Description:
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)
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
CBYL719H12301
- SECONDARY ID:
2019-002637-11
- NCT ID:
NCT04251533
Conditions
- Triple Negative Breast Neoplasms
Interventions
| Drug | Synonyms | Arms |
|---|
| alpelisib | BYL719 | alpelisib + nab-paclitaxel |
| placebo | alpelisib matching placebo | placebo + nab-paclitaxel |
| nab-paclitaxel | abraxane | alpelisib + nab-paclitaxel |
Purpose
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)
Trial Arms
| Name | Type | Description | Interventions |
|---|
| alpelisib + nab-paclitaxel | Experimental | Double-blinded, Randomized in a 1:1 ratio in Study Parts A and B2 Single arm Open label in Study Part B1 | |
| placebo + nab-paclitaxel | Placebo Comparator | Double-blinded, Randomized in a 1:1 ratio in Study Parts A and B2 Not applicable in Study Part B1 | |
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: patients 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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Progression-free Survival (PFS) Per Investigator Assessment in Study part A |
| Time Frame: | Once approximately 192 PFS events in Study Part A had been observed, up to 35 months |
| Safety Issue: | |
| Description: | 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 |
Secondary Outcome Measures
| Measure: | Overall Survival (OS) in Study Part A |
| Time Frame: | Up to 66 months |
| Safety Issue: | |
| Description: | OS is defined as the time from date of randomization to date of death due to any cause |
| Measure: | Overall Survival (OS) in Study Part B2 |
| Time Frame: | Up to 41 months |
| Safety Issue: | |
| Description: | OS is defined as the time from date of randomization to date of death due to any cause |
| Measure: | Overall response rate (ORR) with confirmed response in Study Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Overall response rate (ORR) with confirmed response in Study Part B2 |
| Time Frame: | Up to 22 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Clinical benefit rate (CBR) with confirmed response in Study Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Clinical benefit rate (CBR) with confirmed response in Study Part B1 |
| Time Frame: | Up to 6 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Clinical benefit rate (CBR) with confirmed response in Study Part B2 |
| Time Frame: | Up to 22 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Time to response (TTR) in Study Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Time to response (TTR) in Study Part B1 |
| Time Frame: | Up to 6 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Time to response (TTR) in Study Part B2 |
| Time Frame: | Up to 22 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Duration of Response (DOR) with confirmed response in Study Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Duration of Response (DOR) with confirmed response in Study Part B1 |
| Time Frame: | Up to 6 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Duration of Response (DOR) with confirmed response in Study Part B2 |
| Time Frame: | Up to 22 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Overall Survival (OS) in Study Part B1 |
| Time Frame: | Up to 6 months |
| Safety Issue: | |
| Description: | OS is defined as the time from date of enrolment to date of death due to any cause |
| Measure: | Progression-free Survival (PFS) Per Investigator Assessment in Study part B1 |
| Time Frame: | Up to 6 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Plasma concentrations of alpelisib - Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | Summary statistics of plasma alpelisib concentrations by time point in study Part A |
| Measure: | Plasma concentrations of alpelisib - Part B1 |
| Time Frame: | Up to 6 months |
| Safety Issue: | |
| Description: | Summary statistics of plasma alpelisib concentrations by time point in study Part B1 |
| Measure: | Plasma concentrations of alpelisib -Part B2 |
| Time Frame: | up to 22 months |
| Safety Issue: | |
| Description: | Summary statistics of plasma alpelisib concentrations by time point in study Part B2 |
| Measure: | Plasma concentrations of paclitaxel - Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | Summary statistics of plasma paclitaxel concentrations by time point in study Part A |
| Measure: | Plasma concentrations of paclitaxel - Part B1 |
| Time Frame: | up to 6 months |
| Safety Issue: | |
| Description: | Summary statistics of plasma paclitaxel concentrations by time point in study Part B1 |
| Measure: | Change from baseline in the global health status/Quality of life (QoL) scale score of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core Module (EORTC QLQ-C30) in study Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Change from baseline in the global health status/QoL scale score of the EORTC QLQ-C30 in study Part B2 |
| Time Frame: | Up to 22 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Time to 10% definitive deterioration in the global health status/QOL scale score of the EORTC QLQ-C30 in study Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Time to 10% definitive deterioration in the global health status/QOL scale score of the EORTC QLQ-C30 in study Part B2 |
| Time Frame: | Up to 22 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | 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 |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | PFS in patients with PIK3CA mutation as measured in ctDNA |
| Measure: | 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 |
| Time Frame: | Up to 22 months |
| Safety Issue: | |
| Description: | PFS in patients with PIK3CA mutation as measured in ctDNA |
| Measure: | Time to definitive deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status (PS) from baseline in Study Part A |
| Time Frame: | Up to 35 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Time to definitive deterioration of the ECOG performance status from baseline in Study Part B2 |
| Time Frame: | Up to 22 months |
| Safety Issue: | |
| Description: | 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 |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Novartis Pharmaceuticals |
Trial Keywords
- Triple Negative Breast Cancer
- alpelisib
- BYL719
- nab-paclitaxel
- PIK3CA mutation
- PTEN loss
Last Updated
August 16, 2021
