A Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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. Exclusion Criteria: 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin<br>Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). | Drug: Metformin<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Placebo and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 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 | 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. | From baseline to cycle 2 of chemotherapy | 
| Change in Fasting Glucose (mmol/L) | Change in fasting glucose from baseline to Cycle 2 | Baseline to Cycle 2 | 
| Change in Fasting Insulin | Change in fasting insulin from baseline to Cycle 2 | 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. | 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. | 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. | Baseline and 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Breast Cancer, Metformin