Metastatic Breast CancerPhase 2NCT01310231
A Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer
A Phase 2 study testing Metformin in people with Metastatic Breast Cancer, run by Ozmosis Research Inc. at 5 sites in Canada.
Trial summary
The purpose of this study is to determine if the addition of metformin to standard chemotherapy improves progression free survival in women with metastatic breast cancer. Read more about this study
- Who is it for?
- Ages 18 to 75 years, women only
- Conditions the study is for
- Metastatic Breast Cancer
- What is being tested?
- Metformin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 5 sitesCanada
- Study dates
- 22 Aug 2011to 26 Mar 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 to 75 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically proven invasive breast cancer with metastatic spread outside of breast, ipsilateral axillary and supraclavicular nodal areas (Histological confirmation of metastases is not required) OR, Locally advanced breast cancer that is refractory to initial anticancer treatment.
- A decision has been made to administer single or multiple agent first or second line chemotherapy that includes one of the following agents: anthracycline, taxane, platinum, capecitabine.
- Age: 18 to 75 years at the time of registration
- Invasive breast cancer, any ER or PgR status
- ECOG performance status 0-2
- Life expectancy of at least 6 months
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- Adequate hepatic and renal function (SGOT and ALT < 1.8 X upper limit of normal for the institution, alkaline phosphatase ≤ 2X upper limit of normal for the institution, bilirubin within normal limits for the institution (expect in patients with Gilbert's syndrome who will be eligible regardless of bilirubin) and creatinine ≤ 130 umol/L)
- Blood counts: Neutrophils must be at least 1,000/mm3 and Platelets ≥ 75,000/mm3.
- Ability to understand and to provide written informed consent for the study
- Absence of any psychological, familial, sociological, or other patient related factors that might preclude compliance with the study protocol
- Measurable or non measurable (but evaluable) tumour must be present - radiologic or clinical evaluation must have been performed within 4 weeks prior to registration.
Who cannot join
- More than one previous line(s) of chemotherapy for metastatic disease - if prior chemotherapy has been administered, the last date of treatment must have been given at least 3 weeks prior to registration [any adjuvant systemic treatment is acceptable]
- If prior hormone therapy (as adjuvant or metastatic therapy) has been administered, it must have been stopped at least 3 weeks prior to registration
- Radiotherapy to a target or non target lesion within 4 weeks of registration
- Known CNS metastases
- History of cardiac failure
- Known hypersensitivity or allergy to metformin
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- History of or known diabetes or baseline fasting glucose ≥ 7.0 mmol/L
- History of lactic or other metabolic acidosis
- Use of metformin within 3 months of registration
- Current or planned pregnancy or lactation in women of child-bearing potential. Patients of childbearing potential must have a negative serum pregnancy test.
- Fertile patients must agree to use an effective method of contraception while on study treatment; which could include IUD, condoms or other barrier methods of birth control
- Habitual alcohol intake of more than three drinks daily
- Concurrent use of any biguanide medication (other than metformin as a study medication)
- Patients with ≥ grade 2 diarrhea at baseline, malabsorption syndrome or unable to swallow oral medication
- Previous or concurrent malignancies, except non-melanoma skin cancers, unless curatively treated and with no evidence of recurrence for ≥ 5 years.
- Use of any investigational agent within 28 days prior to registration.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Canada5 sites
London Regional Cancer Program
London, Ontario
St. Michael's Hospital
Toronto, Ontario, M5B 1N9
Mount Sinai Hospital
Toronto, Ontario, M5G 1X5
Princess Margaret Hospital
Toronto, Ontario, M5G 2M9
Windsor Regional Cancer Centre
Windsor, Ontario, N8W 2X3
About this study
Official title: A Randomized Phase II, Double Blind Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer Receiving First to Fourth Line Chemotherapy
The purpose of this study is to determine if the addition of metformin to standard chemotherapy improves progression free survival in women with metastatic breast cancer.
Read the detailed description
A double blind Phase II randomized study of metformin versus (vs) placebo in non-diabetic women on first to fourth line chemotherapy with anthracycline, taxane, platinum, capecitabine or vinorelbine based regimens for metastatic or unresectable locally advanced breast cancer (BC). Patients were randomized to receive metformin 850 mg tablets or placebo once daily for two days as ramp-up, followed by one tablet twice a day for the duration of the study. Randomization was stratified by line of chemotherapy (1st, 2nd, 3rd and 4th line) and hormone receptor status (ER and/or PgR positive versus both negative). All patients were required to have measureable or non-measureable, but evaluable metastases at study entry. Metformin or placebo was to be continued until disease progression, even if chemotherapy was changed or stopped prior to disease progression. Recruitment took place at five sites in Ontario, Canada: Mount Sinai Hospital, Princess Margaret Cancer Centre, St. Michael's Hospital, Toronto and London Regional Cancer Centre, London.
- Conditions
- Metastatic Breast Cancer
- Being tested
- Metformin, Placebo
- Keywords
- Metastatic Breast Cancer, 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.
MetforminDrug
metformin 850 mg bid in addition to standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line).
Number of cycles: Until progression or unacceptable toxicity develops.
PlaceboDrug
Placebo bid in addition to standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line).
Number of cycles: until progression or unacceptable toxicity develops.
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Active comparator | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). Receives: Drug: Metformin |
| Placebo | Placebo comparator | Placebo and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival.
Scans will be repeated every 9 weeks. Local follow up for survival will continue until all patients have died or for a maximum total follow up of 3 years, which ever occurs first. The two study arms will be compared in an intent to treat fashion using Cox proportional hazard analysis, with the stratification variables included in the model. Treatment discontinuation for toxicity or other reasons will be considered an event.
Measured: From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years.
Secondary outcomes (9)
Overall Response Rate
Overall response rate in patients with measureable disease based upon RECIST Version 1.1. Patients will have scans repeated every 9 weeks and overall review of response across the study will be done every 6 months. The overall response rate is defined as number of patients with a best overall response of CR or PR, as a proportion of all patient with measurable disease at baseline. The response rate between arms will be compared using logistic regression with treatment as factor, adjusted for strata.
Measured: From baseline until time of best response, assessed up to 3 years
Number of Participants With Grade 1 or 2 Adverse Events
Adverse events graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Lower grade (grade 1 and 2) and higher grade (grade 3 and 4) are presented separately.
A detailed breakdown of adverse events are given in the Adverse Events section
Measured: Up to 30 days after end of study
Number of Participants With Grade 3 or 4 Adverse Events
Adverse events graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Lower grade (grade 1 and 2) and higher grade (grade 3 and 4) are presented separately.
A detailed breakdown of adverse events are given in the Adverse Events section
Measured: Up to 30 days after end of study
EORTC Quality of Life Measures
European Organization for Research and Treatment of Cancer (EORTC) quality of life measures: global health status and 5 functioning scales. Baseline and Cycle 2 outcomes are scaled from 0 to 100; higher scores indicate better functioning or better health status. CHANGE in these scales from baseline to cycle 2 is reported for each arm.
Measured: From baseline to cycle 2 of chemotherapy
Change in Fasting Glucose (mmol/L)
Change in fasting glucose from baseline to Cycle 2
Measured: Baseline to Cycle 2
Change in Fasting Insulin
Change in fasting insulin from baseline to Cycle 2
Measured: Baseline to Cycle 2
Change in Insulin Resistance From Baseline to Cycle 2 Measured Using Homeostatic Model Assessment (HOMA-IR)
HOMA-IR is an index calculated from fasting insulin (pmol/L) and glucose (mmol/L) as insulin/6.9 times glucose/22.5.
Measured: Baseline to Cycle 2
Immunohistochemical Predictors of Metformin Benefit and to Explore Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases.
Immunohistochemical analysis of different markers (IR, LKB1, phosphorylated AKT, S6K, ribosomal protein S6, 4E-BP1, and stathmin) pre and post first cycle of chemotherapy with metformin as well as in the original tumour tissue. Change in the phospho-markers of PI3K/mTOR will be summarized before and after the first cycle of chemotherapy with a focus on detection between the study arms.
Measured: Baseline and 3 weeks.
Gene Expression Predictors of Potential Metformin Benefit Including Exploration of Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases
Gene expression profiles in the baseline (original tumour) and, when available, pre and post cycle 1 chemotherapy will be established and change in gene signature pre and post chemotherapy will be explored.
Measured: Baseline and 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2011 (estimated)
- Study start22 Aug 2011
- Primary completion14 Jul 2016
- Study completion26 Mar 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- 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
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ozmosis Research Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Breast Cancer Research Foundation
- Responsible party
- Sponsor
- Investigators
- Pamela J Goodwin, MD, Principal investigator, MOUNT SINAI HOSPITAL
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01310231
- Sponsor's protocol ID
- OZM-027
- Status last verified
- Mar 2021
- First submitted
- 18 Feb 2011
- Last updated
- 14 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Pimentel I, Lohmann AE, Ennis M, Dowling RJO, Cescon D, Elser C, Potvin KR, Haq R, Hamm C, Chang MC, Stambolic V, Goodwin PJ. A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy. Breast. 2019 Dec;48:17-23. doi: 10.1016/j.breast.2019.08.003. Epub 2019 Aug 22.
PubMed 31472446
Study at a glance
From the registry record, last updated by the sponsor on 14 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Phase II, Double Blind Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer Receiving First to Fourth Line Chemotherapy
- ClinicalTrials.gov ID
- NCT01310231
- Acronym / sponsor ID
- OZM-027
- Conditions
- Metastatic Breast Cancer
- Keywords
- Metastatic Breast Cancer, Metformin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Ozmosis Research Inc.Industry (pharma, biotech, devices)
- Collaborators
- Breast Cancer Research Foundation
- Study start
- 22 Aug 2011 (actual)
- Primary completion
- 14 Jul 2016 (actual)
- Study completion
- 26 Mar 2018 (actual)
- First posted
- 8 Mar 2011 (estimated)
- Results
- Posted 14 Apr 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine if the addition of metformin to standard chemotherapy improves progression free survival in women with metastatic breast cancer.
Detailed description
A double blind Phase II randomized study of metformin versus (vs) placebo in non-diabetic women on first to fourth line chemotherapy with anthracycline, taxane, platinum, capecitabine or vinorelbine based regimens for metastatic or unresectable locally advanced breast cancer (BC). Patients were randomized to receive metformin 850 mg tablets or placebo once daily for two days as ramp-up, followed by one tablet twice a day for the duration of the study. Randomization was stratified by line of chemotherapy (1st, 2nd, 3rd and 4th line) and hormone receptor status (ER and/or PgR positive versus both negative). All patients were required to have measureable or non-measureable, but evaluable metastases at study entry. Metformin or placebo was to be continued until disease progression, even if chemotherapy was changed or stopped prior to disease progression. Recruitment took place at five sites in Ontario, Canada: Mount Sinai Hospital, Princess Margaret Cancer Centre, St. Michael's Hospital, Toronto and London Regional Cancer Centre, London.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Active comparator | Drug: MetforminMetformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Histologically proven invasive breast cancer with metastatic spread outside of breast, ipsilateral axillary and supraclavicular nodal areas (Histological confirmation of metastases is not required) OR, Locally advanced breast cancer that is refractory to initial anticancer treatment.
- A decision has been made to administer single or multiple agent first or second line chemotherapy that includes one of the following agents: anthracycline, taxane, platinum, capecitabine.
- Age: 18 to 75 years at the time of registration
- Invasive breast cancer, any ER or PgR status
- ECOG performance status 0-2
Key exclusion criteria (16 listed)
- More than one previous line(s) of chemotherapy for metastatic disease - if prior chemotherapy has been administered, the last date of treatment must have been given at least 3 weeks prior to registration [any adjuvant systemic treatment is acceptable]
- If prior hormone therapy (as adjuvant or metastatic therapy) has been administered, it must have been stopped at least 3 weeks prior to registration
- Radiotherapy to a target or non target lesion within 4 weeks of registration
- Known CNS metastases
- History of cardiac failure
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 |
|---|---|---|
| Metforminmetformin 850 mg bid in addition to standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). Number of cycles: Until progression or unacceptable toxicity develops. | Drug | Metformin |
| PlaceboPlacebo bid in addition to standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). Number of cycles: until progression or unacceptable toxicity develops. | Drug | Placebo |
Primary outcome
Progression Free Survival.
Time frame: From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years.
Scans will be repeated every 9 weeks. Local follow up for survival will continue until all patients have died or for a maximum total follow up of 3 years, which ever occurs first. The two study arms will be compared in an intent to treat fashion using Cox proportional hazard analysis, with the stratification variables included in the model. Treatment discontinuation for toxicity or other reasons will be considered an event.
9 secondary outcomes
Overall Response Rate
Time frame: From baseline until time of best response, assessed up to 3 years
Number of Participants With Grade 1 or 2 Adverse Events
Time frame: Up to 30 days after end of study
Number of Participants With Grade 3 or 4 Adverse Events
Time frame: Up to 30 days after end of study
EORTC Quality of Life Measures
Time frame: From baseline to cycle 2 of chemotherapy
Change in Fasting Glucose (mmol/L)
Time frame: Baseline to Cycle 2
Change in Fasting Insulin
Time frame: Baseline to Cycle 2
Change in Insulin Resistance From Baseline to Cycle 2 Measured Using Homeostatic Model Assessment (HOMA-IR)
Time frame: Baseline to Cycle 2
Immunohistochemical Predictors of Metformin Benefit and to Explore Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases.
Time frame: Baseline and 3 weeks.
Gene Expression Predictors of Potential Metformin Benefit Including Exploration of Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases
Time frame: Baseline and 4 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Apr 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 31472446Pimentel I, Lohmann AE, Ennis M, Dowling RJO, Cescon D, Elser C, Potvin KR, Haq R, Hamm C, Chang MC, Stambolic V, Goodwin PJ. A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy. Breast. 2019 Dec;48:17-23. doi: 10.1016/j.breast.2019.08.003. Epub 2019 Aug 22.
- Study ResultsLink provided by the sponsor.
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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.
Pamela J Goodwin, MD principal investigator
MOUNT SINAI HOSPITAL
5 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 Metformin in people with Metastatic Breast Cancer, run by Ozmosis Research Inc. at 5 sites in Canada.
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 11 inclusion and 16 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: finished, as of the sponsor's last update on 14 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Canada. 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. Some participants in this study may receive a placebo. 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?
Yes. Results are posted in the registry (first posted 14 Apr 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Progression Free Survival. (time frame: From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01310231, which also lists 1 linked publication.
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 14 Apr 2021.