Clinical trial NCT05038735: Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant in Participants With HR-postitive (HR+), HER2-negative, Advanced Breast Cancer After Treatment With a CDK4/6 Inhibitor and an Aromatase Inhibitor.
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Alpelisib
Fulvestrant
Advanced breast cancer
Phase III
HR-positive
HER-2 negative
CDK4/6 inhibitor
PIK3CA mutation
Progression free survival
aromatase inhibitor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-09-09
Enrollment: 211
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: This is a Phase III, randomized, double-blind, placebo-controlled, international, multi-center trial. Approximately 234 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.

Participants randomized to the alpelisib-matching placebo plus fulvestrant arm who have disease progression per RECIST v1.1 as assessed by BIRC will have the option to crossover to be treated with alpelisib plus fulvestrant.

Unblinding a single participant at a site will be permitted after disease progression confirmed by BIRC after discussion with the Novartis team to determine eligibility for cross-over to treatment with alpelisib plus fulvestrant.

Eligibility criteria: 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.
* If female, then the participant must be in postmenopausal status. Postmenopausal status is defined either by: prior bilateral oophorectomy, age ≥60 or age \<60 and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range per local normal range.
* 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).
* Participant must show the presence of a PIK3CA mutation(s) determined in tumor tissue prior ro 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.

Exclusion Criteria:

* Participant with symptomatic visceral disease 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 (SERDs), any Phosphatidylinositol-3-Kinase (PI3K), mammalian Target of Rapamycin (mTOR) or Protein Kinase B (AKT) inhibitor

Other Inclusion and Exclusion Criteria do apply

Primary outcomes:
measure: Progression-free survival (PFS) based on BIRC assessments and using RECIST v1.1 criteria
timeFrame: 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 outcomes:
measure: Overall survival (OS)
timeFrame: From the date of randomization to the date of death up to a maximum duration of 60 months
measure: Overall response rate (ORR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria
timeFrame: From the date of randomization up to a maximum duration of 60 months
measure: Clinical benefit rate (CBR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria
timeFrame: From the date of randomization up to a maximum duration of 60 months
measure: Duration of response (DOR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria
timeFrame: From first documented response to the date of first progression or deaths, up to a maximum duration of 60 months
measure: Time to response (TTR) based on BIRC assessments and using RECIST v1.1 criteria
timeFrame: From the date of randomization to the first documented response up to a maximum duration of 60 months
measure: PFS based on BIRC assessment and using RECIST v1.1 criteria for participants by PIK3CA mutation status
timeFrame: From the date of randomization up to a maximum duration of 60 months
measure: Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) from baseline
timeFrame: From the date of randomization up to maximum duration of 60 months
measure: 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)
timeFrame: From the date of randomization up to maximum duration of 60 months
measure: Change from baseline in global health status/QoL and symptom scale scores of the EORTC QLQ-C30
timeFrame: From the date of randomization up to maximum duration of 60 months
measure: Time from randomization to objective tumour progression on next line treatment or death from any cause (PFS2)
timeFrame: From the date of randomization up to maximum duration of 60 months
Other outcomes:
Locations:
city: Sint Niklaas
country: Belgium
facility: Novartis Investigative Site
state: Oost Vlaanderen
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Brno
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Novy Jicin
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Praha 10
country: Czechia
facility: Novartis Investigative Site
city: Praha 4
country: Czechia
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Aalborg
country: Denmark
facility: Novartis Investigative Site
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Odense C
country: Denmark
facility: Novartis Investigative Site
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Besancon Cedex
country: France
facility: Novartis Investigative Site
city: Clermont-Ferrand
country: France
facility: Novartis Investigative Site
city: La Roche Sur Yon
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Valenciennes
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Luebeck
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Patras
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Dublin 4
country: Ireland
facility: Novartis Investigative Site
city: Bari
country: Italy
facility: Novartis Investigative Site
state: BA
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Aviano
country: Italy
facility: Novartis Investigative Site
state: PN
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Terni
country: Italy
facility: Novartis Investigative Site
state: TR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Bydgoszcz
country: Poland
facility: Novartis Investigative Site
city: Coimbra
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Floresti
country: Romania
facility: Novartis Investigative Site
state: Cluj
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Jerez
country: Spain
facility: Novartis Investigative Site
state: Cadiz
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Badajoz
country: Spain
facility: Novartis Investigative Site
state: Extremadura
city: A Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Pozuelo de Alarcon
country: Spain
facility: Novartis Investigative Site
state: Madrid
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Zaragoza
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: