Study Assessing the Efficacy and Safety of Alpelisib + Nab-paclitaxel in Subjects With Advanced TNBC Who Carry Either a PIK3CA Mutation or Have PTEN Loss

Study Overview
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Brief Summary
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The purpose of this study is to determine whether treatment with alpelisib in combination with nab-paclitaxel is safe and effective in subjects with advanced triple negative breast cancer (aTNBC) who carry either a PIK3CA mutation (Study Part A) or have PTEN loss (Study Part B1) or PTEN loss without PIK3CA mutation (Study Part B2)

Detailed Description
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The recruitment of Part A was halted on 11-Nov-2022 due to slow recruitment. Since Part B1 did not meet its primary objective for confirmed overall response rate the Part B2 will not be initiated and the recruitment was halted for the entire study

Official Title
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A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Nab-paclitaxel in Patients With Advanced Triple Negative Breast Cancer With Either Phosphoinositide-3-kinase Catalytic Subunit Alpha (PIK3CA) Mutation or Phosphatase and Tensin Homolog Protein (PTEN) Loss Without PIK3CA Mutation

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: alpelisib
* Drug: placebo
* Drug: nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has histologically confirmed diagnosis of advanced (loco-regionally recurrent and not amenable to curative therapy), or metastatic (stage IV) TNBC Participant has either a measurable disease per RECIST 1.1 criteria or, if no measurable disease is present, then at least one predominantly lytic bone lesion or mixed lytic-blastic bone lesion with identifiable soft tissue component (that can be evaluated by CT/MRI) must be present Part B1: Participants must have measurable disease Participant has adequate tumor tissue to identify the PIK3CA mutation status (either carrying a mutation or without a mutation) and the PTEN loss status; both of which will determine whether the subject can be allocated to Part A - PIK3CA mutation regardless of PTEN status; or to Part B1 - PTEN loss or to Part B2 - PTEN loss without a PIK3CA mutation Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Participant has received no more than one line of therapy for metastatic disease Participant has adequate bone marrow and organ function Exclusion Criteria: Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor Participant has a known hypersensitivity to alpelisib, nab-paclitaxel or to any of their excipients Participant has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1; with the exception of alopecia Participant has central nervous system (CNS) involvement which was not previously treated and/or was newly detected at screening Participant with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on Fasting Plasma Glucose and HbA1c Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) based on investigator discretion Participant has a history of acute pancreatitis within 1 year prior to screening or past medical history of chronic pancreatitis Participant has currently documented pneumonitis/interstitial lung disease Participant has a history of severe cutaneous reactions, such as Steven-Johnson Syndrome (SJS), erythema multiforme (EM),Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS) Participant with unresolved osteonecrosis of the jaw Other protocol-defined inclusion/exclusion criteria 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: alpelisib + nab-paclitaxel<br>Double-blinded, Randomized in a 1:1 ratio in Study Parts A and B2 Single arm Open label in Study Part B1 | Drug: alpelisib<br>* 300 mg orally once per day (QD)<br>* Other names: BYL719;Drug: nab-paclitaxel<br>* 100 mg/m² as IV infusion on Days 1, 8 and 15 of a 28-day cycle<br>* Other names: abraxane;|
| Placebo Comparator: placebo + nab-paclitaxel<br>Double-blinded, Randomized in a 1:1 ratio in Study Parts A and B2 Not applicable in Study Part B1 | Drug: placebo<br>* 300 mg orally once per day (QD)<br>* Other names: alpelisib matching placebo;Drug: nab-paclitaxel<br>* 100 mg/m² as IV infusion on Days 1, 8 and 15 of a 28-day cycle<br>* Other names: abraxane;|

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 Study Part A | PFS, defined as 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 all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months | 
| Progression-free Survival (PFS) Per Investigator Assessment in Study Part B2 | PFS, defined as 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 192 PFS events in Study Part B2 had been observed, up to 22 months | 
| Overall Response Rate (ORR) based on local radiology assessments in subjects with measurable disease at baseline in Study Part B1 | ORR is defined as the proportion of subjects with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Study Part A | OS is defined as the time from date of randomization to date of death due to any cause | Up to 66 months | 
| Overall Survival (OS) in Study Part B2 | OS is defined as the time from date of randomization to date of death due to any cause | Up to 41 months | 
| Overall response rate (ORR) with confirmed response in Study Part A | ORR with confirmed response is the proportion of subjects with BOR of confirmed complete response (CR) or confirmed partial response (PR), as per local review and according to RECIST 1.1 | Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months | 
| Overall response rate (ORR) with confirmed response in Study Part B2 | ORR with confirmed response is the proportion of subjects with BOR of confirmed complete response (CR) or confirmed partial response (PR), as per local review and according to RECIST 1.1 | Up to 22 months | 
| Clinical benefit rate (CBR) with confirmed response in Study Part A | Clinical benefit rate (CBR) with confirmed response is defined as the proportion of subjects with a best overall response of confirmed complete response (CR), or confirmed partial response (PR), or an overall response of stable disease (SD) lasting for a duration of at least 24 weeks. CR, PR, and SD are defined as per local review according to RECIST 1.1 | Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months | 
| Clinical benefit rate (CBR) with confirmed response in Study Part B1 | Clinical benefit rate (CBR) with confirmed response is defined as the proportion of subjects with a best overall response of confirmed complete response (CR), or confirmed partial response (PR), or an overall response of stable disease (SD) lasting for a duration of at least 24 weeks. CR, PR, and SD are defined as per local review according to RECIST 1.1 | Up to 6 months | 
| Clinical benefit rate (CBR) with confirmed response in Study Part B2 | Clinical benefit rate (CBR) with confirmed response is defined as the proportion of subjects with a best overall response of confirmed complete response (CR), or confirmed partial response (PR), or an overall response of stable disease (SD) lasting for a duration of at least 24 weeks. CR, PR, and SD are defined as per local review according to RECIST 1.1 | Up to 22 months | 
| Time to response (TTR) in Study Part A | Time to response (TTR) is defined as the time from the date of randomization/enrolment to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed (although date of initial response is used, not date of confirmation). CR and PR are based on tumor response data as per local review and according to RECIST 1.1 | Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months | 
| Time to response (TTR) in Study Part B1 | Time to response (TTR) is defined as the time from the date of randomization/enrolment to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed (although date of initial response is used, not date of confirmation). CR and PR are based on tumor response data as per local review and according to RECIST 1.1 | Up to 6 months | 
| Time to response (TTR) in Study Part B2 | Time to response (TTR) is defined as the time from the date of randomization/enrolment to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed (although date of initial response is used, not date of confirmation). CR and PR are based on tumor response data as per local review and according to RECIST 1.1 | Up to 22 months | 
| Duration of Response (DOR) with confirmed response in Study Part A | Duration of response (DOR) with confirmed response only applies to subjects whose best overall response is confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date is the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to underlying cancer | Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months | 
| Duration of Response (DOR) with confirmed response in Study Part B1 | Duration of response (DOR) with confirmed response only applies to subjects whose best overall response is confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date is the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to underlying cancer | Up to 6 months | 
| Duration of Response (DOR) with confirmed response in Study Part B2 | Duration of response (DOR) with confirmed response only applies to subjects whose best overall response is confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date is the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to underlying cancer | Up to 22 months | 
| Overall Survival (OS) in Study Part B1 | OS is defined as the time from date of enrolment to date of death due to any cause | Up to 6 months | 
| Progression-free Survival (PFS) Per Investigator Assessment in Study Part B1 | PFS, defined as time from the date of enrolment 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 | Up to 6 months | 
| Plasma concentrations of alpelisib in Study Part B2 | Summary statistics of plasma alpelisib concentrations by time point | up to 22 months | 
| Change from baseline in the global health status/QoL scale score of the EORTC QLQ-C30 in Study Part B2 | Summary of composite measure of change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment | Up to 22 months | 
| Time to 10% definitive deterioration in the global health status/QOL scale score of the EORTC QLQ-C30 in Study Part B2 | Definitive deterioration: time from date of randomization to date of event, defined as at least a 10% worsening from baseline with no later improvement above this threshold observed during the course of the treatment or until death due to any cause, in the global health status/QOL scale score of EORTC QLQ-C30, a questionnaire to assess the quality of life of cancer patients. The questionnaire contains 30 items & is composed of both multi-item scales & single-item measures based on the patient's experience over the past week. This includes 5 functional scales, 3 symptom scales, 6 single items & a global health status/QoL scale. The scales & single-item measures range in score from 0 - 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning; a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems | Up to 22 months | 
| PFS based on local radiology assessments using RECIST 1.1 criteria for subjects by PIK3CA mutation status measured in baseline ctDNA in Study Part A | PFS in patients with PIK3CA mutation as measured in ctDNA | Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months | 
| PFS based on local radiology assessments using RECIST 1.1 criteria for subjects by PIK3CA mutation status measured in baseline ctDNA in Study Part B2 | PFS in patients with PIK3CA mutation as measured in ctDNA | Up to 22 months | 
| Time to definitive deterioration of the ECOG performance status from baseline in Study Part B2 | Definitive deterioration of ECOG PS is defined as the time from the date of randomization to the date of event defined as a worsening of at least once category from baseline in ECOG PS with no later improvement above this threshold observed during the course of the treatment or until death due to any cause | Up to 22 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple Negative Breast Cancer, alpelisib, BYL719, nab-paclitaxel, PIK3CA mutation, PTEN loss