A Randomized Trial With Factorial Design Comparing Fulvestrant ± Lapatinib ± Aromatase Inhibitor in Metastatic Breast Cancer Progressing After Aromatase Inhibitor Therapy
试验速览
- 阶段
- 3 期
- 入组人数
- 396
- 试验地点
- 69
- 主要终点
- Progression Free Survival
研究概览
简要总结
Based on these results it can be envisioned that the majority of endocrine-responsive post-menopausal breast cancer patients will be treated with an AI as adjuvant therapy (front-line, switching or extending) and/or as first-line management of metastatic breast cancer.
详细描述
In presence of ER hypersensitivity even a small amount of ER may be sufficient for sustained growth signalling. On the other hand, ER disruption operated by fulvestrant is not complete, particularly in the initial phase of treatment. From phase III trials, indeed, The invertigators know that with the standard 250mg monthly dose the steady state of circulating drug is reached only after 5-6 injections. This may play a role since, as long as ER downregulation is concerned, a clear dose-response relationship has been reported. In such a situation, fulvestrant efficacy may be partial, particularly because the concomitant AI discharge yields a restoration of physiologic postmenopausal levels of circulating oestrogens. New dosing schedule are currently under investigation both to accelerate the achievement of the steady state (loading dose) and to achieve higher circulating drug levels (high dose) (86).
In this trial the investigators will be using the so-called 'loading dose'.
Further potential strategies to improve fulvestrant efficacy in this setting are:
A) avoid the restoration of circulating oestrogens; B) interfere with molecular mechanisms that produce ER hypersensitivity by targeting the EGFR/ERBB2/ERB3 system.
A) avoid the restoration of circulating oestrogens: this should be achieved by holding the AI treatment. Because some cases of progression upon AIs may be related to an inefficient inhibition of the aromatase it is a logical step to test whether changing AI class (from type I, steroidal, to type II, non steroidal, and vice-versa) (87), may improve fulvestrant efficay. In this view, pts in this trial will be randomized to receive fulvestrant (loading dose) with or without the alternate class AI treatment. Circulating oestrogens levels will be tracked to verify inhibition of aromatase for pts assigned to concurrent AI treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 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
- Female
- 接受健康志愿者
- 否
入选标准
- •Provision of written informed consent
- •Histological/cytological confirmation of breast cancer
- •Documented positive hormone receptor status (ER+ve and/or PgR+ve) of primary or metastaic tumor issue, according to the local laboratory parameters
- •Postmenopausal women
- •Confirmed progression of disease after an adjuvant therapy or a therapy for metastatic disease with an aromatase inhibitors
- •Patients demonstrating prior response to AI therapy
- •Patients with measurable disease as per RECIST criteria /Patients with bone lesions, lytic or mixed (lytic + sclerotic), in the absence of measurable disease as defined by RECIST criteria.
- •May have received prior radiotherapy as treatment for primary or metastatic tumour; however, is not required for study entry;
- •Life expectancy of at least 8 months
- •WHO performance status 0, 1 or 2
- •Patients with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence.
- •Are able to swallow and retain oral medication;
- •Are able to complete all screening assessments as outlined in the protocol;
- •Patients must have normal organ and marrow function
- •Left ventricular ejection fraction (LVEF) within the institutional normal range
排除标准
- •Previous therapy with Fulvestrant and/or Lapatinib;
- •Patients with HER 2 overexpressing, either IHC 3+ or FISH +;
- •Concurrent non study anti-cancer therapy (
- •Have unresolved or unstable, serious toxicity from prior administration
- •Have malabsorption syndrome,
- •Have a concurrent disease or condition that would make the patient inappropriate for study participation,
- •Have an active or uncontrolled infection;
- •Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;
- •Have a known history of uncontrolled or symptomatic angina, arrhythmias, or CHF;
- •Receive concurrent treatment with an investigational agent or participate in another clinical trial;
- •Receive concurrent treatment with prohibited medications
- •Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication;
- •Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to fulvestrant, aromatase inhibitors or lapatinib or excipients.
研究组 & 干预措施
ARM 1
Fulvestrant + Placebo Lapatinib
干预措施: Fulvestrant (Drug)
ARM 1
Fulvestrant + Placebo Lapatinib
干预措施: Placebo Lapatinib (Drug)
ARM 2
Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib
干预措施: Fulvestrant (Drug)
ARM 2
Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib
干预措施: Aromatase Inhibitors (Drug)
ARM 2
Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib
干预措施: Placebo Lapatinib (Drug)
ARM 3
Fulvestrant + Lapatinib
干预措施: Fulvestrant (Drug)
ARM 3
Fulvestrant + Lapatinib
干预措施: Lapatinib (Drug)
ARM 4
Fulvestrant + Lapatinib + Aromatase Inhibitors
干预措施: Fulvestrant (Drug)
ARM 4
Fulvestrant + Lapatinib + Aromatase Inhibitors
干预措施: Lapatinib (Drug)
ARM 4
Fulvestrant + Lapatinib + Aromatase Inhibitors
干预措施: Aromatase Inhibitors (Drug)
结局指标
主要结局
Progression Free Survival
时间窗: Defined as the time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first assessed up to 12 months
Progression free survival (PFS): it is defined as the time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first.
次要结局
- Clinical Benefit Rate(Defined as the time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first assessed up to 6 months)
- Safety as measured by expected and Non-expected toxicity events(Defined as the time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first assessed up to 12 months)
- Time To Progression(Defined as the time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first assessed up to 12 months)
- Overall Survival(Defined as the time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first assessed up to 12 months)
- Response Rate:(Defined as the time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first assessed up to 12 months)
- Safety assessed by number of Participants with Adverse Events(time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first assessed up to 12 months)