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

Triple Negative Breast Neoplasms Clinical Trial

— EPIK-B3  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04251533
• Other study ID #: CBYL719H12301
• Secondary ID: 2019-002637-11
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 8, 2020
• Est. completion date: September 2, 2024

Study information

• Verified date: February 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 137
• Est. completion date: September 2, 2024
• Est. primary completion date: May 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Neoplasms

Intervention

Drug:
• alpelisib
300 mg orally once per day (QD)
• placebo
300 mg orally once per day (QD)
• nab-paclitaxel
100 mg/m² as IV infusion on Days 1, 8 and 15 of a 28-day cycle

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Australia	Novartis Investigative Site	Melbourne	Victoria
Australia	Novartis Investigative Site	Nedlands	Western Australia
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Austria	Novartis Investigative Site	Leoben
Brazil	Novartis Investigative Site	Barretos	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Bulgaria	Novartis Investigative Site	Plovdiv
China	Novartis Investigative Site	Chang Chun	Jilin
China	Novartis Investigative Site	Changsha	Hunan
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Dalian
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Hefei	Anhui
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shengyang	Liaoning
China	Novartis Investigative Site	Shenyang
China	Novartis Investigative Site	Shijiazhuang	Hebei
China	Novartis Investigative Site	Tianjin
Colombia	Novartis Investigative Site	Bogota
Croatia	Novartis Investigative Site	Zagreb
France	Novartis Investigative Site	Angers Cedex 02
France	Novartis Investigative Site	Saint-Cloud	Hauts De Seine
France	Novartis Investigative Site	Saint-Herblain Cédex
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Leipzig
Hungary	Novartis Investigative Site	Budapest
India	Novartis Investigative Site	Faridabad	Haryana
India	Novartis Investigative Site	Hyderabad	Telangana
India	Novartis Investigative Site	Mumbai	Maharashtra
India	Novartis Investigative Site	Vellore	Tamil Nadu
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Meldola	FC
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Roma	RM
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Petaling Jaya	Selangor
Mexico	Novartis Investigative Site	Monterrey	Nuevo Leon
Norway	Novartis Investigative Site	Oslo
Peru	Novartis Investigative Site	Trujillo	La Libertad
Poland	Novartis Investigative Site	Gdynia
Poland	Novartis Investigative Site	Opole
Poland	Novartis Investigative Site	Poznan
Russian Federation	Novartis Investigative Site	Arkhangelsk
Russian Federation	Novartis Investigative Site	Chelyabinsk
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Pushkin Saint Petersburg
Slovakia	Novartis Investigative Site	Bratislava	Slovak Republic
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Kosice
Slovenia	Novartis Investigative Site	Ljubljana
South Africa	Novartis Investigative Site	Johannesburg
South Africa	Novartis Investigative Site	Port Elizabeth	Western Cape
Spain	Novartis Investigative Site	Alicante	Comunidad Valenciana
Spain	Novartis Investigative Site	Badajoz	Extremadura
Spain	Novartis Investigative Site	Palma De Mallorca	Islas Baleares
Switzerland	Novartis Investigative Site	Lausanne
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul
United Kingdom	Novartis Investigative Site	Nottingham
United Kingdom	Novartis Investigative Site	Oxford
United States	Hematology and Oncology Clinic SC	Baton Rouge	Louisiana
United States	University Of California Los Angeles Santa Monica Location	Los Angeles	California
United States	SCRI Oncology Partners Tennessee Oncology (3)	Nashville	Tennessee
United States	Mayo Clinic Rochester Mayo - Roch.	Rochester	Minnesota
United States	Park Nicollet Institute Dept Onc	Saint Louis Park	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Brazil,  Bulgaria,  China,  Colombia,  Croatia,  France,  Germany,  Hungary,  India,  Israel,  Italy,  Korea, Republic of,  Malaysia,  Mexico,  Norway,  Peru,  Poland,  Russian Federation,  Slovakia,  Slovenia,  South Africa,  Spain,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Plasma concentrations of alpelisib in Study Part B2	Summary statistics of plasma alpelisib concentrations by time point	up to 22 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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