A Phase III, Double-blind, Randomised Study to Assess Switching to AZD9833 (a Next Generation, Oral SERD) + CDK4/6 Inhibitor vs Continuing Aromatase Inhibitor (Letrozole or Anastrozole)+ CDK4/6 Inhibitor in HR+/HER2-MBC Patients With Detectable ESR1Mutation Without Disease Progression During 1L Treatment With Aromatase Inhibitor+ CDK4/6 Inhibitor- A ctDNA Guided Early Switch Study
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 315
- 试验地点
- 265
- 主要终点
- Progression-free survival (PFS) assessed by the Investigator as defined by response evaluation criteria in solid tumors (RECIST version 1.1)
研究概览
简要总结
The study is intended to show superiority of AZD9833 in combination with CDK4/6 inhibitor (palbociclib, abemaciclib or ribociclib) versus aromatase inhibitors (anastrozole or letrozole) in combination with CDK4/6 inhibitor in patients with hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) metastatic breast cancer with detectable ESR1 mutation.
详细描述
Breast cancer is the most common type of cancer among women. In people with breast cancer, the body is not able to control the growth of some cells. These extra cells can form tumors in the breast. When tumor cells move to different parts of the body this is called advanced cancer. Researchers are looking for better ways to treat advanced breast cancer.
This trial will look at six drugs: palbociclib, abemaciclib, ribociclib, letrozole, anastrozole, and AZD9833. AZD9833 is the trial drug, and is the only drug not yet approved for use. Palbociclib, abemaciclib and ribociclib work in the same way and are a type of cancer drug called a CDK4/6 inhibitor. Letrozole and anastrozole work in the same way and are both a type of cancer drug called an aromatase inhibitor (AI). CDK4/6 inhibitors and AIs work together to block the tumor's ability to grow. These drugs have been approved for combined use in people with advanced breast cancer that is HR-positive and HER2-negative. But if people get mutations in the ESR1 gene, it can make the AI and CDK4/6 inhibitor treatment work less well.
The trial drug, AZD9833, is designed to work with a CDK4/6 inhibitor in the same way that an AI does. Researchers think that AZD9833 might work better with a CDK4/6 inhibitor than an AI does in people who get mutations in their ESR1 gene.
Participants in this trial will have already been receiving one of the following combinations of a CDK4/6 inhibitor and an AI:
- palbociclib + anastrozole
- palbociclib + letrozole
- abemaciclib + anastrozole
- abemaciclib + letrozole
- ribociclib + anastrozole
- ribociclib + letrozole
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INFORMATION FOR TRIAL PARTICIPANTS - Participants can join the trial if they:
- •Have advanced breast cancer that is not able to be treated with surgery or radiation;
- •Have an ESR1 mutation in their cancer;
- •Have breast cancer that is HR-positive and HER2-negative;
- •Are currently being treated with a CDK4/6 inhibitor and an AI and have been taking these drugs for at least 6 months;
- •Have not had their cancer get worse after taking an AI and CDK4/6 inhibitor;
- •Are able to do their daily activities;
- •Are at least
- •Full list of inclusion criteria:
- •Proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent;
- •Documentation of histologically confirmed diagnosis of estrogen receptor positive (ER+) /HER2- breast cancer based on local laboratory results;
- •Currently on AI (letrozole or anastrozole) + CDK4/6 inhibitor (palbociclib, abemaciclib or ribociclib) ± LHRH as the initial endocrine based treatment for advanced disease;
- •Eastern Cooperative Oncology Group performance status of 0 or 1;
- •ESR1m detected by central testing of ctDNA with Guardant360® CDx;
- •Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
- •Adequate organ and marrow function.
排除标准
- •INFORMATION FOR TRIAL PARTICIPANTS - Participants cannot join the trial if they:
- •Had certain types of tumors in the past that may come back;
- •Are currently taking any other treatments for their cancer or other conditions including hormone replacements, medications, or supplements that could interfere with the trial treatment;
- •Have or have had any major health problem, infection, or recent surgery that could make it difficult or dangerous to participate in this trial.
- •Full list of exclusion criteria:
- •Advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term;
- •Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease;
- •Any evidence of severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol;
- •Patient with known or family history of severe heart disease;
- •Previous treatment with AZD9833, investigational SERDs or fulvestrant;
- •Currently pregnant (confirmed with positive pregnancy test) or breastfeeding;
- •Persistent non-haematological toxicities (CTCAE Grade > 2) caused by CDK4/6 inhibitor and/or AI treatment.
研究组 & 干预措施
Anastrozole or letrozole + palbociclib, abemaciclib or ribociclib
The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150, 100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + AZD9833 placebo (PO, once daily)
干预措施: Abemaciclib (Drug)
Anastrozole or letrozole + palbociclib, abemaciclib or ribociclib
The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150, 100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + AZD9833 placebo (PO, once daily)
干预措施: Luteinizing hormone-releasing hormone (LHRH) agonist (Drug)
AZD9833 + palbociclib, abemaciclib or ribociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150,100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (PO, once daily) or letrozole placebo (PO, once daily)
干预措施: Luteinizing hormone-releasing hormone (LHRH) agonist (Drug)
Anastrozole or letrozole + palbociclib, abemaciclib or ribociclib
The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150, 100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + AZD9833 placebo (PO, once daily)
干预措施: AZD9833 Placebo (Drug)
AZD9833 + palbociclib, abemaciclib or ribociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150,100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (PO, once daily) or letrozole placebo (PO, once daily)
干预措施: AZD9833 (Drug)
AZD9833 + palbociclib, abemaciclib or ribociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150,100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (PO, once daily) or letrozole placebo (PO, once daily)
干预措施: Anastrozole placebo (Drug)
AZD9833 + palbociclib, abemaciclib or ribociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150,100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (PO, once daily) or letrozole placebo (PO, once daily)
干预措施: Letrozole placebo (Drug)
AZD9833 + palbociclib, abemaciclib or ribociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150,100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (PO, once daily) or letrozole placebo (PO, once daily)
干预措施: Palbociclib (Drug)
AZD9833 + palbociclib, abemaciclib or ribociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150,100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (PO, once daily) or letrozole placebo (PO, once daily)
干预措施: Abemaciclib (Drug)
AZD9833 + palbociclib, abemaciclib or ribociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150,100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (PO, once daily) or letrozole placebo (PO, once daily)
干预措施: Ribociclib (Drug)
Anastrozole or letrozole + palbociclib, abemaciclib or ribociclib
The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150, 100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + AZD9833 placebo (PO, once daily)
干预措施: Anastrozole (Drug)
Anastrozole or letrozole + palbociclib, abemaciclib or ribociclib
The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150, 100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + AZD9833 placebo (PO, once daily)
干预措施: Letrozole (Drug)
Anastrozole or letrozole + palbociclib, abemaciclib or ribociclib
The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150, 100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + AZD9833 placebo (PO, once daily)
干预措施: Palbociclib (Drug)
Anastrozole or letrozole + palbociclib, abemaciclib or ribociclib
The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment), abemaciclib (PO, twice daily, 150, 100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + AZD9833 placebo (PO, once daily)
干预措施: Ribociclib (Drug)
结局指标
主要结局
Progression-free survival (PFS) assessed by the Investigator as defined by response evaluation criteria in solid tumors (RECIST version 1.1)
时间窗: From randomization until the earlier of the progression event or death (approximately 2 years)
PFS is defined as the time from randomization to objective disease progression (as assessed by RECIST 1.1) or death.
次要结局
- Progression-free survival 2 (PFS2)(From randomization to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy or death (approximately 3.5 years))
- Overall survival (OS)(From randomization until the date of death due to any cause (approximately 5 years))
- Chemotherapy free survival(From randomization until the earlier of the start date of chemotherapy or death due to any cause (approximately 5 years))
- Objective response rate (ORR) assessed by the Investigator as defined by RECIST version 1.1(From randomization until a response or in the absence of a response from randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 5 years))
- Change from baseline in EORTC QLQ-C30 scale scores(From baseline until second progression (approximately 5 years))
- Clinical benefit rate at 24 weeks (CBR24)(At least 23 weeks after randomisation for each patient (1 week window for RECIST assessment))
- Change from baseline in EORTC QLQ-BR23 scale scores(From baseline until second progression (approximately 5 years))
- Plasma concentration of AZD9833 at specified timepoints(on Day 15 for each patient)