotherapy-induced cardiotoxicity in participants with breast cancer undergoing (neo-) adjuvant Anthracycline-based chemotherapy, with or without trastuzumab.

In addition to the experimental treatment, participants may receive standard-of-care therapy as part of their cancer treatment regimen. This includes Anthracycline-based chemotherapy, which is a common treatment for breast cancer, and may also include trastuzumab, depending on the specific treatment plan for each participant. The study is designed to monitor participant compliance with the dosing schedule and to ensure adherence to the treatment protocol. No placebo or comparator treatment is specified in the trial documentation.

The efficacy of the clinical trial will be assessed by evaluating whether the administration of **dapagliflozin** is associated with a lower rate of asymptomatic and symptomatic chemotherapy-induced cardiotoxicity (CTRCD) in participants with breast cancer. The primary endpoint is to determine the reduction in the rate of both asymptomatic and symptomatic CTRCD over an 18-month follow-up period. A secondary endpoint focuses specifically on the reduction of asymptomatic CTRCD during the same timeframe.

Participants will be monitored throughout the study duration to collect data on the occurrence of CTRCD. The trial is designed as a Phase II, randomized, proof-of-concept study, with a 1:1 randomization ratio. The study will involve adult women aged 18 to 70 years who are chemotherapy-naive and scheduled for anthracycline +/- trastuzumab treatment in the (neo-)adjuvant setting for stage I-III breast cancer. The efficacy assessments will be conducted over the course of 18 months, aligning with the maximum treatment period for the administration of dapagliflozin.