此页面是自动翻译的，不保证翻译的准确性。请参阅 英文版 对于源文本。

Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With Metastatic Breast Cancer

2014年2月19日 更新者：Fondazione Michelangelo

Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With HER2-negative, ER and/or PgR Positive Metastatic Brest Cancer With Progressive Disease After First-line Therapy

Target Population: female patients with HER2-negative, ER and/or PgR positive breast cancer in progression after first-line hormonal therapy.

The study rationale is based on the potentiality of reversing endocrine-resistance by Lapatinib

  • Activity on compensatory-adaptive mechanisms of hyperactivity of signals generated by HER2 family
  • Modulation of energy balance and signals associated to survival through AMPK activation (via Calmodulin) Metformin
  • Indirect mechanism, through reduced insulin receptors and IGFR stimulation, with reduces proliferative effects downstream
  • Direct mechanism, through AMPK activation (via LKB1), with reduced protein synthesis (mTOR inhibition) and increased availability of intracellular energy Lapatinib and Metformin
  • AMPK "Double"activation, through different potentially additional mechanisms.

  • Inhibition of proliferative mechanisms for interference on various intracellular target

    • IR (A e/o B); IGFR
    • EGFR; HER2

Primary objectives :

1. To assess the rate of patients free from disease progression at 3 months from randomization

Secondary objectives :

  1. To assess the overall response rate
  2. To assess the duration of response
  3. To assess 3-years overall survival rate
  4. To assess tolerability of each proposed treatment Female patients with HER2-negative, ER and/or PgR positive breast cancer in progression after first-line hormonal therapy will randomized to receive: hormonal therapy + lapatinib or hormonal therapy + metformin or hormonal therapy + metformin + lapatinib with a ratio 1:1:1.

For each arm of the study the following sample size is required:

  • First step: 23 patients, for a total of 69 patients in all 3 arms
  • Second step: further 33 patients, for a total of 168 patients in all 3 arms.

研究概览

地位

终止

条件

干预/治疗

详细说明

Treatment Plan Patient will continue to be treated with the same hormone therapy at the same dose, route and schedule

Patients will be randomized to receive:

A: Lapatinib, 1250 mg/die, os B: Metformin, 1500 mg/die, os C: Lapatinib + Metformin, 1250 mg+1500 mg/die, os Patients will receive study treatment until disease progression is documented, extraordinary medical circumstances occur, intolerable toxicities occur, or the patient withdraws consent

Statistical consideration Randomization will be stratified according to the site of metastases: visceral versus non-visceral lesions. The primary objective of this study is to evaluate the rate of patients free of disease progression at 3 months from randomization. The final analysis of this objective will be conducted when a total of 168 patients are enrolled across the three arms. This is the number of patients needed for a test with an experiment-wise alpha = 0.05 and power = 80% to show a statistically significant increment of 10% to the rate of patients without disease progression at 3 months, assuming a rate of 5% for treatments without lapatinib and/or metformin (P0=5% and P1=15%). After having accrued a total of 23 evaluable patients in each arm, the trial design can proceed to step 2 randomizing additional patients to each arm only if two or more patients are free of disease progression at 3 months. Otherwise, the study arm with less than expected responses will be discontinued. In the second stage 33 additional patients will be enrolled in each study arm to reach a total of 56 total patients per arm. If less than 6 patients per arm will be free of disease progression then the increment of corresponding treatment will be considered not significant.

Procedures:

The study will consist of a screening period, a treatment period and follow up for survival Screening Phase

Within 4 weeks prior randomization:

A signed written, informed consent will be obtained prior to any study specific assessments are initiated. The following will be performed prior to randomization

  • Radiographic complete assessment of disease status (chest Xray; liver ultrasound, bone scan and CT or MR of target lesions and involved sites)
  • Hematology and biochemistry
  • Pregnancy test for women of child-bearing potential
  • Cardiac assessment with ECG, echocardiography or multi-gated scintigraphic scan (MUGA)
  • Medical history, physical examination, vital signs, signs and symptoms of breast cancer lesions, weight, height, ECOG performance status

Treatment Phase:

MONTHLY up to 3 months since randomization

  • Physical examination, including clinical disease assessment, ECOG performance status, vital signs
  • Hematology and biochemistry
  • Safety evaluation (i.e. routine collection of adverse events)
  • Patient's compliance
  • Concomitant therapy

EVERY 3 MONTHS after the first 3 months of treatment until disease progression is documented, intolerable toxicities occur, or the patient withdraws consent:

  • Physical examination, including clinical disease assessment, ECOG performance status, vital signs
  • Radiographic disease assessment (using the same methods at screening)
  • Hematology and biochemistry
  • Safety evaluation (i.e. routine collection of adverse events)
  • Concomitant therapy
  • Patient's compliance

EVERY 6 MONTHS until disease progression is documented, intolerable toxicities occur, or the patient withdraws consent:

  • Complete radiographic assessment
  • Assessment of the LVEF using the same method at screening

Afterwards:

EVERY 6 MONTHS after disease progression or trial discontinuation due to intolerable toxicities or other reasons. Patients may receive other therapy following study discontinuation. Patients will continue to be followed for survival for a minimum of 3 years.

研究类型

介入性

注册 (实际的)

32

阶段

  • 阶段2

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习地点

  • 意大利
    • BG
      • Bergamo、BG、意大利、24125
        • Cliniche Gavazzeni S.p.A. - Humanitas Gavazzeni
    • BS
      • Brescia、BS、意大利、25124
        • Fondazione Poliambulanza
    • MB
      • Monza、MB、意大利、20052
        • Azienda Ospedaliera San Gerardo
    • MI
      • Garbagnate Milanese、MI、意大利、20020
        • Azienda Ospedaliera "G. Salvini" - P.O. Garbagnate Milanese
      • Legnano、MI、意大利、20025
        • Ospedale Civile di Legnano
      • Milano、MI、意大利、20132
        • IRCCS Fondazione San Raffaele Monte Tabor
      • Milano、MI、意大利、20133
        • IRCCS Istituto Nazionale dei Tumori
      • Milano、MI、意大利、20162
        • Azienda Ospedaliera Ospedale Ca' Granda
    • PV
      • Pavia、PV、意大利、27100
        • Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione - Reparto Riabilitazione Oncologica
      • Pavia、PV、意大利、27100
        • Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione - U.O. Oncologia
    • SO
      • Sondrio、SO、意大利、23100
        • Azienda Ospedaliera della Valtellina e della Valchiavenna - P.O. Sondrio

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

18年 及以上 (成人、年长者)

接受健康志愿者

不

有资格学习的性别

女性

描述

Inclusion Criteria:

  1. Female patients with a histologically or cytologically confirmed adenocarcinoma of the breast progressing from prior hormonal therapy
  2. Receptor positive disease (ER+ and/or PgR+)
  3. HER2 negative
  4. Pre- and post-menopausal status
  5. Documented disease progression after first-line hormone therapy
  6. Age ≥18 years.
  7. Measurable or evaluable metastatic disease
  8. Life expectancy > 3 months
  9. ECOG Performance Status < 1

  10. Adequate bone marrow, liver, and renal function as assessed by the following parameters:

    • Hemoglobin > 9.0 g/dl
    • Leucocytes count ≥ 3,000/mL
    • Absolute neutrophil count (ANC) ≥ 1.500/mL
    • Platelet count ≥ 100,000/mL
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement)
    • Albumine and total bilirubin ≤ 1.5 x ULN
    • Prothrombin Time (PT) < 70 %
    • Serum creatinine < 1.4 mg/ml, creatinine clearance > 70 ml/min
  11. Normal Respiratory Function and Saturation level ≥ 90%
  12. New York Hearth Association (NYHA) Classification ≤ 2 and baseline left ventricular ejection fraction (LVEF)≥ 50%
  13. Patients must be willing and able to sign a written informed consent.

Exclusion Criteria:

  1. Previous or concomitant treatment with lapatinib and/or metformin
  2. More than one line of prior hormone therapy for metastatic breast cancer.
  3. More than two lines of prior chemotherapy for metastatic breast cancer
  4. Unique location of disease local-regionally treated (surgery, radiotherapy , other)
  5. Disease progression not documented or less than 30%
  6. Metastatic disease defined as aggressive at investigator's judgement (e.g. visceral disease more than >1/3 of involved parenchyma, symptomatic disease requiring intensive supportive measures or therapies not allowed by protocol)
  7. Patients with brain metastasis
  8. Osteosclerotic bone metastasis as unique disease site
  9. Pathological tumor markers as unique sign of progressive disease
  10. Concomitant treatment with any other anticancer drugs (biphosphonates are permitted)
  11. Serious, not solved or unstable toxicity from previous treatment
  12. Diabetes mellitus Type I and Type II
  13. Renal insufficiency (creatinine ≥ 1.4 mg/ml)
  14. Malabsorption syndrome or diseases that significantly may alter gastroenteric functions
  15. Other serious illness or medical conditions judged by the investigator to be clinically significant that may adversely affect patient's participation in the trial or interfere with safety profile
  16. Active clinically significant or uncontrolled infections (bacterial or viral)
  17. Known history of unstable angina (angina symptoms at rest), cardiac ventricular arrhythmias clinically significant, myocardial infarction, stroke or congestive heart failure within 12 months prior to randomization
  18. History of lactic acidosis
  19. Evidence or symptoms of hepatic insufficiency
  20. Chronic alcoholism
  21. Concomitant treatment with amiodarone or any other agent that could interfere with study drugs
  22. Known or suspected hypersensitivity or allergy to lapatinib, metformin or used excipients
  23. Women who are pregnant or lactating
  24. History of previous cancer, unless at low risk of relapse per investigator's judgement

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

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
其他：ARM A - Lapatinib
hormonal therapy + lapatinib (1250mg/die) until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent.
药品：Lapatinib
1250 mg/ die, os
其他：ARM B - Metformin
Hormonal therapy + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent.
药品：Metformin
1500 mg/die, os
其他：ARM C - Lapatinib + Metformin
Hormonal therapy + lapatinib + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent.
药品：Lapatinib
1250 mg/ die, os
药品：Metformin
1500 mg/die, os

研究衡量的是什么？

主要结果指标

结果测量
大体时间
Rate of patients free from disease progression
大体时间：3 months from randomization
3 months from randomization

次要结果测量

结果测量
措施说明
大体时间
无进展生存期
大体时间：3年
3年
进展时间
大体时间：3年
3年
overall response rate
大体时间：3 years
3 years
Overall survival
大体时间：3 years
To assess 3-years overall survival rate
3 years
Number of participants with toxicities as a measure of tolerability of each proposed treatment
大体时间：3 years
3 years

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

Fondazione Michelangelo

调查人员

  • 首席研究员：Milvia Zambetti, MD、Ospedale San Raffaele

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始

2011年11月1日

初级完成 (实际的)

2013年12月1日

研究完成 (实际的)

2013年12月1日

研究注册日期

首次提交

2011年11月16日

首先提交符合 QC 标准的

2011年11月18日

首次发布 (估计)

2011年11月22日

研究记录更新

最后更新发布 (估计)

2014年2月20日

上次提交的符合 QC 标准的更新

2014年2月19日

最后验证

2014年2月1日

更多信息

与本研究相关的术语

其他相关的 MeSH 术语

其他研究编号

  • CROLT/02
  • 2011-000155-16 (EudraCT编号)

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.

订阅