A Randomized Double-blind, Placebo-controlled Study of Ribociclib in Combination With Fulvestrant for the Treatment of Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer Who Have Received no or Only One Line of Prior Endocrine Treatment
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 726
- 试验地点
- 27
- 主要终点
- Progression Free Survival (PFS) Per Investigator Assessment
研究概览
简要总结
The main aim of this study was to evaluate the efficacy and safety of adding ribociclib to fulvestrant in men and postmenopausal women with hormone receptor positive (HR+), HER2-negative advanced breast cancer.
详细描述
This study was a randomized, phase III, double-blind, placebo-controlled international trial aimed at determining the efficacy and safety of treatment with fulvestrant in combination with ribociclib compared to fulvestrant with placebo in men and postmenopausal women diagnosed with HR+, HER2-negative advanced breast cancer. The study comprised four phases: screening (up to 28 days), randomized treatment, post-treatment disease progression follow-up, and post-treatment survival follow-up.
Enrolled participants were randomly assigned to receive either fulvestrant+ribociclib or fulvestrant+placebo in a ratio of 2:1. The randomization process was stratified based on the presence of liver and/or lung metastases (yes versus no) and prior endocrine therapy. Treatment was administered until disease progression, occurrence of unacceptable toxicity, or discontinuation from the study treatment for other reasons.
Participants who discontinued treatment due to reasons other than disease progression or withdrawal of consent for efficacy follow-up continued to be monitored until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision.
All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached.
A protocol amendment 4 (dated 29-Jan-2020) allowed for unblinding of study participants, and those still receiving placebo had the option to switch to the ribociclib arm. The decision for crossover was made at the investigator's discretion and required patient consent.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Patients were adults, both male and female, aged ≥ 18 years at the time of providing informed consent. Female patients were required to be postmenopausal. Informed consent was obtained prior to any trial-related activities, following local guidelines.
- •Patients had a confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer, determined through histological and/or cytological examination by a local laboratory. Patients also had HER2-negative breast cancer.
- •Patients had either measurable disease as per RECIST 1.1 criteria or at least one predominantly lytic bone lesion.
- •Patients had advanced breast cancer, which included locoregionally recurrent disease not amenable to curative therapies (such as surgery or radiotherapy) or metastatic breast cancer. Patients fell into one of the following categories:
- •Newly diagnosed with advanced/metastatic breast cancer and treatment-naïve.
- •Relapsed with documented evidence of relapse more than 12 months after completing (neo)adjuvant endocrine therapy, without any prior treatment for advanced/metastatic disease.
- •Relapsed with documented evidence of relapse on or within 12 months from completing (neo)adjuvant endocrine therapy, without any prior treatment for advanced/metastatic disease.
- •Relapsed with documented evidence of relapse more than 12 months after completing adjuvant endocrine therapy and subsequently progressed after receiving one line of endocrine therapy (antiestrogen or aromatase inhibitor) for advanced/metastatic disease.
- •Newly diagnosed with advanced/metastatic breast cancer at diagnosis and progressed after receiving one line of endocrine therapy (antiestrogen or aromatase inhibitor), with documented evidence of progression.
- •Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Patients had adequate bone marrow and organ function.
排除标准
- •Patients with symptomatic visceral disease or disease burden that rendered them ineligible for endocrine therapy, based on the investigator's judgment.
- •Patients who had received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), fulvestrant, or any CDK4/6 inhibitor.
- •Patients with inflammatory breast cancer at the screening stage.
- •Patients with central nervous system (CNS) involvement, unless they were at least 4 weeks from completing prior therapy before initiating the study treatment and had a stable CNS tumor at the time of screening. They were also required not to be receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases.
- •Patients with clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
- •Patients who were currently receiving any of the following substances, which could not be discontinued 7 days prior to initiating treatment:
- •Known strong inducers or inhibitors of CYP3A4/
- •Substances with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
- •Substances with a narrow therapeutic window and predominantly metabolized through CYP3A4/
- •Herbal preparations/medications, dietary supplements.
研究组 & 干预措施
Ribociclib + fulvestrant
Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment.
干预措施: Ribociclib (Drug)
Ribociclib + fulvestrant
Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment.
干预措施: Fulvestrant (Drug)
Placebo + fulvestrant
Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment.
Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant.
干预措施: Fulvestrant (Drug)
Placebo + fulvestrant
Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment.
Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant.
干预措施: Placebo (Drug)
结局指标
主要结局
Progression Free Survival (PFS) Per Investigator Assessment
时间窗: From randomization to first documented progression or death, assessed up to approximately 26 months
PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via local radiology assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. The distribution of PFS between the two arms was compared using a stratified log-rank test at a one-sided 2.5% level of significance. The PFS hazard ratio with two-sided 95% confidence interval was derived from the stratified Cox proportional hazards model.
次要结局
- Overall Survival (OS)(From randomization to death, assessed up to approximately 46 months)
- Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) in One Score Category(Up to approximately 26 months)
- Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30(Baseline, every 8 weeks after randomization during 18 months, then every 12 weeks up to end of treatment; end of treatment; and every 8 or 12 weeks post-treatment until progression (post-treatment efficacy visits), assessed up to approximately 26 months)
- Time to Response (TTR) Per Investigator Assessment(From randomization to first response, assessed up to approximately 26 months)
- Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC)(From randomization to first documented progression or death, assessed up to approximately 26 months)
- Overall Response Rate (ORR) Per Investigator Assessment(Up to approximately 26 months)
- Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)(Up to approximately 26 months)
- Ribociclib Plasma Concentrations(Cycle 1 and Cycle 2 at Day 15 pre-dose and at 2, 4, and 6 hours post-dose. Cycle=28 days)
- Clinical Benefit Rate (CBR) Per Investigator Assessment(Up to approximately 26 months)
- Duration of Response (DOR) Per Investigator Assessment(From first documented response to progression or death, assessed up to approximately 26 months)
- LEQ803 Plasma Concentrations(Cycle 1 and Cycle 2 at Day 15 pre-dose and at 2, 4, and 6 hours post-dose. Cycle = 28 days)