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)

• ClinicalTrials.gov Identifier: NCT04899349
• Recruitment Status: Active, not recruiting
• First Posted: May 24, 2021
• Last Update Posted: March 24, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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 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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 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: April 6, 2022
• Estimated Primary Completion Date: May 10, 2023
• Estimated Study Completion Date: May 10, 2023

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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Hyperglycemia Grade ≥ 3 over the first eight weeks of alpelisib treatment [ Time Frame: 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 :

1. Progression-free Survival (PFS) Per Investigator Assessment [ 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) ]
   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
2. Overall Response Rate (ORR) with confirmed response [ Time Frame: 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.
3. Clinical Benefit Rate (CBR) with confirmed response [ Time Frame: 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

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

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

Contacts and Locations

Locations

United States, Missouri

Washington University School of Medicine Siteman Cancer Center

Saint Louis, Missouri, United States, 63110

Hong Kong

Novartis Investigative Site

Hong Kong, Hong Kong

Malaysia

Novartis Investigative Site

Kuala Lumpur, Malaysia, 59100

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04899349
• Other Study ID Numbers: CBYL719C2202
• First Posted: May 24, 2021
• Last Update Posted: March 24, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Alpelisib; Fulvestrant; Metformin XR; Dapagliflozin + metformin XR; Advanced breast cancer; Phase II; HR+; HER2-; PIK3CA; Hyperglycemia

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Metformin; Dapagliflozin; Fulvestrant; Hypoglycemic Agents; Physiological Effects of Drugs; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Estrogen Receptor Antagonists; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists