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 (EPIK-B3)

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

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)

Study Overview

• Status: Active, not recruiting
• Conditions: Triple Negative Breast Neoplasms
• Intervention / Treatment: Drug: alpelisib; Drug: nab-paclitaxel; Drug: placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 137
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1125ABD
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000KZE
      • Novartis Investigative Site
• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Austria
  • Leoben, Austria, A 8700
    • Novartis Investigative Site
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Novartis Investigative Site
• Brazil
  • SP
    • Barretos, SP, Brazil, 14784 400
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 01317-002
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 04014-002
      • Novartis Investigative Site
• Bulgaria
  • Plovdiv, Bulgaria, 4004
    • Novartis Investigative Site
• China
  • Dalian, China, 116000
    • Novartis Investigative Site
  • Shanghai, China, 200025
    • Novartis Investigative Site
  • Shenyang, China, 110001
    • Novartis Investigative Site
  • Tianjin, China, 300480
    • Novartis Investigative Site
  • Anhui
    • Hefei, Anhui, China, 230001
      • Novartis Investigative Site
  • Hebei
    • Shijiazhuang, Hebei, China, 050011
      • Novartis Investigative Site
  • Hunan
    • Changsha, Hunan, China, 410013
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Novartis Investigative Site
  • Jilin
    • Chang Chun, Jilin, China, 130021
      • Novartis Investigative Site
  • Liaoning
    • Shengyang, Liaoning, China, 110042
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310016
      • Novartis Investigative Site
• Colombia
  • Bogota, Colombia, 110221
    • Novartis Investigative Site
• Croatia
  • Zagreb, Croatia, 10000
    • Novartis Investigative Site
• France
  • Angers Cedex 02, France, 49055
    • Novartis Investigative Site
  • Saint-Herblain Cédex, France, 44805
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
  • Hauts De Seine
    • Saint-Cloud, Hauts De Seine, France, 92210
      • Novartis Investigative Site
• Germany
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Essen, Germany, 45136
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1062
    • Novartis Investigative Site
• India
  • Haryana
    • Faridabad, Haryana, India, 121 001
      • Novartis Investigative Site
  • Maharashtra
    • Mumbai, Maharashtra, India, 400056
      • Novartis Investigative Site
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632 004
      • Novartis Investigative Site
  • Telangana
    • Hyderabad, Telangana, India, 500034
      • Novartis Investigative Site
• Israel
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • FC
    • Meldola, FC, Italy, 47014
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00128
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 05505
    • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
  • Selangor
    • Petaling Jaya, Selangor, Malaysia, 46050
      • Novartis Investigative Site
• Mexico
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Novartis Investigative Site
• Norway
  • Oslo, Norway, NO 0450
    • Novartis Investigative Site
• Peru
  • La Libertad
    • Trujillo, La Libertad, Peru, 13011
      • Novartis Investigative Site
• Poland
  • Gdynia, Poland, 81 519
    • Novartis Investigative Site
  • Opole, Poland, 45-061
    • Novartis Investigative Site
  • Poznan, Poland, 61 485
    • Novartis Investigative Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Novartis Investigative Site
  • Chelyabinsk, Russian Federation, 454048
    • Novartis Investigative Site
  • Moscow, Russian Federation, 117997
    • Novartis Investigative Site
  • Moscow, Russian Federation, 123056
    • Novartis Investigative Site
  • Pushkin Saint Petersburg, Russian Federation, 196603
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 812 50
    • Novartis Investigative Site
  • Kosice, Slovakia, 041 91
    • Novartis Investigative Site
  • Slovak Republic
    • Bratislava, Slovak Republic, Slovakia, 83310
      • Novartis Investigative Site
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Novartis Investigative Site
• South Africa
  • Johannesburg, South Africa, 2196
    • Novartis Investigative Site
  • Western Cape
    • Port Elizabeth, Western Cape, South Africa, 6045
      • Novartis Investigative Site
• Spain
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03010
      • Novartis Investigative Site
  • Extremadura
    • Badajoz, Extremadura, Spain, 06080
      • Novartis Investigative Site
  • Islas Baleares
    • Palma De Mallorca, Islas Baleares, Spain, 07120
      • Novartis Investigative Site
• Switzerland
  • Lausanne, Switzerland, 1011
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 10449
    • Novartis Investigative Site
• Turkey
  • Istanbul, Turkey, 34722
    • Novartis Investigative Site
  • Istanbul, Turkey, 35100
    • Novartis Investigative Site
• United Kingdom
  • Nottingham, United Kingdom, NG5 1PB
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University Of California Los Angeles Santa Monica Location
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Hematology and Oncology Clinic SC
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester Mayo - Roch.
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Institute Dept Onc
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI Oncology Partners Tennessee Oncology (3)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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 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 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 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 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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2020
• Primary Completion (Actual): May 31, 2023
• Study Completion (Estimated): September 2, 2024

Study Registration Dates

• First Submitted: January 30, 2020
• First Submitted That Met QC Criteria: January 30, 2020
• First Posted (Actual): February 5, 2020

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: BYL719; Triple Negative Breast Cancer; nab-paclitaxel; PTEN loss; PIK3CA mutation; alpelisib
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel
• Other Study ID Numbers: CBYL719H12301; 2019-002637-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No