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 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: CBYL719C2202
• Study Type: interventional
• Target: 2
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Breast Cancer

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Progression-free Survival (PFS) Based on Local 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 7.4 months

• Overall Response Rate (ORR) With Confirmed Response Based on Local Investigator Assessment as Per RECIST 1.1.

  Up to 7.4 months

• Clinical Benefit Rate (CBR) With Confirmed Response Based on Local Investigator Assessment as Per RECIST 1.1

  Up to 7.4 months

• Number of Participants With Dose Modifications

  From first dose of study medication up to 30 days after last dose of study medication, assessed up to 7.4 months

Study Arms (2)

Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR

EXPERIMENTAL

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; Drug: Fulvestrant; Drug: Metformin XR; Drug: Dapagliflozin + metformin XR; Drug: Dapagliflozin

Alpelisib + Fulvestrant + Metformin XR

ACTIVE COMPARATOR

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; Drug: Fulvestrant; Drug: Metformin XR

Interventions

Alpelisib DRUG

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 + Dapagliflozin + Metformin XR; Alpelisib + Fulvestrant + Metformin XR

Fulvestrant DRUG

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.

Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR; Alpelisib + Fulvestrant + Metformin XR

Metformin XR DRUG

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.

Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR; Alpelisib + Fulvestrant + Metformin XR

Dapagliflozin + metformin XR DRUG

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

Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR

Dapagliflozin DRUG

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

Alpelisib + Fulvestrant + Dapagliflozin + Metformin XR

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (2)

Washington Uni School of Med Siteman Cancer Center

St Louis, Missouri, 63110, United States

Location

Novartis Investigative Site

Kuala Lumpur, 59100, Malaysia

Location

Related Links

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

MeSH Terms

Conditions

Breast Neoplasms; Hereditary Sensory and Autonomic Neuropathies; Hyperglycemia

Interventions

Alpelisib; Fulvestrant; dapagliflozin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Study director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2021
• First Posted: May 24, 2021
• Study Start: April 6, 2022
• Primary Completion: May 10, 2023
• Study Completion: May 10, 2023
• Last Updated: October 9, 2024
• Results First Posted: December 12, 2023

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share

Locations

US (1); MY (1)