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

NCT01477060 | Terminated Phase 2

• 2 other identifiers: CROLT/022011-000155-16
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 11

Brief Summary

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 :
• 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.
• 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.

Conditions

Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Rate of patients free from disease progression

  3 months from randomization

Secondary Outcomes (5)

• overall response rate

  3 years

• Progression Free Survival

  3 years

• Time to progression

  3 years

• Overall survival

  3 years

• Number of participants with toxicities as a measure of tolerability of each proposed treatment

  3 years

Study Arms (3)

ARM A - Lapatinib

OTHER

hormonal therapy + lapatinib (1250mg/die) until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent.

Drug: Lapatinib

ARM B - Metformin

OTHER

Hormonal therapy + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent.

Drug: Metformin

ARM C - Lapatinib + Metformin

OTHER

Hormonal therapy + lapatinib + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent.

Drug: Lapatinib; Drug: Metformin

Interventions

Lapatinib DRUG

1250 mg/ die, os

ARM A - Lapatinib; ARM C - Lapatinib + Metformin

Metformin DRUG

1500 mg/die, os

ARM B - Metformin; ARM C - Lapatinib + Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Fondazione Michelangelo: lead

Study Sites (11)

Cliniche Gavazzeni S.p.A. - Humanitas Gavazzeni

Bergamo, BG, 24125, Italy

Location

Fondazione Poliambulanza

Brescia, BS, 25124, Italy

Location

Azienda Ospedaliera San Gerardo

Monza, MB, 20052, Italy

Location

Azienda Ospedaliera "G. Salvini" - P.O. Garbagnate Milanese

Garbagnate Milanese, MI, 20020, Italy

Location

Ospedale Civile Di Legnano

Legnano, MI, 20025, Italy

Location

IRCCS Fondazione San Raffaele Monte Tabor

Milan, MI, 20132, Italy

Location

IRCCS Istituto Nazionale dei Tumori

Milan, MI, 20133, Italy

Location

Azienda Ospedaliera Ospedale Ca' Granda

Milan, MI, 20162, Italy

Location

Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione - Reparto Riabilitazione Oncologica

Pavia, PV, 27100, Italy

Location

Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione - U.O. Oncologia

Pavia, PV, 27100, Italy

Location

Azienda Ospedaliera della Valtellina e della Valchiavenna - P.O. Sondrio

Sondrio, SO, 23100, Italy

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Lapatinib; Metformin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Milvia Zambetti, MD

  Ospedale San Raffaele

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2011
• First Posted: November 22, 2011
• Study Start: November 1, 2011
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2013
• Last Updated: February 20, 2014

Record last verified: 2014-02

Locations

IT (11)