Clinical trial NCT01310231: A Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Keywords: Metastatic Breast Cancer
Metformin
Lead sponsor: Ozmosis Research Inc.
Sponsor class: INDUSTRY
Collaborators: name: Breast Cancer Research Foundation
First posted: 2011-03-08
Enrollment: 40
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility 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.

Primary outcomes:
measure: Progression Free Survival.
timeFrame: From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years.
Secondary outcomes:
measure: Overall Response Rate
timeFrame: From baseline until time of best response, assessed up to 3 years
measure: Number of Participants With Grade 1 or 2 Adverse Events
timeFrame: Up to 30 days after end of study
measure: Number of Participants With Grade 3 or 4 Adverse Events
timeFrame: Up to 30 days after end of study
measure: EORTC Quality of Life Measures
timeFrame: From baseline to cycle 2 of chemotherapy
measure: Change in Fasting Glucose (mmol/L)
timeFrame: Baseline to Cycle 2
measure: Change in Fasting Insulin
timeFrame: Baseline to Cycle 2
measure: Change in Insulin Resistance From Baseline to Cycle 2 Measured Using Homeostatic Model Assessment (HOMA-IR)
timeFrame: Baseline to Cycle 2
measure: Immunohistochemical Predictors of Metformin Benefit and to Explore Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases.
timeFrame: Baseline and 3 weeks.
measure: Gene Expression Predictors of Potential Metformin Benefit Including Exploration of Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases
timeFrame: Baseline and 4 weeks
Other outcomes:
Locations:
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
state: Ontario
Study officials:
affiliation: MOUNT SINAI HOSPITAL
name: Pamela J Goodwin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.