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Hyperglycemia

Breast Diseases

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Metformin

Dapagliflozin

Fulvestrant

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Antineoplastic Agents, Hormonal

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Hormone Antagonists

Alpelisib 300mg administered orally once daily starting at Cycle 1 Day 8 in combination with fulvestrant 500mg intramuscular at Cycle 1 Day 1 and 15 and then at Day 1 of each subsequent cycle. Participants also received a combination treatment of dapagliflozin+metformin XR (as a single tablet or as two separate tablets, at the discretion of the investigator) at a starting dose of 5 mg dapagliflozin + 500 mg metformin XR orally once daily which could be titrated to a maximum dose of 10 mg dapagliflozin + 2000 mg metformin XR once daily.

Alpelisib 300mg administered orally once daily starting at cycle 1 Day 8 in combination with fulvestrant 500mg intramuscular at Cycle 1 Day 1 and 15 and then at Day 1 of each subsequent cycle. Participants also received metformin XR 500mg orally once daily which could be titrated to a maximum dose of 2000 mg once daily.

Alpelisib (tablets) administered at 300mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 8 in a 28 days cycle.

Alpelisib

Fulvestrant (prefilled syringe) 500mg administered intramuscularly at Cycle 1 Day 1 and 15 after randomization and then at Day 1 of each subsequent cycle during the randomized treatment phase.

Metformin XR (tablets) administered at a starting dose of 500mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 days cycle. Dose titration from 500 mg once a day to 2000 mg once a day.

Metformin XR

Dapagliflozin + metformin XR administered as a single tablet combination at a starting dose of 5 mg dapagliflozin + 500 mg metformin XR orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 days cycle. Dose titration from 5 mg dapagliflozin + 500 mg metformin XR orally once daily to 10 mg dapagliflozin + 2000 mg metformin XR once daily

Dapagliflozin + metformin XR

Dapagliflozin (tablet) at a starting dose of 5mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 days cycle. Dose titration from 5 mg to 10 mg once daily

Novartis Pharmaceuticals

This study was designed to assess the safety and efficacy of the combination of dapagliflozin plus metformin extended release (XR) compared with metformin XR during treatment with alpelisib plus fulvestrant in participants with Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor-2 (HER2)-negative advanced breast cancer with a Phosphoinositide-3-Kinase Catalytic subunit Alpha (PIK3CA) mutation following progression on or after endocrine-based therapy.

This was a multicenter, randomized, open-label, active-controlled trial, stratified by diabetic status at baseline (i.e., normal vs prediabetic/diabetic based on fasting plasma glucose (FPG) and/or Hemoglobin A1c (HbA1c) laboratory values). The study included only participants with at least one baseline risk factor for the development of severe hyperglycemia which were diabetes (FPG ≥ 126 milligram (mg)/deciliter (dL) or ≥ 7.0 millimole (mmol)/liter (L) and/or HbA1c ≥ 6.5%), prediabetes (FPG ≥ 100 mg/dL to \< 126 mg/dL or 5.6 to \< 7.0 mmol/L and/or HbA1c 5.7 to \< 6.5%), obesity (body mass index \[BMI\] ≥ 30) and age (≥ 75 years).

The planned duration of treatment with alpelisib and fulvestrant was 12 cycles (28 days in each cycle) or until disease progression, unacceptable toxicity, or discontinuation from study treatment for any other reason, whichever came first.

Approximately 66 participants in each treatment arm were planned to be randomized to receive the combination of alpelisib and fulvestrant with either dapagliflozin plus metformin extended release (XR) or metformin XR alone. As a result of the early termination of the study due to emerging data demonstrating the impact of prophylactic metformin and slow recruitment, only 2 participants were enrolled in the study.

Study of Safety and Efficacy of Dapagliflozin + Metformin XR Versus Metformin XR in Participants With HR+, HER2-, Advanced Breast Cancer While on Treatment With Alpelisib and Fulvestrant

EPIK-B4: A Phase II, Multicenter, Randomized, Open-label, Active-controlled Study to Assess the Safety and Efficacy of Dapagliflozin + Metformin XR Versus Metformin XR During Treatment With Alpelisib (BYL719) in Combination With Fulvestrant in Participants With HR+, HER2-, Advanced Breast Cancer With a PIK3CA Mutation Following Progression on/After Endocrine-based Therapy

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Number of participants with severe hyperglycemia over the first eight weeks of alpelisib plus fulvestrant treatment. Severe hyperglycemia (Grade ≥ 3) is defined as any glucose laboratory values \> 250 milligram (mg)/ deciliter (dL) (\> 13.9 millimole (mmol)/ liter (L))

PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local investigator assessment according to RECIST 1.1. If a subject did not have an event, PFS was censored at the date of last adequate tumor assessment.

The PFS distribution was using the Kaplan-Meier method, and the Kaplan-Meier median and 95% confidence intervals of the medians was presented.

ORR with confirmed response was defined as the percentage of participants with best overall response of confirmed complete response (CR) or confirmed partial response (PR) based on local investigator's assessment according to RECIST 1.1.

CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions and all lymph nodes assigned as non-target lesions must have a reduction in short axis to \< 10 mm.

PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Clinical benefit rate with confirmed response was defined as the percentage of participants with a best overall response of confirmed CR or confirmed PR or stable disease (SD) or Non-CR/Non-progressive disease (PD) lasting more than 24 weeks based on local investigator assessment as per RECIST 1.1.

CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions and all lymph nodes assigned as non-target lesions must have a reduction in short axis to \< 10 mm.

PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

Number of participants with dose interruptions and dose reductions

All participants who received at least one dose of study treatment (i.e. at least one dose of any component of alpelisib, fulvestrant, dapagliflozin + metformin XR, metformin XR).

The trial was early terminated and no participants were randomized to the Alpelisib + Fulvestrant + Metformin XR arm.

Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR

Alpelisib + Fulvestrant + Metformin XR

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

The trial was early terminated and no participants were randomized to the Alpelisib+Fulvestrant+Metformin XR arm.

Study director

Number of Participants With Hyperglycemia Grade ≥ 3 Over the First Eight Weeks of Alpelisib Plus Fulvestrant Treatment

All participants to whom study treatment was assigned by randomization. The trial was early terminated and no participants were randomized to the Alpelisib + Fulvestrant + Metformin XR arm.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Safety and Efficacy of Dapagliflozin + Metformin XR Versus Metformin XR in Participants With HR+, HER2-, Advanced Breast Cancer While on Treatment With Alpelisib and Fulvestrant	NCT04899349	Breast Cancer	Alpelisib Fulvestrant Metformin XR Dapagliflozin +... Dapagliflozin	18 Years -	Novartis
Study of Safety and Efficacy of Dapagliflozin + Metformin XR Versus Metformin XR in Participants With HR+, HER2-, Advanced Breast Cancer While on Treatment With Alpelisib and Fulvestrant	NCT04899349	Breast Cancer	Alpelisib Fulvestrant Metformin XR Dapagliflozin +... Dapagliflozin	18 Years -	Novartis

Spots Global Cancer Trial Database for dapagliflozin + metformin xr