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

Study Overview
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Brief Summary
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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 Doubleactivation, 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 : To assess the overall response rate To assess the duration of response To assess 3-years overall survival rate 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.

Detailed Description
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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.

Official Title
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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

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Lapatinib
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients with a histologically or cytologically confirmed adenocarcinoma of the breast progressing from prior hormonal therapy Receptor positive disease (ER+ and/or PgR+) HER2 negative Pre- and post-menopausal status Documented disease progression after first-line hormone therapy Age ≥18 years. Measurable or evaluable metastatic disease Life expectancy > 3 months ECOG Performance Status < 1 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 Normal Respiratory Function and Saturation level ≥ 90% New York Hearth Association (NYHA) Classification ≤ 2 and baseline left ventricular ejection fraction (LVEF)≥ 50% Patients must be willing and able to sign a written informed consent. Exclusion Criteria: Previous or concomitant treatment with lapatinib and/or metformin More than one line of prior hormone therapy for metastatic breast cancer. More than two lines of prior chemotherapy for metastatic breast cancer Unique location of disease local-regionally treated (surgery, radiotherapy , other) Disease progression not documented or less than 30% 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) Patients with brain metastasis Osteosclerotic bone metastasis as unique disease site Pathological tumor markers as unique sign of progressive disease Concomitant treatment with any other anticancer drugs (biphosphonates are permitted) Serious, not solved or unstable toxicity from previous treatment Diabetes mellitus Type I and Type II Renal insufficiency (creatinine ≥ 1.4 mg/ml) Malabsorption syndrome or diseases that significantly may alter gastroenteric functions 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 Active clinically significant or uncontrolled infections (bacterial or viral) 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 History of lactic acidosis Evidence or symptoms of hepatic insufficiency Chronic alcoholism Concomitant treatment with amiodarone or any other agent that could interfere with study drugs Known or suspected hypersensitivity or allergy to lapatinib, metformin or used excipients Women who are pregnant or lactating History of previous cancer, unless at low risk of relapse per investigator's judgement

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: ARM A - Lapatinib<br>hormonal therapy + lapatinib (1250mg/die) until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent. | Drug: Lapatinib<br>* 1250 mg/ die, os<br>|
| Other: ARM B - Metformin<br>Hormonal therapy + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent. | Drug: Metformin<br>* 1500 mg/die, os<br>|
| Other: ARM C - Lapatinib + Metformin<br>Hormonal therapy + lapatinib + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent. | Drug: Lapatinib<br>* 1250 mg/ die, os<br>Drug: Metformin<br>* 1500 mg/die, os<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients free from disease progression |  | 3 months from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate |  | 3 years | 
| Progression Free Survival |  | 3 years | 
| Time to progression |  | 3 years | 
| Overall survival | To assess 3-years overall survival rate | 3 years | 
| Number of participants with toxicities as a measure of tolerability of each proposed treatment |  | 3 years |