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.
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
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
2
Alpelisib (tablets) administered at 300mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 8 in a 28 days cycle.
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.
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.
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
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
Washington Uni School of Med Siteman Cancer Center
St Louis, Missouri, United States
Novartis Investigative Site
Kuala Lumpur, Malaysia
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))
Time frame: From Cycle 1 Day 8 to Cycle 3 Day 8 (first eight weeks of treatment with alpelisib). Cycle = 28 days.
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.
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 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.
Time frame: 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.
Time frame: Up to 7.4 months
Number of Participants With Dose Modifications
Number of participants with dose interruptions and dose reductions
Time frame: From first dose of study medication up to 30 days after last dose of study medication, assessed up to 7.4 months
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