Metastatic Breast CancerPhase 2NCT01477060
Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With Metastatic Breast Cancer
A Phase 2 study testing Lapatinib and Metformin in people with Metastatic Breast Cancer, run by Fondazione Michelangelo at 11 sites in Italy.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Metastatic Breast Cancer
- What is being tested?
- Lapatinib and Metformin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 11 sitesItaly
- Study dates
- Nov 2011to Dec 2013
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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)
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- 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
Trial locations and contacts
11 sites in 1 country.
11 sites in 1 country
Italy11 sites
Cliniche Gavazzeni S.p.A. - Humanitas Gavazzeni
Bergamo, BG, 24125
Fondazione Poliambulanza
Brescia, BS, 25124
Azienda Ospedaliera "G. Salvini" - P.O. Garbagnate Milanese
Garbagnate Milanese, MI, 20020
Ospedale Civile Di Legnano
Legnano, MI, 20025
IRCCS Fondazione San Raffaele Monte Tabor
Milan, MI, 20132
IRCCS Istituto Nazionale dei Tumori
Milan, MI, 20133
Azienda Ospedaliera Ospedale Ca' Granda
Milan, MI, 20162
Azienda Ospedaliera San Gerardo
Monza, MB, 20052
Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione - Reparto Riabilitazione Oncologica
Pavia, PV, 27100
Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione - U.O. Oncologia
Pavia, PV, 27100
Azienda Ospedaliera della Valtellina e della Valchiavenna - P.O. Sondrio
Sondrio, SO, 23100
About this study
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
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
Read more
- 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 :
- 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.
Read the detailed description
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.
- Conditions
- Metastatic Breast Cancer
- Being tested
- Lapatinib, Metformin
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LapatinibDrug
1250 mg/ die, os
MetforminDrug
1500 mg/die, os
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Lapatinib; Drug: Metformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of patients free from disease progression
Measured: 3 months from randomization
Secondary outcomes (5)
overall response rate
Measured: 3 years
Progression Free Survival
Measured: 3 years
Time to progression
Measured: 3 years
Overall survival
To assess 3-years overall survival rate
Measured: 3 years
Number of participants with toxicities as a measure of tolerability of each proposed treatment
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Nov 2011 (estimated)
- Study startNov 2011
- Primary completionDec 2013
- Study completionDec 2013
Why it stopped: The study was stopped due to insufficient accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione Michelangelo
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Milvia Zambetti, MD, Principal investigator, Ospedale San Raffaele
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01477060
- Sponsor's protocol ID
- CROLT/02
- Other IDs
- 2011-000155-16
- Status last verified
- Feb 2014
- First submitted
- 16 Nov 2011
- Last updated
- 20 Feb 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01477060
- Acronym / sponsor ID
- CROLT/02
- Conditions
- Metastatic Breast Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was stopped due to insufficient accrual
- Enrolment
- 32 participants (actual)
- Lead sponsor
- Fondazione MichelangeloUniversity, hospital or other
- Study start
- Nov 2011
- Primary completion
- Dec 2013 (actual)
- Study completion
- Dec 2013 (actual)
- First posted
- 22 Nov 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 :
- 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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| ARM A - Lapatinib | Other | Drug: Lapatinibhormonal therapy + lapatinib (1250mg/die) until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent. |
| ARM B - Metformin | Other | Drug: MetforminHormonal therapy + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent. |
| ARM C - Lapatinib + Metformin | Other | Drug: Lapatinib, Drug: MetforminHormonal therapy + lapatinib + metformin until disease progression or extraordinary medical circumstances occur or intolerable toxicities occur or the patient withdraws consent. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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
Key exclusion criteria (24 listed)
- 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%
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Lapatinib1250 mg/ die, os | Drug | ARM A - Lapatinib, ARM C - Lapatinib + Metformin |
| Metformin1500 mg/die, os | Drug | ARM B - Metformin, ARM C - Lapatinib + Metformin |
Primary outcome
Rate of patients free from disease progression
Time frame: 3 months from randomization
5 secondary outcomes
overall response rate
Time frame: 3 years
Progression Free Survival
Time frame: 3 years
Time to progression
Time frame: 3 years
Overall survival
Time frame: 3 years
Number of participants with toxicities as a measure of tolerability of each proposed treatment
Time frame: 3 years
Results and safety
The study was stopped early (reason given: The study was stopped due to insufficient accrual). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Feb 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Milvia Zambetti, MD principal investigator
Ospedale San Raffaele
11 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lapatinib and Metformin in people with Metastatic Breast Cancer, run by Fondazione Michelangelo at 11 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: The study was stopped due to insufficient accrual). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of patients free from disease progression (time frame: 3 months from randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Feb 2014.