Clinical trial NCT04251533: 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
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Triple Negative Breast Neoplasms
Keywords: Triple Negative Breast Cancer
alpelisib
BYL719
nab-paclitaxel
PIK3CA mutation
PTEN loss
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-02-05
Enrollment: 137
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was 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)

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 was not initiated, and the recruitment was halted for the entire study.

Upon confirming either PIK3CA mutation and/or PTEN loss status, advanced TNBC participants meeting all other eligibility criteria were assigned to either Part A (PIK3CA mutation regardless of PTEN loss) or Part B1 (PTEN loss with PIK3CA unknown or non-mutant).

In Part A, participants were randomized a 1:1 to receive either:

* alpelisib 300 mg daily orally + nab-paclitaxel 100 mg/m\^2 intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle or
* placebo + nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day cycle.

In Part B1, participants received alpelisib 300 mg daily orally + nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day cycle.

Eligibility criteria: 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

Primary outcomes:
measure: Progression-free Survival (PFS) Per Investigator Assessment in Study Part A
timeFrame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
measure: Overall Response Rate (ORR) Based on Local Radiology Assessments in Participants With Measurable Disease at Baseline in Study Part B1
timeFrame: Up to 6 months
Secondary outcomes:
measure: Overall Survival in Study Part A
timeFrame: Up to 66 months
measure: Overall Response Rate (ORR) With Confirmed Response in Study Part A
timeFrame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
measure: Clinical Benefit Rate (CBR) With Confirmed Response in Study Part A
timeFrame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
measure: Clinical Benefit Rate (CBR) With Confirmed Response in Study Part B1
timeFrame: Up to 6 months
measure: Time to Response (TTR) in Study Part A
timeFrame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
measure: Time to Response (TTR) in Study Part B1
timeFrame: Up to 6 months
measure: Duration of Response (DOR) With Confirmed Response in Study Part A
timeFrame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
measure: Duration of Response (DOR) With Confirmed Response in Study Part B1
timeFrame: Up to approximately 20 months
measure: Overall Survival in Study Part B1
timeFrame: Up to approximately 26 months.
measure: Progression-free Survival (PFS) Per Investigator Assessment in Study Part B1
timeFrame: Up to 6 months
measure: PFS Based on Local Radiology Assessments Using RECIST 1.1 Criteria for Participants by PIK3CA Mutation Status Measured in Baseline Circulating Tumor Deoxyribonucleic Acid (ctDNA) in Study Part A
timeFrame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
measure: Post-Hoc: All Collected Deaths
timeFrame: On-treatment deaths: Up to approximately 28 months (Part A) or approximately 17 months (Part B1). Post-treatment survival follow-up deaths: Up to approximately 7 additional months (Part A) or approximately 9 additional months (Part B1).
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California LA
state: California
city: Baton Rouge
country: United States
facility: Hematology and Oncology Clinic
state: Louisiana
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Institute
state: Minnesota
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Innsbruck
country: Austria
facility: Novartis Investigative Site
state: Tyrol
city: Leoben
country: Austria
facility: Novartis Investigative Site
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Hefei
country: China
facility: Novartis Investigative Site
state: Anhui
city: Shijiazhuang
country: China
facility: Novartis Investigative Site
state: Hebei
city: Changsha
country: China
facility: Novartis Investigative Site
state: Hunan
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Nanchang
country: China
facility: Novartis Investigative Site
state: Jiangxi
city: Chang Chun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Shengyang
country: China
facility: Novartis Investigative Site
state: Liaoning
city: Shenyang
country: China
facility: Novartis Investigative Site
state: Liaoning
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Dalian
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Bogota
country: Colombia
facility: Novartis Investigative Site
city: Zagreb
country: Croatia
facility: Novartis Investigative Site
city: Saint-Cloud
country: France
facility: Novartis Investigative Site
state: Hauts De Seine
city: Angers 02
country: France
facility: Novartis Investigative Site
city: Saint Herblain
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Faridabad
country: India
facility: Novartis Investigative Site
state: Haryana
city: Mumbai
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Telangana
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Meldola
country: Italy
facility: Novartis Investigative Site
state: FC
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Petaling Jaya
country: Malaysia
facility: Novartis Investigative Site
state: Selangor
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo Leon
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Trujillo
country: Peru
facility: Novartis Investigative Site
state: La Libertad
city: Gdynia
country: Poland
facility: Novartis Investigative Site
city: Opole
country: Poland
facility: Novartis Investigative Site
city: Poznan
country: Poland
facility: Novartis Investigative Site
city: Arkhangelsk
country: Russian Federation
facility: Novartis Investigative Site
city: Chelyabinsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Pushkin Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
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: Ljubljana
country: Slovenia
facility: Novartis Investigative Site
city: Port Elizabeth
country: South Africa
facility: Novartis Investigative Site
state: Western Cape
city: Johannesburg
country: South Africa
facility: Novartis Investigative Site
city: Alicante
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Badajoz
country: Spain
facility: Novartis Investigative Site
state: Extremadura
city: Palma De Mallorca
country: Spain
facility: Novartis Investigative Site
state: Islas Baleares
city: Lausanne
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: