Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment.

Study Overview
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Brief Summary
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To determine whether treatment with alpelisib plus fulvestrant prolongs progression-free survival compared to fulvestrant and placebo in men and postmenopausal women with hormone receptor positive (HR+), HER2-negative advanced breast cancer, who received prior treatment with an Aromatase Inhibitor either as (neo)adjuvant or for advanced disease.

Official Title
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A Phase III Randomized Double-blind, Placebo Controlled Study of Alpelisib in Combination With Fulvestrant for Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Fulvestrant
* Drug: Alpelisib
* Drug: Alpelisib placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: If female, patient is postmenopausal Patient has identified PIK3CA status Patients may be: relapsed with documented evidence of progression while on (neo) adjuvant endocrine therapy or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease; relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy and then subsequently; progressed with documented evidence of progression while on or after only one line of endocrine 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 therapy Patient has recurrence or progression of disease during or after AI therapy (i.e. letrozole, anastrozole, exemestane). Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive breast cancer by local laboratory and has HER2 negative breast cancer Patient has either measurable disease per RECIST 1.1 criteria OR at least one predominantly lytic bone lesion must be present Patient has adequate bone marrow function Exclusion Criteria: Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor (pre-treatment with CDK4/6 inhibitors is allowed) Patient with inflammatory breast cancer at screening Patients with Child pugh score B or C Patients with an established diagnosis of diabetes mellitus type I or not controlled type II Patient has Eastern Cooperative Oncology Group (ECOG) performance status 2 or more Patient with CNS involvement unless he/she is at least 4 weeks from prior therapy completion to starting the study treatment and has stable CNS tumor at time of screening and not receiving steroids and/or enzyme inducing ant-epileptic medications for brain metastases Patient has participated in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer Patient has a history of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis Patient who relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease Other protocol-defined inclusion/esclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: fulvestrant + alpelisib<br>Alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle) | Drug: Fulvestrant<br> <br> * Other names: Faslodex;Drug: Alpelisib<br> <br> |
| Placebo Comparator: fulvestrant + placebo<br>Placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle) | Drug: Fulvestrant<br> <br> * Other names: Faslodex;Drug: Alpelisib placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Per Investigator Assessment in the PIK3CA Mutant Cohort | PFS, 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 | Once approximately 243 PFS events in this cohort had been observed, up to 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) for Patients With PI3KCA Mutant Status | OS is defined as the time from date of randomization to date of death due to any cause. | Up to approximatly 59 months | 
| Overall Response Rate (ORR) | ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. | Up to approximatly 36 months | 
| Time to Definitive Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Baseline, Up to approximatly 36 months | 
| Safety and Tolerability of Alpelisib in Combination With Fulvestrant | Safety will be determined by type, frequency and severity of adverse events per CTCAEv4.03 and type, frequency and severity of laboratory toxicities per CTCAEv4.03. Patients will be followed up for the duration of the study. | Up to approximatly 37 months | 
| Time to 10% Deterioration in the Global Health Status/Quality of Life (QOL) Scale Score of the EORTC QLQ-C30 | Composite measure of change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment will be summarized | Up to approximatly 36 months | 
| Plasma Concentration-time Profile of Alpelisib Given in Combinatio With Fulvestrant and Appropriate Pharmacokinetics (PK) Parameters | Assessment of any potential impact of fulvestrant on the pharmacokinetics of alpelisib by collection of sparse and trough PK samples. PK parameters includes,but not limited to, Cmin, Cmax, t1/2, AUClast for alpelisib (and any relevant metabolites) and fulvestrant | Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2,4, 6, 8 | 
| PFS Based on Radiology Assessments and Using RECIST 1.1 Criteria | PFS in patients with PIK3CA mutant status and patients with PIK3CA non-mutant status as measured in ctDNA. | Baseline, Up to approximatly 36 months | 
| Clinical Benefit Rate (CBR) | Clinical benefit rate is defined as the proportion of patients with a best overall response of CR or PR or SD or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment. | Up to approximatly 36 months | 
| Change in the Global Health Status/(QOL) Scale Score of the EORTC QLQ-C30 | Composite measure of change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment will be summarized | Baseline, Up to approximatly 36 months | 
| Summary Statistics of Fulvestrant and Alpelisib Plasma Concentrations | Assessment of any potential impact of fulvestrant on the pharmacokinetics of alpelisib by collection of sparse and trough PK samples. | Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2,4, 6, 8 | 
| PFS for Patients With PIK3CA Non-mutant Status | PFS based on local radiology assessments and using RECIST 1.1 criteria in the PIK3CA non-mutant cohort | Up to approximatly 36 months | 
| OS for Patients With PIK3CA Non-mutant Status | OS is defined as the time from date of randomization to date of death due to any cause. | Up to approximatly 59 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BYL719, HR+, HER2-negative, advanced breast cancer, alpelisib, fulvestrant, PI3K, Phase III, ER+, PgR+, men, postmenopausal, aromatase inhibitor, neoplasms