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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.

調査の概要

状態

終了しました

条件

介入・治療

詳細な説明

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.

研究の種類

介入

入学 (実際)

32

段階

  • フェーズ2

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

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

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年歳以上 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

女性

説明

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

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：ランダム化
  • 介入モデル：並列代入
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
他の：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.
薬：Lapatinib
1250 mg/ die, os
他の：ARM B - Metformin
Hormonal therapy + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent.
薬：Metformin
1500 mg/die, os
他の：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.
薬：Lapatinib
1250 mg/ die, os
薬：Metformin
1500 mg/die, os

この研究は何を測定していますか？

主要な結果の測定

結果測定
時間枠
Rate of patients free from disease progression
時間枠：3 months from randomization
3 months from randomization

二次結果の測定

結果測定
メジャーの説明
時間枠
無増悪サバイバル
時間枠：3年
3年
進行までの時間
時間枠：3年
3年
overall response rate
時間枠：3 years
3 years
Overall survival
時間枠：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
時間枠：3 years
3 years

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Fondazione Michelangelo

捜査官

  • 主任研究者：Milvia Zambetti, MD、Ospedale San Raffaele

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始

2011年11月1日

一次修了 (実際)

2013年12月1日

研究の完了 (実際)

2013年12月1日

試験登録日

最初に提出

2011年11月16日

QC基準を満たした最初の提出物

2011年11月18日

最初の投稿 (見積もり)

2011年11月22日

学習記録の更新

投稿された最後の更新 (見積もり)

2014年2月20日

QC基準を満たした最後の更新が送信されました

2014年2月19日

最終確認日

2014年2月1日

詳しくは

本研究に関する用語

追加の関連 MeSH 用語

その他の研究ID番号

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

この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。

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