Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant in Participants With HR-positive (HR+), HER2-negative, Advanced Breast Cancer After Treatment With a CDK4/6 Inhibitor and an Aromatase Inhibitor. (EPIK-B5)

EPIK-B5: A Phase III, Randomized, Double-blind, Placebo-controlled Study of Alpelisib in Combination With Fulvestrant for Men and Postmenopausal Women With HR-positive, HER2-negative Advanced Breast Cancer With a PIK3CA Mutation, Who Progressed on or After Aromatase Inhibitor and a CDK4/6 Inhibitor

The purpose of this study is to complement Study CBYL719C2301 (SOLAR-1) and obtain more comprehensive data on the efficacy and safety of alpelisib (BYL719) in combination with fulvestrant compared with placebo plus fulvestrant in men or postmenopausal women with HR-positive, HER2-negative advanced breast cancer with a PIK3CA mutation who progressed or relapsed on or after treatment with an AI plus a CDK4/6 inhibitor.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Alpelisib; Drug: Fulvestrant; Drug: Alpelisib-matching placebo

Detailed Description

This is a Phase III, randomized, double-blind, placebo-controlled, international, multi-center trial. Men and postmenopausal women will be randomized to either alpelisib plus fulvestrant or alpelisib-matching placebo plus fulvestrant. Randomization will follow a 1:1 randomization ratio and be stratified by presence of lung and/or liver metastases (yes vs. no) and setting at last prior CDK4/6 inhibitor therapy (adjuvant vs metastatic).

Study treatment with alpelisib plus fulvestrant or alpelisib-matching placebo plus fulvestrant will be initiated on Cycle 1 Day 1, and will continue until disease progression per RECIST v1.1 as per BIRC assessment, start of new antineoplastic therapy, death, lost to follow-up, or withdrawal of consent. A cycle is defined as 28 days.

• Study Type: Interventional
• Enrollment (Actual): 210
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Novartis Investigative Site
  • Brussels, Belgium, 1000
    • Novartis Investigative Site
  • Ghent, Belgium, 9000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Liège, Belgium, 4000
    • Novartis Investigative Site
  • Oost Vlaanderen
    • Sint-Niklaas, Oost Vlaanderen, Belgium, 9100
      • Novartis Investigative Site
• Bulgaria
  • Plovdiv, Bulgaria, 4004
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1330
    • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 5G2
      • Novartis Investigative Site
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
• Czechia
  • Brno, Czechia, 656 53
    • Novartis Investigative Site
  • Nový Jičín, Czechia, 741 01
    • Novartis Investigative Site
  • Prague, Czechia, 128 08
    • Novartis Investigative Site
  • Prague, Czechia, 100 34
    • Novartis Investigative Site
  • Prague, Czechia, 140 59
    • Novartis Investigative Site
• Denmark
  • Aalborg, Denmark, 9000
    • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00029
    • Novartis Investigative Site
  • Tampere, Finland, FIN-33521
    • Novartis Investigative Site
• France
  • Besançon, France, 25030
    • Novartis Investigative Site
  • Clermont-Ferrand, France, 63011
    • Novartis Investigative Site
  • La Roche-sur-Yon, France, 85925
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Montpellier, France, 34298
    • Novartis Investigative Site
  • Paris, France, 75970
    • Novartis Investigative Site
  • Paris, France, 75475
    • Novartis Investigative Site
  • Valenciennes, France, 59300
    • Novartis Investigative Site
• Germany
  • Augsburg, Germany, 86150
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Essen, Germany, 45136
    • Novartis Investigative Site
  • Lübeck, Germany, 23538
    • Novartis Investigative Site
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 22
    • Novartis Investigative Site
  • Pátrai, Greece, 265 04
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H 1122
    • Novartis Investigative Site
• Ireland
  • Dublin, Ireland, DO4
    • Novartis Investigative Site
• Italy
  • Milan, Italy, 20141
    • Novartis Investigative Site
  • Naples, Italy, 80131
    • Novartis Investigative Site
  • BA
    • Bari, BA, Italy, 70124
      • Novartis Investigative Site
  • BG
    • Bergamo, BG, Italy, 24127
      • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • FI
    • Florence, FI, Italy, 50134
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20133
      • Novartis Investigative Site
    • Milan, MI, Italy, 20132
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • PA
    • Palermo, PA, Italy, 90127
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • PN
    • Aviano, PN, Italy, 33081
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
  • TR
    • Terni, TR, Italy, 05100
      • Novartis Investigative Site
• Poland
  • Bydgoszcz, Poland, 85 796
    • Novartis Investigative Site
• Portugal
  • Coimbra, Portugal, 3000-075
    • Novartis Investigative Site
  • Lisbon, Portugal, 1400-038
    • Novartis Investigative Site
  • Lisbon, Portugal, 1099-023
    • Novartis Investigative Site
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Romania
  • Cluj
    • Floreşti, Cluj, Romania, 407280
      • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 812 50
    • Novartis Investigative Site
  • Bratislava, Slovakia, 83310
    • Novartis Investigative Site
  • Košice, Slovakia, 041 91
    • Novartis Investigative Site
• Spain
  • A Coruña, Spain, 15009
    • Novartis Investigative Site
  • Barcelona, Spain, 08036
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Málaga, Spain, 29011
    • Novartis Investigative Site
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Extremadura
    • Badajoz, Extremadura, Spain, 06080
      • Novartis Investigative Site
  • Madrid
    • Pozuelo de Alarcón, Madrid, Spain, 28223
      • Novartis Investigative Site
  • Principality of Asturias
    • Oviedo, Principality of Asturias, Spain, 33011
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

• Participant is an adult ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines.
• Participant has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory.
• Participant has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (Fluorescent in situ hybridization (FISH), Chromogenic in situ hybridization (CISH), or Silver-enhanced in situ hybridization (SISH)) test is required by local laboratory testing.
• Participant has at least one measurable lesion as per RECIST v1.1 criteria as assessed by Investigator (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).
• Participant has recurrence or progression of disease during or after combined AI (i.e. letrozole, anastrozole, exemestane) and CDK4/6 inhibitor therapy. The combined AI and CDK4/6 inhibitor therapy does not need to be the latest treatment regimen (including adjuvant setting).
• Participant has received ≤ 2 prior lines of systemic therapies overall in the metastatic setting, of which a maximum of 1 line of prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy) is permitted.
• The presence of PIK3CA mutation(s) determined in tumor tissue prior to enrollment either by a Novartis designated laboratory or in tumor tissue or plasma ctDNA by a local laboratory using a Food and Drug Administration (FDA)-approved PIK3CA Companion Diagnostics (CDx) test for alpelisib or the CE-IVD QIAGEN Therascreen® PIK3CA RGQ PCR test.
• If female, then the participant must be in postmenopausal status.

Key Exclusion Criteria:

• Participant with symptomatic visceral disease or any disease burden that makes the participant ineligible for endocrine therapy (ET) per the Investigator's best judgment.
• Participant who relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine/endocrine-based therapy with no treatment for metastatic disease.
• Participant has received prior treatment with fulvestrant, any oral selective estrogen receptor degrader (SERD), any Phosphatidylinositol-3-Kinase (PI3K), mammalian Target of Rapamycin (mTOR) or Protein Kinase B (AKT) inhibitor.

Other Inclusion and Exclusion Criteria do apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alpelisib plus fulvestrant; Alpelisib 300 mg orally once daily on a continuous dosing schedule, in a 28-day cycle + fulvestrant 500 mg as intramuscular injection on Cycle 1 Day 1 and 15, and on Day 1 on every Cycle thereafter, in a 28 days cycle.	Drug: Alpelisib; Alpelisib (tablets) administered at 300mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 day cycle.; Drug: Fulvestrant; Fulvestrant (prefilled syringe) 500mg administered intramuscularly at Cycle 1 Day 1 and 15 and then at Day 1 of each subsequent cycle (each cycle is 28 days).
Placebo Comparator: Alpelisib-matching placebo plus fulvestrant; Alpelisib-matching placebo orally once daily on a continuous dosing schedule, in a 28-day cycle + fulvestrant 500 mg as intramuscular injection on Cycle 1 Day 1 and 15 and on Day 1 on every Cycle thereafter, in a 28 days cycle. After Protocol Amendment 5 is implemented, alpelisib matching-placebo will no longer be supplied or administered once participants have been unblinded.	Drug: Fulvestrant; Fulvestrant (prefilled syringe) 500mg administered intramuscularly at Cycle 1 Day 1 and 15 and then at Day 1 of each subsequent cycle (each cycle is 28 days).; Drug: Alpelisib-matching placebo; Alpelisib-matching placebo (tablets) administered orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 day cycle. After Protocol Amendment 5 is implemented, alpelisib matching-placebo will no longer be supplied or administered once participants have been unblinded.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) based on BIRC assessments and using RECIST v1.1 criteria	Progression-free survival (PFS) is 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 by the Blinded Independent Review Committee (BIRC) according to RECIST 1.1.	From randomization to date of the first documented progression or death due to any cause, assessed up to a maximum duration of 60 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Overall survival (OS) is defined as the time from randomization to the date of death due to any cause	From the date of randomization to the date of death up to a maximum duration of 60 months
Overall response rate (ORR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria	Overall response rate (ORR) with confirmed response is defined as the proportion of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), as per BIRC and according to RECIST 1.1	From the date of randomization up to a maximum duration of 60 months
Clinical benefit rate (CBR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria	Clinical benefit rate (CBR) with confirmed response is defined as the proportion of participants with a best overall response of confirmed CR or PR, or SD lasting for a duration of at least 24 weeks. CR, PR and SD are defined as per BIRC review according to RECIST 1.1	From the date of randomization up to a maximum duration of 60 months
Duration of response (DOR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria	Duration of response (DOR) with confirmed response only applies to participants 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 BIRC review. The start date is the date of first documented response of CR or PR and the end date is defined as the date of the first documented progression or death due to underlying cancer.	From first documented response to the date of first progression or deaths, up to a maximum duration of 60 months
Time to response (TTR) based on BIRC assessments and using RECIST v1.1 criteria	Time to response (TTR) is defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed. CR and PR are based on tumor response data as per BIRC review and according to RECIST 1.1	From the date of randomization to the first documented response up to a maximum duration of 60 months
PFS based on BIRC assessment and using RECIST v1.1 criteria for participants by PIK3CA mutation status	Progression-free survival (PFS) is 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 by the Blinded Independent Review Committee (BIRC) according to RECIST 1.1. Results will be presented by PIK3CA mutation status measured in circulating tumor deoxyribonucleic acid (ctDNA) collected at baseline.	From the date of randomization up to a maximum duration of 60 months
Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) from baseline	Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) from baseline is defined as the time from the date of randomization to the date when ECOG PS has definitively worsened by at least one category compared to baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG PS back to the baseline category or better.	From the date of randomization up to maximum duration of 60 months
Time to definitive (10%) deterioration in the global health status/Quality of Life (QoL) and symptom scale scores of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core Module (EORTC QLQ-C30)	Time to definitive (10%) deterioration in global health status/Quality of Life (QoL) and symptom scale scores of the EORTC QLQ-C30 is defined as the time from the date of randomization to the date of the first occurrence of at least a 10% worsening from baseline in the global health status/QoL or symptom scale scores, with no subsequent improvement above this threshold during treatment or until death from any cause. The EORTC QLQ-C30 is a validated questionnaire assessing cancer patients' quality of life over the past week, comprising 30 items across 5 functional scales, 3 symptom scales, 6 single items, and a global health status/QoL scale. Scores range from 0 to 100, with higher scores indicating a higher response level.	From the date of randomization up to maximum duration of 60 months
Change from baseline in global health status/QoL and symptom scale scores of the EORTC QLQ-C30	Change from baseline in global health status/Quality of Life (QoL) and symptom scale scores of the EORTC QLQ-C30 refers to the variation in scores from baseline across domain scores, health states, overall health status, and index values at each assessment timepoint. The EORTC QLQ-C30 is a validated questionnaire designed to assess the quality of life of cancer patients over the past week. It includes 30 items comprising 5 functional scales, 3 symptom scales, 6 single items, and a global health status/QoL scale. Each scale and item is scored from 0 to 100, with higher scores indicating a higher response level.	From the date of randomization up to maximum duration of 60 months
Time from randomization to objective tumour progression on next line treatment or death from any cause (PFS2)	Time from randomization to objective tumor progression on next-line treatment or death from any cause (PFS2) is defined as the time from the date of randomization to the earliest occurrence of either documented disease progression on next-line therapy, as assessed by the investigator, or death from any cause.	From the date of randomization up to maximum duration of 60 months

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2021
• Primary Completion (Estimated): January 28, 2027
• Study Completion (Estimated): February 26, 2027

Study Registration Dates

• First Submitted: September 1, 2021
• First Submitted That Met QC Criteria: September 1, 2021
• First Posted (Actual): September 9, 2021

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Phase III; aromatase inhibitor; Fulvestrant; Advanced breast cancer; PIK3CA mutation; Alpelisib; HER-2 negative; CDK4/6 inhibitor; HR-positive; Progression free survival
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Fulvestrant; Alpelisib
• Other Study ID Numbers: CBYL719C2303; 2023-509133-39-00 (Registry Identifier: CTIS (EU))

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