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.

Breast Cancer Clinical Trial

— EPIK-B5  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05038735
• Other study ID #: CBYL719C2303
• Secondary ID: 2021-001966-39
• Status: Recruiting
• Phase: Phase 3
• Start date: November 29, 2021
• Est. completion date: August 23, 2027

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: +41613241111
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 234
• Est. completion date: August 23, 2027
• Est. primary completion date: August 22, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

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.
• 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).
• 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.

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Belgium	Novartis Investigative Site	Sint Niklaas	Oost Vlaanderen
Bulgaria	Novartis Investigative Site	Burgas
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Varna
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	Oshawa	Ontario
Canada	Novartis Investigative Site	Ottawa	Ontario
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Novy Jicin	Czech Republic
Czechia	Novartis Investigative Site	Praha
Czechia	Novartis Investigative Site	Praha 10
Czechia	Novartis Investigative Site	Praha 4
Denmark	Novartis Investigative Site	Aalborg
Denmark	Novartis Investigative Site	Copenhagen
Denmark	Novartis Investigative Site	Odense C
Finland	Novartis Investigative Site	Helsinki
Finland	Novartis Investigative Site	Tampere
France	Novartis Investigative Site	Besancon Cedex
France	Novartis Investigative Site	Clermont Ferrand
France	Novartis Investigative Site	La Roche sur Yon Cedex
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Valenciennes
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Luebeck
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Ravensburg
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Patras
Greece	Novartis Investigative Site	Thessaloniki	GR
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Gyor
Ireland	Novartis Investigative Site	Dublin 4
Ireland	Novartis Investigative Site	Dublin 8
Ireland	Novartis Investigative Site	Dublin 9
Italy	Novartis Investigative Site	Aviano	PN
Italy	Novartis Investigative Site	Bari	BA
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Brindisi	BR
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Novara
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Rozzano	MI
Italy	Novartis Investigative Site	Terni	TR
Poland	Novartis Investigative Site	Bydgoszcz
Poland	Novartis Investigative Site	Gdansk
Poland	Novartis Investigative Site	Opole
Portugal	Novartis Investigative Site	Coimbra
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Romania	Novartis Investigative Site	Constanta
Romania	Novartis Investigative Site	Craiova	Dolj
Romania	Novartis Investigative Site	Floresti	Cluj
Romania	Novartis Investigative Site	Timisoara
Slovakia	Novartis Investigative Site	Bratislava	Slovak Republic
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Kosice
Spain	Novartis Investigative Site	A Coruna	Galicia
Spain	Novartis Investigative Site	Badajoz	Extremadura
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Jerez	Cadiz
Spain	Novartis Investigative Site	Lerida	Cataluna
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Pozuelo de Alarcon	Madrid
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  Bulgaria,  Canada,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Hungary,  Ireland,  Italy,  Poland,  Portugal,  Romania,  Slovakia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS) based on BIRC assessments and using RECIST v1.1 criteria	To determine whether treatment with alpelisib plus fulvestrant prolongs progression-free survival (PFS) compared to treatment with placebo plus fulvestrant. PFS is the defined as the time from randomization to date of randomization to the date of the first documented progression as per BIRC criteria using RECIST v1.1 or death due to any cause, whichever comes first.	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	Overall survival (OS)	To determine whether treatment with alpelisib plus fulvestrant prolongs overall survival (OS) compared to treatment with placebo plus fulvestrant. 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
Secondary	Overall response rate (ORR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria	To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 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
Secondary	Clinical benefit rate (CBR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria	To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 criteria. 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
Secondary	Duration of response (DOR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria	To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 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
Secondary	Time to response (TTR) based on BIRC assessments and using RECIST v1.1 criteria	To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 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
Secondary	PFS based on BIRC assessment and using RECIST v1.1 criteria for participants by PIK3CA mutation status	To evaluate the association between PIK3CA mutation status with PFS upon treatment with alpelisib. PFS is the defined as the time from randomization to date of randomization to the date of the first documented progression as per BIRC criteria using RECIST v1.1 or death due to any cause, whichever comes first. 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
Secondary	Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) from baseline	To evaluate treatment with alpelisib plus fulvestrant compared to placebo plus fulvestrant, with respect to time to deterioration of ECOG performance status. Time to definitive deterioration in ECOG PS is defined as the time from the date of randomization to the date when ECOG PS has definitively deteriorated by at least one category compared with baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG PS back to the baseline category or above.	From the date of randomization up to maximum duration of 60 months
Secondary	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)	To evaluate patient-reported outcomes of alpelisib plus fulvestrant compared to placebo and fulvestrant. 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 and symptom scale scores of EORTC QLQ-C30, a questionnaire to assess the quality of life of cancer patients. The questionnaire contains 30 items and is composed of both multi-item scales and single-item measures based on the patient's experience over the past week. This includes 5 functional scales, 3 symptom scales, 6 single items and a global health status/QoL scale. The scales and single-item measures range in score from 0 - 100. A high scale score represents a higher response level.	From the date of randomization up to maximum duration of 60 months
Secondary	Change from baseline in global health status/QoL and symptom scale scores of the EORTC QLQ-C30	To evaluate patient-reported outcomes of alpelisib plus fulvestrant compared to placebo and fulvestrant. Change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment. EORTC QLQ-C30 is a questionnaire to assess the quality of life of cancer patients. The questionnaire contains 30 items and is composed of both multi-item scales and single-item measures based on the patient's experience over the past week. This includes 5 functional scales, 3 symptom scales, 6 single items and a global health status/QoL scale. The scales and single-item measures range in score from 0 - 100. A high scale score represents a higher response level.	From the date of randomization up to maximum duration of 60 months
Secondary	Time from randomization to objective tumour progression on next line treatment or death from any cause (PFS2)	To explore the long-term benefit intermediate to PFS and OS. PFS2 is defined as time from date of randomization to the first documented progression on nextline therapy or death from any cause, whichever occurs first. Disease progression will be determined based on investigator assessment of progression on next-line therapy.	From the date of randomization up to maximum duration of 60 months