Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutant, HR+, HER2- Advanced Breast Cancer Who Have Progressed on or After Prior Treatments

Study Overview
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Brief Summary
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Study assessing the efficacy and safety of alpelisib plus fulvestrant or letrozole, based on prior endocrine therapy, in patients with hormone receptor (HR) positive, HER2-negative advanced breast cancer (aBC), harboring PIK3CA mutations, who have progressed on or after prior treatments.

Detailed Description
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This is a phase II, multicenter, open-label, three-cohort, noncomparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients with HR+, HER2- aBC harboring PIK3CA mutation(s) in the tumor whose disease has progressed on or after prior treatments. The study includes two phases: Core Phase: Includes treatment phase for all patients from First Patient First Treatment (FPFT) until 18 months post Last Patient First Treatment (LPFT) + 1 month Safety follow-up (total 19 months post LPFT) Extension Phase: includes treatment phase starting at the end of the treatment Core Phase until 36 months + 1 month safety follow-up (total of 37 months post Core phase). The extension treatment phase is only for patients who are continuing to benefit from treatment at the end of the Core Phase and are not eligible for PSDS (Post-Study Drug Supply) in their country based on local regulations. Patients will continue on their existing treatment assigned in the Core Phase. If PSDS becomes available for a patient, the patient should be discontinued from the study and access treatment via PSDS. Patients who are benefiting from treatment and are eligible for PSDS will exit the trial at the end of the Core Phase.

Official Title
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BYLieve: A Phase II, Multicenter, Open-label, Three-cohort, Non- Comparative Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole in Patients With PIK3CA Mutant, Hormone Receptor (HR) Positive, HER2-negative Advanced Breast Cancer (aBC), Who Have Progressed on or After Prior Treatments

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Alpelisib
* Drug: Fulvestrant
* Drug: Letrozole
* Drug: Goserelin
* Drug: Leuprolide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is male or female 18 years or older Males or females with advanced (locoregionally recurrent or metatstatic) breast cancer not amenable to curative therapy In case of women, both premenopausal and postmenopausal patients are allowed to be included in study; menopausal status is relevant for the requirement of LHRH agonist (examples for use in this study include but not limited to goserelin, leuprolide or locally available treatment) to be used concomitantly with alpelisib and letrozole/fulvestrant Patient is postmenopausal woman defined as either: Prior bilateral oophorectomy or Age ≥60 or Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and/or estradiol in the postmenopausal range per local normal range. If patient is taking tamoxifen or toremifene and age <60, then FSH and plasma estradiol levels should be in post-menopausal range per local normal range. Note: For women using therapy-induced amenorrhea other than ovarian radiation, goserelin or leuprolide, etc., serial measurements of FSH and/or estradiol are needed to ensure menopausal status Patient is premenopausal defined as either: Patient had last menstrual period within the last 12 months or If on tamoxifen or toremifene with in the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range, or In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range Patient has confirmed HER2-negative advanced breast cancer (aBC) Patient has histological and/or cytological confirmed ER+ and/or PgR+ aBC Patient has a PIK3CA mutation confirmed by Novartis designated central lab or patient has a pathology report confirming PIK3CA mutant status by certified laboratory (using validated PI3KCA mutation assay) either from tissue or blood and must (mandatory) send tumor tissue to Novartis designated central lab for confirmation of mutational status Patient must have: CDK 4/6 inhibitor treatment as last treatment regimen in cohorts A and B AI treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET(as monotherapy or in combination except CDK 4/6i + AI) as last treatment regimen in cohort C Maintenance therapies, where applicable, must be regarded as part of the main treatment. No more than two (2) prior anti-cancer therapies for aBC Received no more than one prior regimen of chemotherapy in the metastatic setting Patient has either measurable disease per RECIST v1.1 or at least one predominantly lytic bone lesion must be present ECOG performance status ≤ 2 Patient has fasting plasma glucose (FPG) ≤140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met) Patient has adequate bone marrow, coagulation, liver and renal function Exclusion Criteria: Patient has a known hypersensitivity to alpelisib, fulvestrant, letrozole, goserelin or leuprolide or to any of the excipients of alpelisib, fulvestrant, letrozole, goserelin or leuprolide. Patient has received prior treatment with any PI3K inhibitors Patient with an established diagnosis of diabetes mellitus type I or uncontrolled type II Patient has a concurrent malignancy or malignancy within 3 years of study screening period, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanoma skin cancer or curatively resected cervical cancer Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to enrollment, and who has not recovered to grade 1 or better from related side effects of such therapy ( History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria: At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment Clinically stable CNS tumor at the time of screening untreated or without evidence of progressions for at least 4 weeks after treatment as determined by clinical examination and brain imaging (MRI or CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment Patient with severe liver impairment (Child Pugh score B/C) Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs Patient has documented pneumonitis/interstitial lung disease which is active and requiring treatment Patient has a history of severe cutaneous reactions like Stevens-Johnson-Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necroloysis (TEN) or Drug Reaction with Eosinphilia and Systemic Symptoms (DRESS). Patient is concurrently using other anti-cancer therapy. All anti-cancer therapy must be discontinued prior to day one of study treatment. Subjects with unresolved osteonecrosis of the jaw. Other inclusion/exclusion 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Prior CDK 4/6 + aromatase<br>Patients who received any Cyclin-Dependent Kinases 4 and 6 (CDK 4/6) inhibitor plus aromatase inhibitor as treatment (immediately prior) will receive alpelisib 300 mg oral.+ fulvestrant 500 mg intramuscular (i.m) | Drug: Alpelisib<br>* 300 mg; oral; once daily<br>* Other names: BYL719;Drug: Fulvestrant<br>* 500 mg; intramuscular injection on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days<br>|
| Experimental: Cohort B: Prior CDK 4/6 + fulvestrant<br>Patients who received any CDK 4/6 inhibitor plus fulvestrant as treatment (immediately prior) will receive alpelisib 300 mg oral + letrozole 2.5 mg oral | Drug: Alpelisib<br>* 300 mg; oral; once daily<br>* Other names: BYL719;Drug: Letrozole<br>* 2.5 mg; oral; once daily<br>Drug: Goserelin<br>* Every 28 days (only for men in cohort B and premenopausal women). Administered as injectable subcutaneous implant (3.6 mg)<br>Drug: Leuprolide<br>* Every 28 days (only for men in cohort B and premenopausal women). Administered as injectable intramuscular depot (7.5 mg)<br>|
| Experimental: Cohort C: Prior systemic chemo or ET<br>Patients who received systemic chemotherapy or endrocrine therapy (ET) , (including monotherapy or in combination with targeted therapy except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib 300 mg oral + fulvestrant 500 mg i.m. | Drug: Alpelisib<br>* 300 mg; oral; once daily<br>* Other names: BYL719;Drug: Fulvestrant<br>* 500 mg; intramuscular injection on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who are alive without disease progression at 6 months | Percentage of participants without disease progression at 6 months of treatment based on local investigator assessment per RECIST v1.1 in cohort A, cohort B and cohort C | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) for each cohort | PFS is defined as the time from the date of first dose of study medication to the date of the first documented progression or death due to any cause occurring in the study. PFS will be assessed based on local investigator's assessment according to RECIST v1.1 | From date of first dose to date of first documented progression or death, up to approximately 25 months | 
| Progression free survival (PFS) on next line treatment PFS2) for each cohort | Progression free survival (PFS) on next line treatment (PFS2) is defined as time from the date of first dose of study medication to the date of first documented progression on next-line therapy or death from any cause. The first documented progression on next-line treatment is based on investigator assessment of progressive disease (PD) | From date of first dose to date of first documented progression on next-line therapy or death, up to approximately 25 months | 
| Overall response rate (ORR) for each cohort | ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1 in each cohort | Up to approximately 25 months | 
| Clinical benefit rate (CBR) for each cohort | CBR is defined as the percentage of participants with a BOR of CR or PR or an overall lesion response of stable disease (SD) or Non-CR/ Non-PD lasting ≥ 24 weeks based on local investigator's assessment according to RECIST v1.1. | Up to approximately 25 months | 
| Duration of response (DOR) | Duration of Response is the time from the date of first documented response (confirmed CR or PR based on local investigator's assessment according to RECIST v1.1 ) to the date of first documented progression or death due to underlying cancer | From date of first documented response to first documented progression or death, up to approximately 25 months | 
| Overall suvivial (OS) for each cohort | Overall Survival is defined as the time of start of treatment to date of death or lost to follow-up. | From date of first dose and up to approximately 25 months | 
| Percentage of participants with clinical benefit as assessed by the Investigator during the extension phase | Percentage of participants with clinical benefit as assessed by the Investigator at scheduled visits during the extension phase | From end of core phase up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HR+, advanced breast cancer, PIK3CA, CDK 4/6 inhibitor, fulvestrant, letrozole, HER2-negative, post menopausal, pre-menopausal, aromatase inhibitor, endocrine treatment, AI, ET