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Dapagliflozin

Fulvestrant

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Sodium-Glucose Transporter 2 Inhibitors

A cycle length is defined as 28 days.

Fulvestrant 500 mg intramuscular, Cycle 1, Day 1 and Day 15; Cycle 2 and beyond 500 mg Intramuscular Day 1.

Alpelisib 300 mg by mouth, daily, continuously beginning on Cycle 1, Day 1.

Dapagliflozin 10 mg by mouth, daily, continuously beginning Cycle 1, Day 3.

Hyperglycemia is an expected effect of PI3K inhibitors given the pivotal role of PI3K in mediating the response to insulin in multiple tissues. Blocking insulin signaling by p110α inhibitors leads to glycogen breakdown in the liver along with decreased glucose uptake in peripheral tissues. The resulting hyperglycemia causes a compensatory response of increase insulin secretion by the pancreas.

If concurrent treatment with dapagliflozin can abrogate the alpelisib induced hyperglycemia and subsequent rebound hyperinsulinemia it may significantly improve the therapeutic efficacy of alpelisib.

Dapagliflozin 10Mg Tab

Kelley Aldrich, RN

Timothy J Pluard, MD

Elizabeth Cathcart-Rake, MD

This will be a single arm, open label pilot to test the combination of dapagliflozin, a commercially available SGLT-2 inhibitor, in combination with alpelisib + fulvestrant in patients with HR+/HER2- mBC. The objective of this study is to determine if the addition of dapagliflozin to the combination of alpelisib and fulvestrant leads to significant reduction in all-grade hyperglycemia.

Alpelisib is a p110α specific PI3K inhibitor that has shown significant clinical benefit in patients with HR+/HER2 negative mBC harboring activating PIK3CA mutations. The SOLAR-1 study randomized patients with MBC progressing after aromatase inhibitor therapy patients had a PFS of 11 months with fulvestrant plus alpelisib versus 5.7 months with fulvestrant alone. Alpelisib was associated with a 65% incidence of hyperglycemia, including 37% Grade 3 or 4 hyperglycemia.

Hyperglycemia is an expected effect of PI3K inhibitors given the pivotal role of PI3K in mediating the response to insulin in multiple tissues. Blocking insulin signaling by p110α inhibitors leads to glycogen breakdown in the liver along with decreased glucose uptake in peripheral tissues. The resulting hyperglycemia causes a compensatory response of increase insulin secretion by the pancreas.

Cantley and colleagues have shown in animal models that treatment with BYL-719(alpelisib) results in rapid increase in plasma glucose level and a compensatory increase in insulin.

They went on to show that this rebound hyperinsulinemia was able to rescue KPC tumor allografts from BYL-719 inhibition as evidenced by increasing phosphorylation of downstream effectors in the PI3K pathway, pAKT and PS6. Pretreatment of the mice with an SGLT-2 inhibitor decreased the hyperglycemia and hyperinsulinemia following treatment with BYL-719. Importantly, the response of the KPC tumor allografts to treatment was concordant with reduction in insulin levels.3

This provides a rationale for combining dapagliflozin with alpelisib in the treatment of HR+, PIK3CA mutant MBC. If concurrent treatment with dapagliflozin can abrogate the alpelisib induced hyperglycemia and subsequent rebound hyperinsulinemia it may significantly improve the therapeutic efficacy of alpelisib.

open label pilot to test the combination of dapagliflozin, a commercially available SGLT-2 inhibitor, in combination with alpelisib + fulvestrant in patients with HR+/HER2- mBC.

Alpelisib, Fulvestrant and Dapagliflozin for the Treatment of HR+, HER2 -, PIK3CA Mutant Metastatic Breast Cancer

Novartis Pharmaceuticals

Saint Luke's Health System

Heart and Blood Diseases

Symptoms and General Pathology

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Doxorubicin Induced Cardiomyopathy

Doxorubicin

Liposomal doxorubicin

23 breast cancer patients which will receive four cycles of AC regimen (Doxorubicin and Cyclophosamide; each cycle is given every 21 days) only.

23 breast cancer patients which will receive four cycles of AC regimen (Doxorubicin and Cyclophosamide; each cycle is given every 21 days) plus Dapagliflozin 10 mg once daily.

Dapagliflozin 10 mg tab once daily given during the duration of AC cycles.

Dapagliflozin 10mg Tab

Sandy Rezkallah, Bachelor

Osama M Ibrahim, Professor

Sandy E Rezkallah, Bachelor

Heba Elsheredy, Professor

Sandy E Rezkallah, bachelor

This is a randomized controlled clinical trial that aims to evaluate the safety and efficacy of Dapagliflozin as a cardioprotective in doxorubicin-induced cardiotoxicity in breast cancer patients.

Breast cancer is the most common type of cancer in women and the first cause of cancer death among them. In Egypt, it represents 33%of female cancer cases and more than 22,000 new cases are diagnosed each year. This is expected to rise exponentially over the next years given the enlarging population and changes in the population pyramid.

The Early Breast Cancer "Trialists" Collaborative Group (EBCTCG) reported that the inclusion of anthracyclines as doxorubicin in the management of breast cancer improved absolute survival by approximately 3% at 5 years and 4% at 10 years. Therefore, anthracyclines remain the cornerstone of treatment for breast cancer patients.

Despite its effectiveness, doxorubicin is associated with cumulative, dose-dependent, and potential cardiotoxicity.

Although the main mechanism of doxorubicin-induced cardiotoxicity has not been fully known, there are several mechanisms proposed for cardiac injury including oxidative stress, free radical generation, and apoptosis are most widely reported. Other mechanisms are also involved such as impaired mitochondrial function, perturbation in iron regulatory protein, disruption of Ca2+ homeostasis, autophagy, and the release of nitric oxide and inflammatory mediators.

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is a class of glucose-lowering agents and is used to treat patients with type 2 diabetes. Besides reducing glucose reabsorption, DAPA has shown protective effects on cardiovascular diseases. The cardioprotective effects of DAPA have been demonstrated in patients with diabetic cardiomyopathy, heart failure (HF) with preserved ejection fraction (EF), and HF with reduced EF. SGLT2 inhibitors exert their cardioprotective effect by increasing energy metabolism, mitochondrial biogenesis, autophagy, and ketone bodies while decreasing endoplasmic reticulum (ER) stress, ferroptosis, oxidative stress, and inflammation.

In a recent animal study, DAPA protected against doxorubicin-induced cardiotoxicity by reducing ER stress, as evidenced by the decreased expression of the ER-related proteins including glucose-regulated protein 78, protein kinase R-like endoplasmic reticulum kinase and transcription factor 4.

Doxorubicin administration have been shown to increase HF incidence, HF admissions, and the development of cardiomyopathy which is defined by a decline in left ventricle ejection fraction and these outcomes were attenuated by SGLT2 inhibitors.

It is known that doxorubicin increases the circulating level of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and cardiac Troponin T (cTnT) which DAPA significantly reduced in a recent animal study.

Evaluation of the Possible Safety and Efficacy of Dapagliflozin in the Prophylaxis of Doxorubicin-Induced Cardiotoxicity

Clinical Study to Evaluate the Possible Safety and Efficacy of Dapagliflozin in the Prophylaxis of Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients

Initial evaluation of cardiac function by Echocardiography at baseline and after the end of chemotherapy. The primary outcome is to avoid reduction in patients' ejection fraction during doxorubicin administration.

Monitoring the serum biomarker Cardiac Troponin T at baseline and after the end of chemotherapy.

Monitoring the serum biomarker NT-pro-BNP at baseline and after the end of chemotherapy.

Tanta University

Clinical Pharmacist

Trastuzumab

Laura Scelsi, Cardiologist

Gianpiero Rizzo, Oncologist

Alessandra Greco, Cardiologist

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.

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)

Investigator initiated Phase II "proof of concept", multicentre, randomized 1:1, open label, parallel-groups study, designed to evaluate if dapagliflozin reduces chemotherapy induced cardiotoxicity in participants with breast cancer treated with (neo-) adjuvant Anthracycline-based chemotherapy +/- trastuzumab.

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

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

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.

Investigators should control decline in eGFR under 25 ml/min/1.7 mq.

Investigators should control the level of glycemia (mg/dL) documenting clinical hypoglycaemic events.

Investigators should control genito-urinary tract infections (urinalysis).

Investigators should control symptomatic hypotension.

Investigators should control quality of life of the patient with a QOL questionaire (EQ-5D-5L).

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.

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.

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).

Change in plasma levels of the bio-humoral marker between baseline and follow-up at three, six, twelve and eighteen months: hsTNI (ng/mL).

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).

Change in plasma levels of the bio-humoral marker between baseline and follow-up at three, six, twelve and eighteen months: hsCRP (mg/dL).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Alpelisib, Fulvestrant and Dapagliflozin for the Treatment of HR+, HER2 -, PIK3CA Mutant Metastatic Breast Cancer	NCT05025735	Metastatic Brea... HER2-negative B...	Dapagliflozin 1...	18 Years - 65 Years	Saint Luke's Health System
Alpelisib, Fulvestrant and Dapagliflozin for the Treatment of HR+, HER2 -, PIK3CA Mutant Metastatic Breast Cancer	NCT05025735	Metastatic Brea... HER2-negative B...	Dapagliflozin 1...	18 Years - 65 Years	Saint Luke's Health System
Evaluation of the Possible Safety and Efficacy of Dapagliflozin in the Prophylaxis of Doxorubicin-Induced Cardiotoxicity	NCT06427226	Doxorubicin Ind... Breast Cancer	Dapagliflozin 1...	18 Years - 65 Years	Tanta University
Potential Protective Role of SGLT-2 Inhibitors for Chemotherapy-induced Cardiotoxicity	NCT06341842	Breast Cancer	Dapagliflozin 1...	18 Years - 70 Years	Fondazione IRCCS Policlinico San Matteo di Pavia
Potential Protective Role of SGLT-2 Inhibitors for Chemotherapy-induced Cardiotoxicity	NCT06341842	Breast Cancer	Dapagliflozin 1...	18 Years - 70 Years	Fondazione IRCCS Policlinico San Matteo di Pavia
Evaluation of the Possible Safety and Efficacy of Dapagliflozin in the Prophylaxis of Doxorubicin-Induced Cardiotoxicity	NCT06427226	Doxorubicin Ind... Breast Cancer	Dapagliflozin 1...	18 Years - 65 Years	Tanta University

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