LEE011、BYL719 和来曲唑在晚期 ER+ 乳腺癌中的研究
LEE011 和 BYL719 联合来曲唑治疗晚期 ER+ 乳腺癌成年患者的 Ib/II 期多中心研究
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.
研究概览
研究类型
注册 (实际的)
阶段
- 阶段2
- 阶段1
扩展访问
联系人和位置
学习地点
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PI
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Pisa、PI、意大利、56126
- Novartis Investigative Site
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Marseille、法国、13273
- Novartis Investigative Site
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Paris、法国、75475
- Novartis Investigative Site
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Saint-Herblain、法国、44805
- Novartis Investigative Site
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New South Wales
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Westmead、New South Wales、澳大利亚、2145
- Novartis Investigative Site
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Victoria
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Parkville、Victoria、澳大利亚、3050
- Novartis Investigative Site
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Western Australia
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Nedlands、Western Australia、澳大利亚、6009
- Novartis Investigative Site
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Bellinzona、瑞士、6500
- Novartis Investigative Site
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California
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San Diego、California、美国、92103
- Univ of California at San Diego Moores Cancer Ctr
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San Francisco、California、美国、94143
- UCSF Medical Center
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Florida
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Tampa、Florida、美国、33612
- H Lee Moffitt Cancer Center and Research Institute
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Massachusetts
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Boston、Massachusetts、美国、02114
- Massachusetts General Hospital
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Boston、Massachusetts、美国、02114
- Massachusetts General Hospital SC-5
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Tennessee
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Nashville、Tennessee、美国、37203
- Tennessee Oncology
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Nashville、Tennessee、美国、37232
- Vanderbilt University Medical Ctr
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Texas
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Amarillo、Texas、美国、79124
- Texas Oncology
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San Antonio、Texas、美国、78229
- Mays Cancer Ctr Uthsa Mdacc
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Washington
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Tacoma、Washington、美国、98405
- Northwest Medical Specialties
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Glasgow、英国、G12 0YN
- Novartis Investigative Site
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Manchester、英国、M20 2BX
- Novartis Investigative Site
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Madrid、西班牙、28050
- Novartis Investigative Site
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Madrid、西班牙、28009
- Novartis Investigative Site
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Seville、西班牙、41013
- Novartis Investigative Site
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Valencia、西班牙、46010
- Novartis Investigative Site
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Seoul、韩国、03080
- Novartis Investigative Site
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：随机化
- 介入模型：并行分配
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
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实验性的：LEE011 + letrozole Arm 1
LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day |
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4. Letrozole 2.5 mg/day |
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实验性的：BYL719 + letrozole Arm 2
BYL719 - daily (dose escalating) letrozole - 2.5 mg/day |
Letrozole 2.5 mg/day BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4 |
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实验性的：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 |
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4. Letrozole 2.5 mg/day BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4 |
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实验性的：LEE011+ BYL719+letrozole Arm 4
LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day |
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4. Letrozole 2.5 mg/day BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4 |
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
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剂量限制性毒性 (DLT) 的发生率 - 仅限 lb 期
大体时间：28天
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28天
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Safety and tolerability
大体时间：Average 18 months
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Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity. |
Average 18 months
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PK profiles of LEE011 and letrozole
大体时间：18 months
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To characterize PK profiles of LEE011 and Letrozole. |
18 months
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
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Safety and tolerability of LEE011 in combination with letrozole, BYL719 in combination with letrozole, and the triple combination of LEE011 +BYL719 with letrozole
大体时间：Average 24 months
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Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
Average 24 months
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Plasma concentration-time profiles of LEE011, BYL719 and letrozole
大体时间：Average 24 months
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To characterize the PK profiles of LEE011, BYL719, and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. |
Average 24 months
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Overall Response Rate (ORR)
大体时间：Average 24 months
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ORR is defined as the proportion of patients with a best overall response of complete response or partial response. |
Average 24 months
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Duration of Response (DOR)
大体时间：Average 24 months
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DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer. |
Average 24 months
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Progression Free Survival (PFS)
大体时间：Average 24 months
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PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. |
Average 24 months
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Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc)
大体时间：Average 24 months
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To characterize the PK profiles of LEE011, BYL719, and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. |
Average 24 months
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Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet
大体时间：Average 24 months
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Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
Average 24 months
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合作者和调查者
调查人员
- 研究主任：Novartis Pharmaceuticals、Novartis Pharmaceuticals
出版物和有用的链接
一般刊物
- Ji Y, Yartsev V, Quinlan M, Serra P, Wang Y, Chakraborty A, Miller M. Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials. Clin Pharmacokinet. 2023 Mar;62(3):493-504. doi: 10.1007/s40262-022-01206-2. Epub 2023 Feb 17.
- Ji Y, Wang C, Combes FP, Ho YY, Fasching PA, Untch M, Zarate JP, Crown J. Quantitative Pharmacology Justifying Ribociclib Dose in Early Breast Cancer. Clin Pharmacokinet. 2026 Aug;65(8):1217-1228. doi: 10.1007/s40262-026-01643-3. Epub 2026 Jun 23.
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (估计的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
关键字
其他相关的 MeSH 术语
其他研究编号
- CLEE011X2107
- 2023-509511-84-00 (注册表标识符：EU CT Number)
- 2023 (美国 NIH 拨款/合同)
计划个人参与者数据 (IPD)
计划共享个人参与者数据 (IPD)？
IPD 计划说明
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
药物和器械信息、研究文件
研究美国 FDA 监管的药品
研究美国 FDA 监管的设备产品
此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.