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
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 137
- 试验地点
- 91
- 主要终点
- Progression-free Survival (PFS) Per Investigator Assessment in Study Part A
研究概览
简要总结
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)
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Part A: placebo + nab-paclitaxel
Participants received placebo + nab-paclitaxel 100 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle.
干预措施: placebo (Drug)
Part A: alpelisib + nab-paclitaxel
Participants received alpelisib 300 mg orally + nab-paclitaxel 100 mg/m^2 intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle
干预措施: alpelisib (Drug)
Part B1: alpelisib + nab-paclitaxel
Participants received alpelisib 300 mg orally + nab-paclitaxel 100 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle.
干预措施: alpelisib (Drug)
Part A: placebo + nab-paclitaxel
Participants received placebo + nab-paclitaxel 100 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle.
干预措施: nab-paclitaxel (Drug)
Part B1: alpelisib + nab-paclitaxel
Participants received alpelisib 300 mg orally + nab-paclitaxel 100 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle.
干预措施: nab-paclitaxel (Drug)
Part A: alpelisib + nab-paclitaxel
Participants received alpelisib 300 mg orally + nab-paclitaxel 100 mg/m^2 intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle
干预措施: nab-paclitaxel (Drug)
结局指标
主要结局
Progression-free Survival (PFS) Per Investigator Assessment in Study Part A
时间窗: Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months
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.
Overall Response Rate (ORR) Based on Local Radiology Assessments in Participants With Measurable Disease at Baseline in Study Part B1
时间窗: Up to 6 months
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.
次要结局
- Overall Survival in Study Part B1(Up to approximately 26 months.)
- Post-Hoc: All Collected Deaths(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).)
- Overall Survival in Study Part A(Up to 66 months)
- Overall Response Rate (ORR) With Confirmed Response in Study Part A(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(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(Up to 6 months)
- Time to Response (TTR) in Study Part A(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(Up to 6 months)
- Duration of Response (DOR) With Confirmed Response in Study Part A(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(Up to approximately 20 months)
- Progression-free Survival (PFS) Per Investigator Assessment in Study Part B1(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(Once all participants have completed at least 6 months of study treatment or have discontinued from study treatment, up to 35 months)