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)

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

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.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Alpelisib; Drug: Fulvestrant; Drug: Metformin XR; Drug: Dapagliflozin + metformin XR; Drug: Dapagliflozin

Detailed Description

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 Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington Uni School of Med Siteman Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Participant had a histologically and/or cytologically confirmed diagnosis of estrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+) breast cancer by a local laboratory.
• Participant had a PIK3CA mutation(s) present in the tumor prior to enrollment.

• Participant had prior treatment with an endocrine-based treatment (e.g. letrozole, anastrozole, exemestane, fulvestrant, or oral SERD) and may have fallen into one of the following categories:

  1. Relapsed with documented evidence of progression while on (neo) adjuvant endocrine-based therapy or within 12 months from completion of (neo) adjuvant endocrine-based therapy with no treatment for metastatic disease.
  2. Relapsed with documented evidence of progression more than 12 months from completion of (neo) adjuvant endocrine-based therapy and then subsequently progressed with documented evidence of progression while on or after only one line of endocrine-based therapy for metastatic disease.
  3. Newly diagnosed advanced breast cancer, then relapsed with documented evidence of progression while on or after only one line of endocrine-based therapy.

Note: Participants with newly diagnosed endocrine-based treatment naïve advanced breast cancer were NOT included in the study.

• Participants might or might not have received prior CDK4/6i therapy. If prior CDK4/6i therapy was administered, it may have been in the adjuvant or metastatic setting.
• If female, the participant was postmenopausal.
• Participant had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Participant had adequate bone marrow and organ function.

Key Exclusion Criteria:

• Participant relapsed with documented evidence of progression more than 12 months from completion of (neo) adjuvant endocrine therapy with no treatment for metastatic disease.
• Participant had more than 1 line of prior treatment in the metastatic setting.
• Participant had received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), any PI3K, Mammalian Target of Rapamycin (mTOR) or Protein Kinase B (Akt) inhibitor.
• Participant had inflammatory breast cancer at screening.
• Participants with an established diagnosis of diabetes mellitus type I or participants with type II diabetes mellitus requiring antihyperglycemic therapy.
• Participant had a history of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis.
• Participant had currently documented pneumonitis/interstitial lung disease.
• Participant had a history of severe cutaneous reaction, such as Steven-Johnson Syndrome (SJS), erythema multiforme (EM), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR; 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.	Drug: Alpelisib; Alpelisib (tablets) administered at 300mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 8 in a 28 days cycle.; Drug: Fulvestrant; 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.; Drug: Metformin XR; 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.; Drug: Dapagliflozin + 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; Drug: Dapagliflozin; 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
Active Comparator: Alpelisib + Fulvestrant + Metformin XR; 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.	Drug: Alpelisib; Alpelisib (tablets) administered at 300mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 8 in a 28 days cycle.; Drug: Fulvestrant; 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.; Drug: Metformin XR; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Hyperglycemia Grade ≥ 3 Over the First Eight Weeks of Alpelisib Plus Fulvestrant Treatment	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))	From Cycle 1 Day 8 to Cycle 3 Day 8 (first eight weeks of treatment with alpelisib). Cycle = 28 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Based on Local Investigator Assessment	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.	From the date of randomization to the date of the first documented progression or death due to any cause, whichever comes first, assessed up to a maximum duration of 7.4 months
Overall Response Rate (ORR) With Confirmed Response Based on Local Investigator Assessment as Per RECIST 1.1.	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.	Up to 7.4 months
Clinical Benefit Rate (CBR) With Confirmed Response Based on Local Investigator Assessment as Per RECIST 1.1	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.	Up to 7.4 months
Number of Participants With Dose Modifications	Number of participants with dose interruptions and dose reductions	From first dose of study medication up to 30 days after last dose of study medication, assessed up to 7.4 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2022
• Primary Completion (Actual): May 10, 2023
• Study Completion (Actual): May 10, 2023

Study Registration Dates

• First Submitted: May 21, 2021
• First Submitted That Met QC Criteria: May 21, 2021
• First Posted (Actual): May 24, 2021

Study Record Updates

• Last Update Posted (Estimated): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Hyperglycemia; PIK3CA; Phase II; HR+; HER2-; Fulvestrant; Advanced breast cancer; Alpelisib; Metformin XR; Dapagliflozin + metformin XR
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Sodium-Glucose Transporter 2 Inhibitors; Fulvestrant; Dapagliflozin; Metformin
• Other Study ID Numbers: CBYL719C2202

Plan for Individual participant data (IPD)

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

IPD Plan Description

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No