Back to resultsStudy 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)
Primary Purpose
Breast Cancer
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Alpelisib
Fulvestrant
Metformin XR
Dapagliflozin + metformin XR
Dapagliflozin
Sponsored by
About this trial
This is an interventional prevention trial for Breast Cancer focused on measuring Alpelisib, Fulvestrant, Metformin XR, Dapagliflozin + metformin XR, Advanced breast cancer, Phase II, HR+, HER2-, PIK3CA, Hyperglycemia
Eligibility Criteria
Inclusion Criteria:
- Participant has a histologically and/or cytologically confirmed diagnosis of estrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+) breast cancer by local laboratory
- Participant has a PIK3CA mutation(s) present in tumor prior to enrollment
Participant has prior treatment with an endocrine-based treatment (i.e. letrozole, anastrozole, exemestane, fulvestrant or oral SERD) and may be:
- 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
- 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
- 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 will NOT be included in the study.
- Participants may or may 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, then the participant is postmenopausal
- Participant has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Participant has adequate bone marrow and organ function
Exclusion Criteria:
- Participant who 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 has received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), any PI3K, Mammalian Target of Rapamycin (mTOR) or Protein Kinase B (Akt) inhibitor
- Participant has 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 has a history of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis
- Participant has currently documented pneumonitis/interstitial lung disease
- Participant has 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)
Other inclusion/exclusion criteria may apply
Sites / Locations
- Washington University School Siteman Cancer Center
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR
Alpelisib + Fulvestrant + Metformin XR
Arm Description
Alpelisib 300mg 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 will receive 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 can be titrated to a maximum dose of 10 mg dapagliflozin + 2000 mg metformin XR once daily.
Alpelisib 300mg 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 will receive metformin XR 500mg orally once daily which can be titrated to a maximum dose of 2000 mg once daily.
Outcomes
Primary Outcome Measures
Number of Participants With Hyperglycemia Grade ≥ 3 over the first eight weeks of alpelisib treatment
Severe hyperglycemia (Grade ≥ 3) is defined as any glucose laboratory values > 250 milligram (mg)/ deciliter (dL) (> 13.9 millimole (mmol)/ liter (L))
Secondary Outcome Measures
Progression-free Survival (PFS) Per Investigator Assessment
PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST 1.1
Overall Response Rate (ORR) with confirmed response
ORR with confirmed response is defined as the proportion of patients 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.
Clinical Benefit Rate (CBR) with confirmed response
Clinical benefit rate with confirmed response is defined as the proportion of patients with a best overall response of confirmed CR or confirmed PR or stable disease (SD) or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04899349
Brief Title
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
Acronym
EPIK-B4
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Terminated
Why Stopped
Study was early terminated due to slow recruitment and emerging data showing that prophylactic use of metformin may prevent or reduce the incidence of all-grades alpelisib-related hyperglycemia. The decision was not driven by safety concerns
Study Start Date
April 6, 2022 (Actual)
Primary Completion Date
May 10, 2023 (Actual)
Study Completion Date
May 10, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a Phase II, multicenter, randomized, open-label, active-controlled trial 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 HR-positive, HER2-negative advanced breast cancer with a PIK3CA mutation following progression on or after endocrine-based therapy.
Detailed Description
The study will only include participants who have at least one baseline risk factor for the development of severe hyperglycemia, defined as:
Diabetes (FPG ≥ 126 mg/dL or ≥ 7.0 mmol/L and/or HbA1c ≥ 6.5%)
Pre-diabetes (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 (BMI ≥ 30)
Age ≥ 75 years Participants will be randomized in a 1:1 ratio (approximately 66 participants in each treatment arm) to receive the combination of dapagliflozin plus metformin XR or metformin XR alone starting on Cycle 1 Day 1. For both arms participants will receive fulvestrant starting at Cycle 1 Day 1 and alpelisib starting at Cycle 1 Day 8. Randomization will be stratified by diabetic status at baseline, i.e. normal vs pre- diabetic/diabetic (based on fasting plasma glucose (FPG) and/or hemoglobin A1c (HbA1c) laboratory values).
The study will consist of a 28-day screening phase, a 12 cycle treatment phase, and a post-treatment phase which includes safety and efficacy follow-up (if applicable).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
Alpelisib, Fulvestrant, Metformin XR, Dapagliflozin + metformin XR, Advanced breast cancer, Phase II, HR+, HER2-, PIK3CA, Hyperglycemia
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
2 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR
Arm Type
Experimental
Arm Description
Alpelisib 300mg 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 will receive 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 can be titrated to a maximum dose of 10 mg dapagliflozin + 2000 mg metformin XR once daily.
Arm Title
Alpelisib + Fulvestrant + Metformin XR
Arm Type
Active Comparator
Arm Description
Alpelisib 300mg 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 will receive metformin XR 500mg orally once daily which can be titrated to a maximum dose of 2000 mg once daily.
Intervention Type
Drug
Intervention Name(s)
Alpelisib
Intervention Description
Alpelisib (tablets) administered at 300mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 8 in a 28 days cycle.
Intervention Type
Drug
Intervention Name(s)
Fulvestrant
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Metformin XR
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin + metformin XR
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin
Intervention Description
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
Primary Outcome Measure Information:
Title
Number of Participants With Hyperglycemia Grade ≥ 3 over the first eight weeks of alpelisib treatment
Description
Severe hyperglycemia (Grade ≥ 3) is defined as any glucose laboratory values > 250 milligram (mg)/ deciliter (dL) (> 13.9 millimole (mmol)/ liter (L))
Time Frame
From Cycle 1 Day 8 to Cycle 3 Day 8 (first eight weeks of treatment with alpelisib)
Secondary Outcome Measure Information:
Title
Progression-free Survival (PFS) Per Investigator Assessment
Description
PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST 1.1
Time Frame
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 12 cycles.(1 cycle = 28 days)
Title
Overall Response Rate (ORR) with confirmed response
Description
ORR with confirmed response is defined as the proportion of patients 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.
Time Frame
From the date of randomization up to a maximum duration of 12 cycles.(1 cycle = 28 days)
Title
Clinical Benefit Rate (CBR) with confirmed response
Description
Clinical benefit rate with confirmed response is defined as the proportion of patients with a best overall response of confirmed CR or confirmed PR or stable disease (SD) or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment.
Time Frame
From the date of randomization up to a maximum duration of 12 cycles.(1 cycle = 28 days)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Participant has a histologically and/or cytologically confirmed diagnosis of estrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+) breast cancer by local laboratory
Participant has a PIK3CA mutation(s) present in tumor prior to enrollment
Participant has prior treatment with an endocrine-based treatment (i.e. letrozole, anastrozole, exemestane, fulvestrant or oral SERD) and may be:
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
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
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 will NOT be included in the study.
Participants may or may 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, then the participant is postmenopausal
Participant has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Participant has adequate bone marrow and organ function
Exclusion Criteria:
Participant who 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 has received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), any PI3K, Mammalian Target of Rapamycin (mTOR) or Protein Kinase B (Akt) inhibitor
Participant has 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 has a history of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis
Participant has currently documented pneumonitis/interstitial lung disease
Participant has 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)
Other inclusion/exclusion criteria may apply
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Washington University School Siteman Cancer Center
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Novartis Investigative Site
City
Hong Kong
Country
Hong Kong
Facility Name
Novartis Investigative Site
City
Kuala Lumpur
ZIP/Postal Code
59100
Country
Malaysia
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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
Learn more about this trial
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
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