A Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
|Official Title:||A Randomized Phase II, Double Blind Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer Receiving First, Second, Third or Fourth Line Chemotherapy With Anthracycline, Taxane, Platinum, Capecitabine or Vinorelbine Based Regimens|
- 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.
- Overall response rate [ Time Frame: From baseline until time of best response, assessed up to 3 years ]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.
- To examine the effect of the addition of metformin to standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine) on change in frequency and severity of adverse events. [ Time Frame: up to 3 years ]Adverse events will be graded using CTCAE Version 4.0. Frequency tables will be produced per arm of the treatment emergent adverse event rates.The treatment emergent adverse event rates will be further summarized by maximum toxicity grade per patient during treatment.
- Quality of life and treatment related symptoms [ Time Frame: up to 3 years ]The symptom checklist and the symptom related EORTC measures will be compared between arms using frequency tables.
- Physiological parameters fasting insulin, glucose and HOMA change, and to explore the association of these changes with progression free survival (in all subjects) and tumor response (in subjects with measurable disease). [ Time Frame: Up to 3 years ]Physiologic parameters (fasting insulin, glucose, HOMA) will be transformed to normality prior to analyses. The parameters will be modeled over time using graphical methods to find an appropriate functional form. Parameters will be compared between arms over time using a linear mixed-effect model with terms for arm, time and a group-by-time interaction and treating patients as random effects.
- 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. ]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.
- 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 ]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.
|Study Start Date:||March 2011|
|Estimated Study Completion Date:||September 2017|
|Primary Completion Date:||July 14, 2016 (Final data collection date for primary outcome measure)|
Active Comparator: Metformin
Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line).
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.
Placebo Comparator: Placebo
Placebo and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line).
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01310231
|London Regional Cancer Program|
|London, Ontario, Canada|
|St. Michael's Hospital|
|Toronto, Ontario, Canada, M5B 1N9|
|Mount Sinai Hospital|
|Toronto, Ontario, Canada, M5G 1X5|
|Princess Margaret Hospital|
|Toronto, Ontario, Canada, M5G 2M9|
|Windsor Regional Cancer Centre|
|Windsor, Ontario, Canada, N8W 2X3|
|Principal Investigator:||Pamela J Goodwin, MD||Mount Sinai Hospital, New York|