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

This study has been terminated.
(The study was stopped due to insufficient accrual)
Sponsor:
Information provided by (Responsible Party):
Fondazione Michelangelo
ClinicalTrials.gov Identifier:
NCT01477060
First received: November 16, 2011
Last updated: February 19, 2014
Last verified: February 2014
  Purpose

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.

Condition Intervention Phase
Metastatic Breast Cancer
Drug: Lapatinib
Drug: Metformin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Fondazione Michelangelo:

Primary Outcome Measures:
  • Rate of patients free from disease progression [ Time Frame: 3 months from randomization ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • overall response rate [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Progression Free Survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Time to progression [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    To assess 3-years overall survival rate

  • Number of participants with toxicities as a measure of tolerability of each proposed treatment [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Enrollment: 32
Study Start Date: November 2011
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Lapatinib
1250 mg/ die, os
ARM B - Metformin
Hormonal therapy + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent.
Drug: Metformin
1500 mg/die, os
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.
Drug: Lapatinib
1250 mg/ die, os
Drug: Metformin
1500 mg/die, os

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01477060

Locations
Italy
Cliniche Gavazzeni S.p.A. - Humanitas Gavazzeni
Bergamo, BG, Italy, 24125
Fondazione Poliambulanza
Brescia, BS, Italy, 25124
Azienda Ospedaliera San Gerardo
Monza, MB, Italy, 20052
Azienda Ospedaliera "G. Salvini" - P.O. Garbagnate Milanese
Garbagnate Milanese, MI, Italy, 20020
Ospedale Civile Di Legnano
Legnano, MI, Italy, 20025
IRCCS Istituto Nazionale dei Tumori
Milano, MI, Italy, 20133
Azienda Ospedaliera Ospedale Ca' Granda
Milano, MI, Italy, 20162
IRCCS Fondazione San Raffaele Monte Tabor
Milano, MI, Italy, 20132
Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione - U.O. Oncologia
Pavia, PV, Italy, 27100
Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione - Reparto Riabilitazione Oncologica
Pavia, PV, Italy, 27100
Azienda Ospedaliera della Valtellina e della Valchiavenna - P.O. Sondrio
Sondrio, SO, Italy, 23100
Sponsors and Collaborators
Fondazione Michelangelo
Investigators
Principal Investigator: Milvia Zambetti, MD Ospedale San Raffaele
  More Information

No publications provided

Responsible Party: Fondazione Michelangelo
ClinicalTrials.gov Identifier: NCT01477060     History of Changes
Other Study ID Numbers: CROLT/02, 2011-000155-16
Study First Received: November 16, 2011
Last Updated: February 19, 2014
Health Authority: Italy: Ethics Committee

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Metformin
Lapatinib
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 28, 2014