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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Breast Cancer Research Foundation
Information provided by (Responsible Party):
Ozmosis Research Inc.
ClinicalTrials.gov Identifier:
NCT01310231
First received: February 18, 2011
Last updated: May 1, 2017
Last verified: May 2017
  Purpose
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.

Condition Intervention Phase
Metastatic Breast Cancer Drug: Metformin Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (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

Resource links provided by NLM:


Further study details as provided by Ozmosis Research Inc.:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 78
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)
Arms Assigned Interventions
Active Comparator: Metformin
Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line).
Drug: Metformin

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).
Drug: Placebo

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.


  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01310231

Locations
Canada, Ontario
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
Sponsors and Collaborators
Ozmosis Research Inc.
Breast Cancer Research Foundation
Investigators
Principal Investigator: Pamela J Goodwin, MD Mount Sinai Hospital, New York
  More Information

Responsible Party: Ozmosis Research Inc.
ClinicalTrials.gov Identifier: NCT01310231     History of Changes
Other Study ID Numbers: OZM-027
Study First Received: February 18, 2011
Last Updated: May 1, 2017

Keywords provided by Ozmosis Research Inc.:
Metastatic Breast Cancer
Metformin

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Metformin
Capecitabine
Taxane
Hypoglycemic Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 19, 2017