EPIK-B4: 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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04899349

Collaborator

(none)

132

Enrollment

Locations

Arms

26.7

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Alpelisib Drug: Fulvestrant Drug: Metformin XR Drug: Dapagliflozin + metformin XR Drug: Dapagliflozin	Phase 2

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

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

132 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

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

Actual Study Start Date :

Apr 6, 2022

Anticipated Primary Completion Date :

Jul 11, 2023

Anticipated Study Completion Date :

Jun 27, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR 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.	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 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.	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.

Arm

Intervention/Treatment

Experimental: Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR

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.

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 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.

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

Outcome Measures

Primary Outcome Measures

Number of Participants With Hyperglycemia Grade ≥ 3 over the first eight weeks of alpelisib treatment [From Cycle 1 Day 8 to Cycle 3 Day 8 (first eight weeks of treatment with alpelisib)]
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 [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)]
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 [From the date of randomization up to a maximum duration of 12 cycles.(1 cycle = 28 days)]
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 [From the date of randomization up to a maximum duration of 12 cycles.(1 cycle = 28 days)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alaska Oncology and Hematology AOH (2)	Anchorage	Alaska	United States	99508
2	Kaiser Permanente Medical Group Kaiser Hawaii -	Anaheim	California	United States	92807
3	Rocky Mountain Cancer Centers RMCC Hale Pkwy	Longmont	Colorado	United States	80501
4	Georgia Cancer Specialists	Decatur	Georgia	United States	30033
5	Washington University School of Medicine Siteman Cancer Center	Saint Louis	Missouri	United States	63110
6	St Vincent Frontier Cancer Center	Billings	Montana	United States	59102
7	Astera Cancer Center	East Brunswick	New Jersey	United States	08816
8	Texas Oncology Austin	Austin	Texas	United States	78731
9	Texas Oncology PA Dallas Presbyterian Hospital SC	Dallas	Texas	United States	75231
10	Tx Onco Sammons Cancer Center	Dallas	Texas	United States	75246
11	Texas Oncology Denton	Denton	Texas	United States	76201
12	Texas Oncology PA - Tyler	Tyler	Texas	United States	75702
13	Virginia Oncology Associates VOA - Lake Wright	Norfolk	Virginia	United States	23502
14	Northwest Medical Specialties NW Medical Specialties	Tacoma	Washington	United States	98405
15	Novartis Investigative Site	Hong Kong		Hong Kong	999077
16	Novartis Investigative Site	Hong Kong		Hong Kong
17	Novartis Investigative Site	Kuala Lumpur	Wilayah Persekutuan	Malaysia	50586
18	Novartis Investigative Site	Putrajaya	Wilayah Persekutuan	Malaysia	62250
19	Novartis Investigative Site	Kuala Lumpur		Malaysia	59100
20	Novartis Investigative Site	Pulau Pinang		Malaysia	10990
21	Novartis Investigative Site	Quezon City		Philippines	1102
22	Novartis Investigative Site	San Juan City		Philippines	1500