A Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer
Sponsor
Ozmosis Research Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01310231
Collaborator
Breast Cancer Research Foundation (Other)
40
5
2
79.1
8
0.1
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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
Study Type:
Interventional
Actual Enrollment
:
40 participants
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 to Fourth Line Chemotherapy
Actual Study Start Date
:
Aug 22, 2011
Actual Primary Completion Date
:
Jul 14, 2016
Actual Study Completion Date
:
Mar 26, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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.
|
Outcome Measures
Primary Outcome Measures
- Progression Free Survival. [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 [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.
- Number of Participants With Grade 1 or 2 Adverse Events [Up to 30 days after end of study]
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
- Number of Participants With Grade 3 or 4 Adverse Events [Up to 30 days after end of study]
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
- EORTC Quality of Life Measures [From baseline to cycle 2 of chemotherapy]
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.
- Change in Fasting Glucose (mmol/L) [Baseline to Cycle 2]
Change in fasting glucose from baseline to Cycle 2
- Change in Fasting Insulin [Baseline to Cycle 2]
Change in fasting insulin from baseline to Cycle 2
- Change in Insulin Resistance From Baseline to Cycle 2 Measured Using Homeostatic Model Assessment (HOMA-IR) [Baseline to Cycle 2]
HOMA-IR is an index calculated from fasting insulin (pmol/L) and glucose (mmol/L) as insulin/6.9 times glucose/22.5.
- Immunohistochemical Predictors of Metformin Benefit and to Explore Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases. [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 [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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 75 Years
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | London Regional Cancer Program | London | Ontario | Canada | |
| 2 | St. Michael's Hospital | Toronto | Ontario | Canada | M5B 1N9 |
| 3 | Mount Sinai Hospital | Toronto | Ontario | Canada | M5G 1X5 |
| 4 | Princess Margaret Hospital | Toronto | Ontario | Canada | M5G 2M9 |
| 5 | 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
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Ozmosis Research Inc.
ClinicalTrials.gov Identifier:
NCT01310231
Other Study ID Numbers:
- OZM-027
First Posted:
Mar 8, 2011
Last Update Posted:
Apr 14, 2021
Last Verified:
Mar 1, 2021
Keywords provided by Ozmosis Research Inc.
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Period Title: Overall Study | ||
| STARTED | 22 | 18 |
| Received Intervention | 22 | 17 |
| Discontinued Intervention | 0 | 1 |
| Analyzed for Survival | 22 | 18 |
| Analyzed for Response, Toxicity, QOL | 22 | 17 |
| COMPLETED | 22 | 17 |
| NOT COMPLETED | 0 | 1 |
Baseline Characteristics
| Arm/Group Title | Metformin | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. | Total of all reporting groups |
| Overall Participants | 22 | 18 | 40 |
| Age (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
55
|
57
|
55.9
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
22
100%
|
18
100%
|
40
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
5
22.7%
|
4
22.2%
|
9
22.5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
1
5.6%
|
1
2.5%
|
| White |
17
77.3%
|
13
72.2%
|
30
75%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| ECOG Performance Scale (Count of Participants) | |||
| ECOG 0-1 |
20
90.9%
|
16
88.9%
|
36
90%
|
| ECOG 2 |
2
9.1%
|
2
11.1%
|
4
10%
|
| Body Mass Index (BMI) (kg/m^2) [Mean (Full Range) ] | |||
| Mean (Full Range) [kg/m^2] |
26.5
|
26.6
|
26.5
|
| Receptor Status (participants) [Number] | |||
| (Estrogen Receptor (ER)/Progesterone Receptor (PR) positive |
19
86.4%
|
15
83.3%
|
34
85%
|
| ER/PR negative |
3
13.6%
|
3
16.7%
|
6
15%
|
| Human epidermal growth factor receptor 2 (HER2) status (participants) [Number] | |||
| HER2 positive |
2
9.1%
|
4
22.2%
|
6
15%
|
| HER2 negative |
20
90.9%
|
14
77.8%
|
34
85%
|
| Any adjuvant chemotherapy (participants) [Number] | |||
| Yes |
13
59.1%
|
12
66.7%
|
25
62.5%
|
| No |
9
40.9%
|
6
33.3%
|
15
37.5%
|
| 1st diagnosis to randomization (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
6.5
|
4
|
5.4
|
| 1st metastasis to randomization (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
0.8
|
1.1
|
0.9
|
| Line of treatment (participants) [Number] | |||
| 1st line treatment |
15
68.2%
|
12
66.7%
|
27
67.5%
|
| 2nd line treatment |
4
18.2%
|
3
16.7%
|
7
17.5%
|
| 3+ lines treatment |
3
13.6%
|
3
16.7%
|
6
15%
|
| Any visceral disease (participants) [Number] | |||
| Yes |
21
95.5%
|
13
72.2%
|
34
85%
|
| No |
1
4.5%
|
5
27.8%
|
6
15%
|
| Involvement beyond bone and lymph nodes (participants) [Number] | |||
| Yes |
22
100%
|
15
83.3%
|
37
92.5%
|
| No |
0
0%
|
3
16.7%
|
3
7.5%
|
Outcome Measures
| Title | Progression Free Survival. |
|---|---|
| Description | 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. |
| Time Frame | From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 22 | 18 |
| Mean (Standard Deviation) [months] |
5.4
(1.04)
|
6.3
(1.68)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Metformin, Placebo |
|---|---|---|
| Comments | Power: Final study plan called for 40 progression events, giving 80% power to detect a hazard ratio (HR) of 0.58 for PFS with a one-sided type I error of 20%, where the relatively high type I error reflects the Phase II status of the trial | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.71 |
| Comments | One-sided p-value for group-effect obtained from Cox model. The prespecified threshold was 0.20 (one-sided). | |
| Method | Regression, Cox | |
| Comments | Cox model for PFS with metf/plac and the two randomization stratification variables line of chemotherapy and hormone receptor status. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.2 | |
| Confidence Interval |
(2-Sided) 95% 0.63 to 2.31 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Ratio of hazard of progression in the Metformin group relative to hazard in the Placebo group | |
| Title | Overall Response Rate |
|---|---|
| Description | 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. |
| Time Frame | From baseline until time of best response, assessed up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Population is everyone with measurable disease (metformin 22, placebo 16) |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 22 | 16 |
| Clinical benefit |
12
54.5%
|
7
38.9%
|
| Progressive disease |
10
45.5%
|
9
50%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Metformin, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.41 |
| Comments | Two-side p-value from a logistic regression model. | |
| Method | Regression, Logistic | |
| Comments | Logistic regression model included metf/plac and the two stratification variables line of chemotherapy and hormone receptor status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.77 | |
| Confidence Interval |
(2-Sided) 95% 0.45 to 6.99 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants With Grade 1 or 2 Adverse Events |
|---|---|
| Description | 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 |
| Time Frame | Up to 30 days after end of study |
Outcome Measure Data
| Analysis Population Description |
|---|
| Population is everyone who received study drug (metformin n=22, placebo n=17). |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 22 | 17 |
| Count of Participants [Participants] |
15
68.2%
|
6
33.3%
|
| Title | Number of Participants With Grade 3 or 4 Adverse Events |
|---|---|
| Description | 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 |
| Time Frame | Up to 30 days after end of study |
Outcome Measure Data
| Analysis Population Description |
|---|
| Population is everyone who received study drug (metformin n=22, placebo n=17). |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 22 | 17 |
| Count of Participants [Participants] |
7
31.8%
|
10
55.6%
|
| Title | EORTC Quality of Life Measures |
|---|---|
| Description | 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. |
| Time Frame | From baseline to cycle 2 of chemotherapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| Population is everyone who completed BOTH baseline and Cycle 2 questionnaires (19 metformin, 16 placebo). 3 metformin and 2 placebo patients did not complete the Cycle 2 EORTC questionnaire. |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 19 | 16 |
| Global health Status |
-12.7
(18.7)
|
6.3
(19.6)
|
| Physical functioning |
-6.0
(12.9)
|
2.1
(12.1)
|
| Role functioning |
-18.4
(27.7)
|
-2.1
(20.1)
|
| Emotional functioning |
-2.6
(21.1)
|
2.3
(16.7)
|
| Cognitive functioning |
-0.9
(10.4)
|
0
(17.2)
|
| Social functioning |
-12.3
(29.8)
|
4.2
(23.2)
|
| Title | Change in Fasting Glucose (mmol/L) |
|---|---|
| Description | Change in fasting glucose from baseline to Cycle 2 |
| Time Frame | Baseline to Cycle 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Population is everyone who had institutional glucose performed at BOTH baseline and Cycle 2 (19 metformin, 15 placebo). |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 12 | 7 |
| Median (Inter-Quartile Range) [mmol/L] |
-0.2
|
0
|
| Title | Change in Fasting Insulin |
|---|---|
| Description | Change in fasting insulin from baseline to Cycle 2 |
| Time Frame | Baseline to Cycle 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Population is everyone who had sufficient fasting blood available for analysis at BOTH baseline and Cycle 2 (12 metformin, 7 placebo). |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 12 | 7 |
| Median (Inter-Quartile Range) [pmol/L] |
-7
|
1
|
| Title | Change in Insulin Resistance From Baseline to Cycle 2 Measured Using Homeostatic Model Assessment (HOMA-IR) |
|---|---|
| Description | HOMA-IR is an index calculated from fasting insulin (pmol/L) and glucose (mmol/L) as insulin/6.9 times glucose/22.5. |
| Time Frame | Baseline to Cycle 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Population is everyone who had sufficient fasting blood available for analysis at BOTH baseline and Cycle 2 (12 metformin, 7 placebo). |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 12 | 7 |
| Median (Inter-Quartile Range) [HOMA-IR score] |
-0.16
|
0.12
|
| Title | Immunohistochemical Predictors of Metformin Benefit and to Explore Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases. |
|---|---|
| Description | 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. |
| Time Frame | Baseline and 3 weeks. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data not collected |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 0 | 0 |
| Title | Gene Expression Predictors of Potential Metformin Benefit Including Exploration of Changes in These Variables in Women Who Undergo Serial Biopsies of Their Metastases |
|---|---|
| Description | 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. |
| Time Frame | Baseline and 4 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data not collected |
| Arm/Group Title | Metformin | Placebo |
|---|---|---|
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | All-cause mortality is available on all subjects (metformin n=22, placebo n=18). All the other Adverse Events are available on patients that received study drug (metformin n=22, placebo n=17). | |||
| Arm/Group Title | Metformin | Placebo | ||
| Arm/Group Description | Metformin plus standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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 and standard chemotherapy (containing anthracyclines, platinum, taxanes or capecitabine; first or second line). 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. | ||
All Cause Mortality |
||||
| Metformin | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 19/22 (86.4%) | 15/18 (83.3%) | ||
Serious Adverse Events |
||||
| Metformin | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/22 (13.6%) | 4/17 (23.5%) | ||
| Gastrointestinal disorders | ||||
| ascites with hyponatraemia | 0/22 (0%) | 0 | 1/17 (5.9%) | 1 |
| Infections and infestations | ||||
| febrile neutropenia with respiratory infection | 1/22 (4.5%) | 1 | 0/17 (0%) | 0 |
| urosepsis | 1/22 (4.5%) | 1 | 0/17 (0%) | 0 |
| febrile neutropenia with urinary tract infection | 0/22 (0%) | 0 | 1/17 (5.9%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| dyspnoea | 1/22 (4.5%) | 1 | 0/17 (0%) | 0 |
| hypoxia | 0/22 (0%) | 0 | 1/17 (5.9%) | 1 |
| Vascular disorders | ||||
| thromboembolism | 0/22 (0%) | 0 | 1/17 (5.9%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Metformin | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 22/22 (100%) | 15/17 (88.2%) | ||
| Blood and lymphatic system disorders | ||||
| ANAEMIA | 0/22 (0%) | 1/17 (5.9%) | ||
| Cardiac disorders | ||||
| DYSPNOEA | 1/22 (4.5%) | 6/17 (35.3%) | ||
| DIZZINESS | 4/22 (18.2%) | 0/17 (0%) | ||
| OEDEMA PERIPHERAL | 0/22 (0%) | 4/17 (23.5%) | ||
| LOCALISED OEDEMA | 0/22 (0%) | 2/17 (11.8%) | ||
| Ear and labyrinth disorders | ||||
| HEARING IMPAIRED | 0/22 (0%) | 1/17 (5.9%) | ||
| Endocrine disorders | ||||
| HYPERGLYCAEMIA | 2/22 (9.1%) | 0/17 (0%) | ||
| Eye disorders | ||||
| VISION BLURRED | 3/22 (13.6%) | 2/17 (11.8%) | ||
| HYPOAESTHESIA EYE | 0/22 (0%) | 1/17 (5.9%) | ||
| LACRIMATION INCREASED | 0/22 (0%) | 1/17 (5.9%) | ||
| Gastrointestinal disorders | ||||
| DIARRHOEA | 16/22 (72.7%) | 7/17 (41.2%) | ||
| NAUSEA | 12/22 (54.5%) | 11/17 (64.7%) | ||
| VOMITING | 10/22 (45.5%) | 4/17 (23.5%) | ||
| CONSTIPATION | 5/22 (22.7%) | 8/17 (47.1%) | ||
| ABDOMINAL DISTENSION | 6/22 (27.3%) | 6/17 (35.3%) | ||
| DYSGEUSIA | 5/22 (22.7%) | 4/17 (23.5%) | ||
| FLATULENCE | 3/22 (13.6%) | 5/17 (29.4%) | ||
| ABDOMINAL PAIN | 3/22 (13.6%) | 3/17 (17.6%) | ||
| DYSPEPSIA | 4/22 (18.2%) | 1/17 (5.9%) | ||
| STOMATITIS | 2/22 (9.1%) | 2/17 (11.8%) | ||
| ABDOMINAL PAIN UPPER | 2/22 (9.1%) | 0/17 (0%) | ||
| EPIGASTRIC DISCOMFORT | 0/22 (0%) | 1/17 (5.9%) | ||
| GASTROINTESTINAL PAIN | 0/22 (0%) | 1/17 (5.9%) | ||
| GASTROOESOPHAGEAL REFLUX DISEASE | 0/22 (0%) | 1/17 (5.9%) | ||
| General disorders | ||||
| FATIGUE | 11/22 (50%) | 7/17 (41.2%) | ||
| HOT FLUSH | 3/22 (13.6%) | 2/17 (11.8%) | ||
| PYREXIA | 2/22 (9.1%) | 3/17 (17.6%) | ||
| MUCOSAL INFLAMMATION | 1/22 (4.5%) | 3/17 (17.6%) | ||
| OEDEMA PERIPHERAL | 0/22 (0%) | 4/17 (23.5%) | ||
| CHILLS | 1/22 (4.5%) | 1/17 (5.9%) | ||
| INFLUENZA LIKE ILLNESS | 2/22 (9.1%) | 0/17 (0%) | ||
| LOCALISED OEDEMA | 0/22 (0%) | 2/17 (11.8%) | ||
| PAIN | 0/22 (0%) | 2/17 (11.8%) | ||
| ASTHENIA | 0/22 (0%) | 1/17 (5.9%) | ||
| Immune system disorders | ||||
| HYPERSENSITIVITY | 2/22 (9.1%) | 1/17 (5.9%) | ||
| Infections and infestations | ||||
| SKIN INFECTION | 1/22 (4.5%) | 1/17 (5.9%) | ||
| CYSTITIS | 0/22 (0%) | 1/17 (5.9%) | ||
| Injury, poisoning and procedural complications | ||||
| PHLEBITIS | 0/22 (0%) | 1/17 (5.9%) | ||
| Investigations | ||||
| ASPARTATE AMINOTRANSFERASE INCREASED | 3/22 (13.6%) | 2/17 (11.8%) | ||
| NEUTROPHIL COUNT DECREASED | 3/22 (13.6%) | 2/17 (11.8%) | ||
| ALANINE AMINOTRANSFERASE INCREASED | 3/22 (13.6%) | 1/17 (5.9%) | ||
| WHITE BLOOD CELL COUNT DECREASED | 0/22 (0%) | 1/17 (5.9%) | ||
| Metabolism and nutrition disorders | ||||
| ANOREXIA | 6/22 (27.3%) | 2/17 (11.8%) | ||
| OEDEMA PERIPHERAL | 0/22 (0%) | 4/17 (23.5%) | ||
| HYPERGLYCAEMIA | 2/22 (9.1%) | 0/17 (0%) | ||
| LOCALISED OEDEMA | 0/22 (0%) | 2/17 (11.8%) | ||
| HYPOCALCAEMIA | 0/22 (0%) | 1/17 (5.9%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| BACK PAIN | 3/22 (13.6%) | 5/17 (29.4%) | ||
| ARTHRALGIA | 4/22 (18.2%) | 3/17 (17.6%) | ||
| BONE PAIN | 2/22 (9.1%) | 3/17 (17.6%) | ||
| MYALGIA | 3/22 (13.6%) | 2/17 (11.8%) | ||
| MUSCULAR WEAKNESS | 3/22 (13.6%) | 1/17 (5.9%) | ||
| PAIN IN EXTREMITY | 2/22 (9.1%) | 1/17 (5.9%) | ||
| MUSCULOSKELETAL PAIN | 1/22 (4.5%) | 1/17 (5.9%) | ||
| NECK PAIN | 2/22 (9.1%) | 0/17 (0%) | ||
| MUSCULOSKELETAL CHEST PAIN | 0/22 (0%) | 1/17 (5.9%) | ||
| SYNOVIAL CYST | 0/22 (0%) | 1/17 (5.9%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| SYNOVIAL CYST | 0/22 (0%) | 1/17 (5.9%) | ||
| Nervous system disorders | ||||
| DYSGEUSIA | 5/22 (22.7%) | 4/17 (23.5%) | ||
| PARAESTHESIA | 5/22 (22.7%) | 4/17 (23.5%) | ||
| HEADACHE | 5/22 (22.7%) | 3/17 (17.6%) | ||
| INSOMNIA | 2/22 (9.1%) | 3/17 (17.6%) | ||
| PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME | 4/22 (18.2%) | 1/17 (5.9%) | ||
| VISION BLURRED | 3/22 (13.6%) | 2/17 (11.8%) | ||
| DIZZINESS | 4/22 (18.2%) | 0/17 (0%) | ||
| MUSCULAR WEAKNESS | 3/22 (13.6%) | 1/17 (5.9%) | ||
| PERIPHERAL SENSORY NEUROPATHY | 2/22 (9.1%) | 0/17 (0%) | ||
| CARPAL TUNNEL SYNDROME | 0/22 (0%) | 1/17 (5.9%) | ||
| HYPOAESTHESIA EYE | 0/22 (0%) | 1/17 (5.9%) | ||
| MEMORY IMPAIRMENT | 0/22 (0%) | 1/17 (5.9%) | ||
| Psychiatric disorders | ||||
| INSOMNIA | 2/22 (9.1%) | 3/17 (17.6%) | ||
| ANXIETY | 1/22 (4.5%) | 2/17 (11.8%) | ||
| DEPRESSION | 0/22 (0%) | 1/17 (5.9%) | ||
| MEMORY IMPAIRMENT | 0/22 (0%) | 1/17 (5.9%) | ||
| Renal and urinary disorders | ||||
| CYSTITIS | 0/22 (0%) | 1/17 (5.9%) | ||
| POLLAKIURIA | 0/22 (0%) | 1/17 (5.9%) | ||
| Reproductive system and breast disorders | ||||
| HOT FLUSH | 3/22 (13.6%) | 2/17 (11.8%) | ||
| BREAST PAIN | 2/22 (9.1%) | 1/17 (5.9%) | ||
| VULVOVAGINAL DRYNESS | 0/22 (0%) | 1/17 (5.9%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| DYSPNOEA | 1/22 (4.5%) | 6/17 (35.3%) | ||
| COUGH | 4/22 (18.2%) | 2/17 (11.8%) | ||
| EPISTAXIS | 2/22 (9.1%) | 1/17 (5.9%) | ||
| NASAL CONGESTION | 2/22 (9.1%) | 0/17 (0%) | ||
| PHARYNGOLARYNGEAL PAIN | 1/22 (4.5%) | 1/17 (5.9%) | ||
| POSTNASAL DRIP | 1/22 (4.5%) | 1/17 (5.9%) | ||
| CHRONIC OBSTRUCTIVE PULMONARY DISEASE | 0/22 (0%) | 1/17 (5.9%) | ||
| MUSCULOSKELETAL CHEST PAIN | 0/22 (0%) | 1/17 (5.9%) | ||
| PULMONARY EMBOLISM | 0/22 (0%) | 1/17 (5.9%) | ||
| Skin and subcutaneous tissue disorders | ||||
| ALOPECIA | 7/22 (31.8%) | 6/17 (35.3%) | ||
| PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME | 4/22 (18.2%) | 1/17 (5.9%) | ||
| NAIL DISORDER | 1/22 (4.5%) | 1/17 (5.9%) | ||
| NAIL DISCOLOURATION | 1/22 (4.5%) | 3/17 (17.6%) | ||
| RASH | 1/22 (4.5%) | 1/17 (5.9%) | ||
| RASH MACULO-PAPULAR | 1/22 (4.5%) | 1/17 (5.9%) | ||
| SKIN INFECTION | 1/22 (4.5%) | 1/17 (5.9%) | ||
| Vascular disorders | ||||
| HOT FLUSH | 3/22 (13.6%) | 2/17 (11.8%) | ||
| DIZZINESS | 4/22 (18.2%) | 0/17 (0%) | ||
| EPISTAXIS | 2/22 (9.1%) | 1/17 (5.9%) | ||
| EMBOLISM | 0/22 (0%) | 1/17 (5.9%) | ||
| HYPOTENSION | 0/22 (0%) | 1/17 (5.9%) | ||
| PHLEBITIS | 0/22 (0%) | 1/17 (5.9%) | ||
| PULMONARY EMBOLISM | 0/22 (0%) | 1/17 (5.9%) | ||
Limitations/Caveats
Limitations include relatively small sample size, with associated imbalances in frequency of visceral (vs nonvisceral) metastatic disease, in HER2 positive and negative cancers, and in type of chemotherapy received in the metformin vs placebo arms.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Pamela Goodwin/PI |
|---|---|
| Organization | Mount Sinai Hospital |
| Phone | 416 586-8211 |
| Pamela.goodwin@sinaihealth.ca |
Responsible Party:
Ozmosis Research Inc.
ClinicalTrials.gov Identifier:
NCT01310231
Other Study ID Numbers:
- OZM-027
First Posted:
Mar 8, 2011
Last Update Posted:
Apr 14, 2021
Last Verified:
Mar 1, 2021