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

Phase 3Active Not RecruitingNCT04251533

Novartis Pharmaceuticals137 enrolled

Overview

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)

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

137

Conditions

Triple Negative Breast Neoplasms

Interventions

alpelisibDRUG

300 mg orally, once per day (QD), tablets

placeboDRUG

300 mg orally, once per day (QD), tablets

nab-paclitaxelDRUG

100 mg/m\^2 IV infusion, once per day (QD)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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

Locations (78)

Outcomes

Primary Outcomes

Progression-free Survival (PFS) Per Investigator Assessment in Study Part A

PFS was defined as time from the date of randomization to the date of the first documented progressive disease (PD) or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. PD=At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm\^2. PFS was censored at the date of the last adequate tumor assessment, if no PFS event was observed prior to the analysis cut-off date.

Time frame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months

Overall Response Rate (ORR) Based on Local Radiology Assessments in Participants With Measurable Disease at Baseline in Study Part B1

ORR was defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1. BOR was defined as the best response recorded from the start of the study treatment until progressive disease (PD)/recurrence. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; PD= At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: Up to 6 months

Secondary Outcomes

Overall Survival in Study Part A

Overall survival is defined as the time from date of randomization to date of death due to any cause.

Time frame: Up to 66 months

Data from ClinicalTrials.gov

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University of California LA

Los Angeles, California, United States

Hematology and Oncology Clinic

Baton Rouge, Louisiana, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Park Nicollet Institute

Saint Louis Park, Minnesota, United States

SCRI Oncology Partners

Nashville, Tennessee, United States

Novartis Investigative Site

Rosario, Santa Fe Province, Argentina

Novartis Investigative Site

CABA, Argentina

Novartis Investigative Site

Melbourne, Victoria, Australia

Novartis Investigative Site

Nedlands, Western Australia, Australia

Novartis Investigative Site

Innsbruck, Tyrol, Austria

...and 68 more locations

Overall Response Rate (ORR) With Confirmed Response in Study Part A

ORR with confirmed response was the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), as per local review and according to RECIST 1.1. BOR was defined as the best response recorded from the start of the study treatment until progressive disease (PD)/recurrence. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; PD= At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months

Clinical Benefit Rate (CBR) With Confirmed Response in Study Part A

Clinical benefit rate (CBR) was defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are defined according to RECIST 1.1 based on investigator's assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

Time frame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months

Clinical Benefit Rate (CBR) With Confirmed Response in Study Part B1

Time frame: Up to 6 months

Time to Response (TTR) in Study Part A

Time to response (TTR) was 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 were based on tumor response data as per local review and according to RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.

Time frame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months

Time to Response (TTR) in Study Part B1

Time to response (TTR) was 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 was used, not date of confirmation). CR and PR were based on tumor response data as per local review and according to RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.

Time frame: Up to 6 months

Duration of Response (DOR) With Confirmed Response in Study Part A

Duration of response (DOR) with confirmed response only applied to participants whose best overall response (BOR) was 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 was 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 was defined as the date of the first documented progressive disease (PD) or death due to underlying cancer. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.

Time frame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months

Duration of Response (DOR) With Confirmed Response in Study Part B1

Time frame: Up to approximately 20 months

Overall Survival in Study Part B1

Overall survival for Part B1 was defined as the number of participants who were alive at the end of the post-treatment period.

Time frame: Up to approximately 26 months.

Progression-free Survival (PFS) Per Investigator Assessment in Study Part B1

PFS was defined as time from the date of enrolment to the date of the first documented progressive disease (PD) or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. PD=At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm\^2. PFS was censored at the date of the last adequate tumor assessment, if no PFS event was observed prior to the analysis cut-off date.

Time frame: Up to 6 months

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

PFS in participants with PIK3CA mutation as measured in ctDNA. PFS was defined as time from the date of randomization to the date of the first documented progression or death due to any cause.

Time frame: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months

Post-Hoc: All Collected Deaths

On-treatment deaths due to any cause were collected from first dose of study medication to 30 days after the last dose of study treatment. Post-treatment survival follow-up deaths were collected from Day 31 after last dose of study medication to the data cut-off date.

Time frame: 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).