A Phase Ib, Open-Label, Dose-Escalation Study of the Safety and Pharmacology of PI3-Kinase Inhibitor GDC-0941 (Pictilisib) in Combination With Paclitaxel, With and Without Bevacizumab or Trastuzumab, and With Letrozole in Patients With Locally Recurrent Or Metastatic Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 71
- 主要终点
- Percentage of Participants With Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This is an open-label, multicenter, Phase Ib dose-escalation study to assess the safety, tolerability, and pharmacokinetics of oral (PO) pictilisib administered with letrozole or intravenous (IV) paclitaxel with and without IV bevacizumab or IV trastuzumab in participants with locally recurrent or metastatic breast cancer. The study consists of three parts. Part 1 (pictilisib will be administered in 21+7 schedule along with paclitaxel and/or bevacizumab), Part 2 (pictilisib will be administered in 5+2 schedule along with paclitaxel and/or bevacizumab or trastuzumab) and Part 3 (pictilisib will be administered in combination with letrozole). Part 1 and Part 2 consists of two stages; a dose escalation stage and a cohort-expansion stage.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease
- •Adequate organ and bone marrow function as assessed by laboratory tests
- •Evaluable disease or disease measurable per RECIST
- •Agreement to use an effective form of contraception for the duration of the study
排除标准
- •History of malabsorption syndrome or other condition that would interfere with enteral absorption
- •Any condition requiring full-dose anticoagulants, such as warfarin, heparin, or thrombolytic agents
- •Prior anti-cancer therapy (e.g., chemotherapy, biologic therapy, radiotherapy, or hormonal therapy) within 4 weeks or 5 half-lives (whichever is shorter) of the first dose of study treatment
- •Uncontrolled current illness
- •Active small or large intestine inflammation (such as Crohn's disease or ulcerative colitis)
- •Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
- •Known HIV infection
- •New York Heart Association (NYHA) Class II or greater congestive heart failure
- •Active ventricular arrhythmia requiring medication
- •Pregnancy, lactation, or breastfeeding
- •Known significant hypersensitivity to study drugs or excipients
- •History of arterial thromboembolic disease within 6 months of first study treatment
- •No more than two prior chemotherapy regimens for metastatic disease
研究组 & 干预措施
Part 1 (Cohort 1-2): Pictilisib 60 mg +Paclitaxel +Bevacizumab
Pictilisib 60 mg will be administered orally (PO) once daily (QD) for 21 consecutive days of each 28-day cycle (21+7 schedule) with paclitaxel 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1, 8, and 15 and bevacizumab 10 milligrams per kilogram (mg/kg) IV on Days 1 and 15 of each 28-day cycle. In Cohort 1 (Part 1), pictilisib will be evaluated with paclitaxel only; participants in Cohort 1 (Part 1) will be eligible to receive bevacizumab starting at Cycle 2. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Bevacizumab (Drug)
Part 1 (Cohort 1-2): Pictilisib 60 mg +Paclitaxel +Bevacizumab
Pictilisib 60 mg will be administered orally (PO) once daily (QD) for 21 consecutive days of each 28-day cycle (21+7 schedule) with paclitaxel 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1, 8, and 15 and bevacizumab 10 milligrams per kilogram (mg/kg) IV on Days 1 and 15 of each 28-day cycle. In Cohort 1 (Part 1), pictilisib will be evaluated with paclitaxel only; participants in Cohort 1 (Part 1) will be eligible to receive bevacizumab starting at Cycle 2. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part 1 (Cohort 1-2): Pictilisib 60 mg +Paclitaxel +Bevacizumab
Pictilisib 60 mg will be administered orally (PO) once daily (QD) for 21 consecutive days of each 28-day cycle (21+7 schedule) with paclitaxel 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1, 8, and 15 and bevacizumab 10 milligrams per kilogram (mg/kg) IV on Days 1 and 15 of each 28-day cycle. In Cohort 1 (Part 1), pictilisib will be evaluated with paclitaxel only; participants in Cohort 1 (Part 1) will be eligible to receive bevacizumab starting at Cycle 2. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part 1 (Cohort 3): Pictilisib 100 mg+ Paclitaxel + Bevacizumab
Pictilisib 100 mg will be administered PO QD for 21 consecutive days of each 28-day cycle (21+7 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Bevacizumab (Drug)
Part 1 (Cohort 3): Pictilisib 100 mg+ Paclitaxel + Bevacizumab
Pictilisib 100 mg will be administered PO QD for 21 consecutive days of each 28-day cycle (21+7 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part 1 (Cohort 3): Pictilisib 100 mg+ Paclitaxel + Bevacizumab
Pictilisib 100 mg will be administered PO QD for 21 consecutive days of each 28-day cycle (21+7 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part 2 (Arm A: Cohort 1a): Pictilisib 165 mg + Paclitaxel
Pictilisib 165 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity
干预措施: Pictilisib (Drug)
Part 2 (Arm A: Cohort 1a): Pictilisib 165 mg + Paclitaxel
Pictilisib 165 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity
干预措施: Paclitaxel (Drug)
Part 2 (Arm A: Cohort 2a): Pictilisib 250 mg + Paclitaxel
Pictilisib 250 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part 2 (Arm A: Cohort 2a): Pictilisib 250 mg + Paclitaxel
Pictilisib 250 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part 2 (Arm A: Cohort 3a): Pictilisib 330 mg + Paclitaxel
Pictilisib 330 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part 2 (Arm A: Cohort 3a): Pictilisib 330 mg + Paclitaxel
Pictilisib 330 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part2(Arm B:Cohort 1b):Pictilisib 200mg+Paclitaxel+Bevacizumab
Pictilisib 200 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Bevacizumab (Drug)
Part2(Arm B:Cohort 1b):Pictilisib 200mg+Paclitaxel+Bevacizumab
Pictilisib 200 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part2(Arm B:Cohort 1b):Pictilisib 200mg+Paclitaxel+Bevacizumab
Pictilisib 200 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part2(Arm B:Cohort 2b):Pictilisib 250mg+Paclitaxel+Bevacizumab
Pictilisib 250 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Bevacizumab (Drug)
Part2(Arm B:Cohort 2b):Pictilisib 250mg+Paclitaxel+Bevacizumab
Pictilisib 250 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part2(Arm B:Cohort 2b):Pictilisib 250mg+Paclitaxel+Bevacizumab
Pictilisib 250 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part2(Arm B:Cohort 3b):Pictilisib 260mg+Paclitaxel+Bevacizumab
Pictilisib 260 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Bevacizumab (Drug)
Part2(Arm B:Cohort 3b):Pictilisib 260mg+Paclitaxel+Bevacizumab
Pictilisib 260 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part2(Arm B:Cohort 3b):Pictilisib 260mg+Paclitaxel+Bevacizumab
Pictilisib 260 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and bevacizumab 10 mg/kg IV on Days 1 and 15 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part2(Arm C:Cohort 1c):Pictilisib 180mg+Paclitaxel+Trastuzumab
Pictilisib 180 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and trastuzumab 2-4 mg/kg IV on Days 1, 8, 15, and 22 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part2(Arm C:Cohort 1c):Pictilisib 180mg+Paclitaxel+Trastuzumab
Pictilisib 180 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and trastuzumab 2-4 mg/kg IV on Days 1, 8, 15, and 22 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part2(Arm C:Cohort 1c):Pictilisib 180mg+Paclitaxel+Trastuzumab
Pictilisib 180 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and trastuzumab 2-4 mg/kg IV on Days 1, 8, 15, and 22 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Trastuzumab (Drug)
Part2(Arm C:Cohort 2c):Pictilisib 260mg+Paclitaxel+Trastuzumab
Pictilisib 260 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and trastuzumab 2-4 mg/kg IV on Days 1, 8, 15, and 22 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part2(Arm C:Cohort 2c):Pictilisib 260mg+Paclitaxel+Trastuzumab
Pictilisib 260 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and trastuzumab 2-4 mg/kg IV on Days 1, 8, 15, and 22 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Part2(Arm C:Cohort 2c):Pictilisib 260mg+Paclitaxel+Trastuzumab
Pictilisib 260 mg will be administered PO QD for repeated rounds of 5 consecutive days followed by 2 consecutive drug-free days in each 28-day cycle (5+2 schedule) with paclitaxel 90 mg/m^2 IV on Days 1, 8, and 15 and trastuzumab 2-4 mg/kg IV on Days 1, 8, 15, and 22 of each 28-day cycle. Cycle 1 will be 29 days and subsequent cycles will be 28 days. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Trastuzumab (Drug)
Part 3: Pictilisib 260 mg + Letrozole
Pictilisib 260 mg will be administered PO QD continuously with letrozole 2.5 mg PO QD for each 28-day cycle. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Pictilisib (Drug)
Part 3: Pictilisib 260 mg + Letrozole
Pictilisib 260 mg will be administered PO QD continuously with letrozole 2.5 mg PO QD for each 28-day cycle. Study treatment will continue until disease progression or unacceptable toxicity.
干预措施: Letrozole (Drug)
结局指标
主要结局
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: First treatment cycle (Day 1 up to Day 29)
Maximum Tolerated Dose (MTD) of Pictilisib
时间窗: First treatment cycle (Day 1 up to Day 29)
Recommended Phase II Dose (RP2D) of Pictilisib
时间窗: Baseline up to 54.2 months
Number of Cycles of Each Component of the Treatment Regimen
时间窗: Baseline up to 54.2 months
Dose Intensity of Each Component of the Treatment Regimen
时间窗: Baseline up to 54.2 months
次要结局
- Cmin of Letrozole(Part 3: Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months))
- Duration of Response According to Modified RECIST(Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months]))
- Percentage of Participants With Objective Response According to Modified Response Evaluation Criteria in Solid Tumors (RECIST)(Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months]))
- Minimum Observed Plasma Concentration (Cmin) of Pictilisib(Parts 1 and 2 (dose escalation): predose (0 hours [h]) on Day (D) 1,3,16, and 17 of Cycle (C) 1. Part 2 (dose expansion): predose (0h) on D3,16,17 of C1; Part 3: Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months))
- Cmin of Paclitaxel(Parts 1 and 2 (dose escalation): pre-paclitaxel infusion (0 h) on D2 and D16 of C1. Part 2 (dose expansion): pre-paclitaxel infusion (0 h) on D1 and D16 of C1 (cycle length=28 days))
- Area Under the Curve From Time Zero to Last Measurable Concentrations (AUClast) of Pictilisib(Parts 1 and 2: D1,D3,D16,D17 of C1; study completion. Part 2: D3,D16, D17 of C1; study completion. Part 3: D15 of C1; D1 of C1 to C6, C≥7 (cycle length=28 days; up to 54.5 months) [detailed timeframe is provided in endpoint description])
- AUClast of Paclitaxel(Parts 1 and 2 (dose escalation): D2 and D16 of C1; study completion. Part 2 (dose expansion): D1 and D16 of C1; study completion (cycle length=28 days; up to 55.5 months) [detailed timeframe is provided in endpoint description])
- AUClast of Letrozole(Part 3: 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months))
- Maximum Observed Plasma Concentration (Cmax) of Pictilisib(Parts 1 and 2: D1,D3,D16,D17 of C1; study completion. Part 2: D3,D16, D17 of C1; study completion. Part 3: D15 of C1; D1 of C1 to C6, C≥7 (cycle length=28 days; up to 54.5 months) [detailed timeframe is provided in endpoint description])
- Cmax of Paclitaxel(Parts 1 and 2 (dose escalation): D2 and D16 of C1; study completion. Part 2 (dose expansion): D1 and D16 of C1; study completion (cycle length=28 days; up to 55.5 months) [detailed timeframe is provided in endpoint description])
- Cmax of Letrozole(Part 3: 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months))
- Percentage of Participants With Death or Disease Progression According to Modified RECIST(Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months]))
- Progression-free Survival According to Modified RECIST(Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months]))