A Phase Ib/II, Multicenter Study of the Combination of LEE011 and BYL719 With Letrozole in Adult Patients With Advanced ER+ Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 255
- 试验地点
- 36
- 主要终点
- Incidence of Dose limiting toxicities (DLTs) - Phase lb only
研究概览
简要总结
The purpose of this trial is to inform the future clinical development of the two investigational agents in ER+ breast cancer, LEE011 (CDK4/6 inhibitor) and BYL719 (PI3K-alpha inhibitor).
This is a multi-center, open-label Phase Ib study. The Phase Ib dose escalation will estimate the MTD and/or RP2D for three regimens: two double combinations, LEE011 with letrozole and BYL719 with letrozole, followed by triple combinations of LEE011 + BYL719 with letrozole (Arms 3 and 4).
The Phase Ib dose escalation part will be followed by Phase Ib dose expansions to further characterize the safety, tolerability, PK and preliminary clinical anti-tumor activity of the combinations. Optional crossover for patients who have progressed while on dose escalation or dose expansion with doublet treatment on Arms 1 or 2 to be treated with the triplet combination (Arm 3) after the determination of the RP2D for Arm 3; is no longer permitted after protocol amendment 6.
Approximately 270 adult women with ER+/HER2- locally advanced or metastatic breast cancer will be enrolled.
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
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Postmenopausal, Estrogen-receptor positive and/or Progesterone-receptor positive breast cancer
- •Phase Ib dose escalation only: Any number of prior lines of endocrine therapy is allowed with the exception of cytotoxic therapy which is limited to one prior line administered in the advanced (metastatic or locally advanced) setting.
- •Phase Ib dose expansions Arms 1, 2 and 3
- •No prior systemic treatment in the advanced (metastatic or locally advanced) setting with the exception of treatment with letrozole for a maximum of one month prior to starting study treatment.
- •Patients who received (neo)adjuvant therapy for breast cancer are eligible. Prior therapy with letrozole or anastrozole in the (neo)adjuvant setting is permitted if the disease-free interval is greater than 12 months from the completion of treatment.
排除标准
- •HER2-overexpression in the patient's tumor tissue
- •Patients with active CNS or other brain metastases
- •Major surgery within 2 weeks
- •Acute or chronic pancreatitis
- •Bilateral diffuse lymphangitic carcinomatosis
- •Another malignancy within 3 years
- •Receiving hormone replacement therapy that cannot be discontinued
- •Impaired cardiac function
- •Patients with clinically manifest diabetes mellitus (treated and/or clinical signs or with fasting glucose ≥ 126 mg/dL / 7.0 mmol/L or hemoglobin A1c >6.5%), history of gestational diabetes mellitus or documented steroid-induced diabetes mellitus.
- •Other protocol-defined inclusion/exclusion criteria may apply
研究组 & 干预措施
LEE011 + letrozole Arm 1
LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day
干预措施: LEE011 (Drug)
BYL719 + letrozole Arm 2
BYL719 - daily (dose escalating) letrozole - 2.5 mg/day
干预措施: BYL719 (Drug)
LEE011 + BYL719 + letrozole Arm 3
LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day
干预措施: LEE011 (Drug)
LEE011 + BYL719 + letrozole Arm 3
LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day
干预措施: BYL719 (Drug)
LEE011+ BYL719+letrozole Arm 4
LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day
干预措施: LEE011 (Drug)
LEE011 + letrozole Arm 1
LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day
干预措施: Letrozole (Drug)
BYL719 + letrozole Arm 2
BYL719 - daily (dose escalating) letrozole - 2.5 mg/day
干预措施: Letrozole (Drug)
LEE011+ BYL719+letrozole Arm 4
LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day
干预措施: BYL719 (Drug)
LEE011 + BYL719 + letrozole Arm 3
LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day
干预措施: Letrozole (Drug)
LEE011+ BYL719+letrozole Arm 4
LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day
干预措施: Letrozole (Drug)
结局指标
主要结局
Incidence of Dose limiting toxicities (DLTs) - Phase lb only
时间窗: 28 days
Safety and tolerability
时间窗: Average 18 months
Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.
PK profiles of LEE011 and letrozole
时间窗: 18 months
To characterize PK profiles of LEE011 and Letrozole.
次要结局
- Safety and tolerability of LEE011 in combination with letrozole, BYL719 in combination with letrozole, and the triple combination of LEE011 +BYL719 with letrozole(Average 24 months)
- Plasma concentration-time profiles of LEE011, BYL719 and letrozole(Average 24 months)
- Overall Response Rate (ORR)(Average 24 months)
- Duration of Response (DOR)(Average 24 months)
- Progression Free Survival (PFS)(Average 24 months)
- Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc)(Average 24 months)
- Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet(Average 24 months)