A Randomized Double-blind, Placebo-controlled Study of LEE011 in Combination With Letrozole for the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative, Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 668
- 试验地点
- 71
- 主要终点
- Progression Free Survival (PFS) by Investigator Assessment
研究概览
简要总结
The primary purpose of this study was to assess the efficacy of ribociclib, as measured by progression free survival (PFS), in postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who received no prior treatment for advanced disease.
详细描述
This was an international, multi-center, randomized, double-blinded, placebo controlled Phase III trial to determine the efficacy and safety of treatment with ribociclib plus letrozole versus placebo plus letrozole in postmenopausal women with HR+, HER2-negative advanced breast cancer who received no prior therapy for advanced disease.
Eligible patients were randomized in 1:1 ratio to either ribociclib group or placebo group. Study treatment continued until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.
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 (post-treatment efficacy follow-up).
All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached.
Following the final OS analysis (performed when approximately 400 deaths were recorded) and with protocol amendment 10 (dated 30-Apr-2021), participants and investigators were unblinded and those participants in the placebo arm had the opportunity to cross-over to the ribociclib arm to receive ribociclib plus letrozole. Cross-over was optional and was conducted at the investigator's discretion and upon participant 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 100 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Women with advanced (locoregionally recurrent or metastatic) breast cancer that was not amenable to curative therapy.
- •The patient was postmenopausal. Postmenopausal status was defined either by:
- •Prior bilateral oophorectomy
- •Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range.
- •There was no prior systemic anti-cancer therapy for advanced disease.
- •The patient had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by the local laboratory.
- •The patient had HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC was 2+, a negative in situ hybridization (FISH, CISH, or SISH) test was required by local laboratory testing.
- •The patient must have had either:
- •Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria (Tumor lesions previously irradiated or subjected to other locoregional therapy were considered measurable if disease progression at the treated site after completion of therapy was clearly documented). OR If no measurable disease was present, then at least one predominantly lytic bone lesion must have been present (Patients with no measurable disease and only one predominantly lytic bone lesion previously irradiated were eligible if there was documented evidence of disease progression of the bone lesion after irradiation).
- •The patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
排除标准
- •The patient had received any CDK4/6 inhibitor.
- •The patient had received any prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy) for advanced breast cancer.
- •Patients who had received (neo) adjuvant therapy for breast cancer were eligible. If the prior neo (adjuvant) therapy included letrozole or anastrozole, the disease-free interval had to be greater than 12 months from the completion of treatment until randomization.
- •Patients who had received ≤ 14 days of letrozole or anastrozole for advanced disease prior to randomization were eligible.
- •Any prior (neo) adjuvant anti-cancer therapy had to be stopped at least 5 half-lives or 7 days, whichever was longer, before randomization.
- •The patient was concurrently using other anti-cancer therapy.
- •The patient had a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.
- •The patient had active cardiac disease or a history of cardiac dysfunction, including any of the following:
- •History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry.
- •History of documented congestive heart failure (New York Heart Association functional classification III-IV).
- •Documented cardiomyopathy.
- •The patient had a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
- •History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months.
- •On screening, any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec.
- •Systolic blood pressure >160 or <90 mmHg.
- •The patient was currently receiving any of the following medications and could not be discontinued 7 days prior to the start of treatment:
- •Medications known to be strong inducers or inhibitors of CYP3A
- •Medications known to have a risk of prolonging the QT interval or inducing Torsades de Pointes.
- •Medications with a narrow therapeutic window and predominantly metabolized through CYP3A
- •Herbal preparations/medications.
研究组 & 干预措施
Ribociclib+ letrozole
Ribociclib 600 mg daily oral (3 weeks on/ 1 week off) in combination with letrozole 2.5 mg daily oral
干预措施: Ribociclib (Drug)
Ribociclib+ letrozole
Ribociclib 600 mg daily oral (3 weeks on/ 1 week off) in combination with letrozole 2.5 mg daily oral
干预措施: Letrozole (Drug)
Placebo + letrozole
Placebo daily oral (3 weeks on/ 1 week off) in combination with letrozole 2.5 mg daily oral.
Participants were unblinded once the final OS analysis was completed and after the implementation of protocol amendment 10 (30-Apr-21) and were given the option to crossover to treatment with ribociclib + letrozole
干预措施: Letrozole (Drug)
Placebo + letrozole
Placebo daily oral (3 weeks on/ 1 week off) in combination with letrozole 2.5 mg daily oral.
Participants were unblinded once the final OS analysis was completed and after the implementation of protocol amendment 10 (30-Apr-21) and were given the option to crossover to treatment with ribociclib + letrozole
干预措施: Placebo (Drug)
结局指标
主要结局
Progression Free Survival (PFS) by Investigator Assessment
时间窗: Up to 23 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 by investigator 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. A stratified Cox regression model was used to estimate the hazard ratio of PFS, along with 95% confidence interval
次要结局
- Overall Survival (OS)(Up to approximately 87 months)
- Overall Response Rate (ORR) by Investigator Assessment(Up to 23 months)
- Clinical Benefit Rate (CBR) by Investigator Assessment(Up to 23 months)
- Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score(From baseline up to 23 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)(From baseline up to 23 months)
- Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30(Baseline, every 2 cycles for 18 months, then every 3 cycles until last dose; at EOT (within 15 days from last dose);every 8 or 12 weeks post-treatment until progression (post-treatment efficacy visits), assessed up to 23 months. Cycle=28 days)