Trial Outcomes & Findings for A Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women With Metastatic Breast Cancer (NCT NCT01310231)

Last Updated: 2021-04-14

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

40 participants

Primary outcome timeframe

From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years.

Results posted on

2021-04-14

Participant Flow

Participant milestones

Participant milestones
Measure	Metformin 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 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.
Overall Study STARTED	22	18
Overall Study Received Intervention	22	17
Overall Study Discontinued Intervention	0	1
Overall Study Analyzed for Survival	22	18
Overall Study Analyzed for Response, Toxicity, QOL	22	17
Overall Study COMPLETED	22	17
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Metformin n=22 Participants 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 n=18 Participants 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 n=40 Participants Total of all reporting groups
Age, Continuous	55 years n=5 Participants	57 years n=7 Participants	55.9 years n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	18 Participants n=7 Participants	40 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	17 Participants n=5 Participants	13 Participants n=7 Participants	30 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
ECOG Performance Scale ECOG 0-1	20 Participants n=5 Participants	16 Participants n=7 Participants	36 Participants n=5 Participants
ECOG Performance Scale ECOG 2	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Body Mass Index (BMI)	26.5 kg/m^2 n=5 Participants	26.6 kg/m^2 n=7 Participants	26.5 kg/m^2 n=5 Participants
Receptor Status (Estrogen Receptor (ER)/Progesterone Receptor (PR) positive	19 participants n=5 Participants	15 participants n=7 Participants	34 participants n=5 Participants
Receptor Status ER/PR negative	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Human epidermal growth factor receptor 2 (HER2) status HER2 positive	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Human epidermal growth factor receptor 2 (HER2) status HER2 negative	20 participants n=5 Participants	14 participants n=7 Participants	34 participants n=5 Participants
Any adjuvant chemotherapy Yes	13 participants n=5 Participants	12 participants n=7 Participants	25 participants n=5 Participants
Any adjuvant chemotherapy No	9 participants n=5 Participants	6 participants n=7 Participants	15 participants n=5 Participants
1st diagnosis to randomization	6.5 years n=5 Participants	4 years n=7 Participants	5.4 years n=5 Participants
1st metastasis to randomization	0.8 years n=5 Participants	1.1 years n=7 Participants	0.9 years n=5 Participants
Line of treatment 1st line treatment	15 participants n=5 Participants	12 participants n=7 Participants	27 participants n=5 Participants
Line of treatment 2nd line treatment	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Line of treatment 3+ lines treatment	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Any visceral disease Yes	21 participants n=5 Participants	13 participants n=7 Participants	34 participants n=5 Participants
Any visceral disease No	1 participants n=5 Participants	5 participants n=7 Participants	6 participants n=5 Participants
Involvement beyond bone and lymph nodes Yes	22 participants n=5 Participants	15 participants n=7 Participants	37 participants n=5 Participants
Involvement beyond bone and lymph nodes No	0 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants

PRIMARY outcome

Timeframe: From date of randomization to first documented progression or death, which ever occurs first, assessed up to 3 years.

Outcome measures

Outcome measures
Measure	Metformin n=22 Participants 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 n=18 Participants 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.
Progression Free Survival.	5.4 months Standard Deviation 1.04	6.3 months Standard Deviation 1.68

SECONDARY outcome

Timeframe: From baseline until time of best response, assessed up to 3 years

Population: Population is everyone with measurable disease (metformin 22, placebo 16)

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.

Outcome measures

Outcome measures
Measure	Metformin n=22 Participants 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 n=16 Participants 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.
Overall Response Rate Clinical benefit	12 Participants	7 Participants
Overall Response Rate Progressive disease	10 Participants	9 Participants

SECONDARY outcome

Timeframe: Up to 30 days after end of study

Population: Population is everyone who received study drug (metformin n=22, placebo n=17).

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

Outcome measures

Outcome measures
Measure	Metformin n=22 Participants 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 n=17 Participants 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.
Number of Participants With Grade 1 or 2 Adverse Events	15 Participants	6 Participants

SECONDARY outcome

Timeframe: Up to 30 days after end of study

Population: Population is everyone who received study drug (metformin n=22, placebo n=17).

Outcome measures

Outcome measures
Measure	Metformin n=22 Participants 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 n=17 Participants 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.
Number of Participants With Grade 3 or 4 Adverse Events	7 Participants	10 Participants

SECONDARY outcome

Timeframe: From baseline to cycle 2 of chemotherapy

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Metformin n=19 Participants 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 n=16 Participants 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.
EORTC Quality of Life Measures Global health Status	-12.7 EORTC functioning scale Standard Deviation 18.7	6.3 EORTC functioning scale Standard Deviation 19.6
EORTC Quality of Life Measures Physical functioning	-6.0 EORTC functioning scale Standard Deviation 12.9	2.1 EORTC functioning scale Standard Deviation 12.1
EORTC Quality of Life Measures Role functioning	-18.4 EORTC functioning scale Standard Deviation 27.7	-2.1 EORTC functioning scale Standard Deviation 20.1
EORTC Quality of Life Measures Emotional functioning	-2.6 EORTC functioning scale Standard Deviation 21.1	2.3 EORTC functioning scale Standard Deviation 16.7
EORTC Quality of Life Measures Cognitive functioning	-0.9 EORTC functioning scale Standard Deviation 10.4	0 EORTC functioning scale Standard Deviation 17.2
EORTC Quality of Life Measures Social functioning	-12.3 EORTC functioning scale Standard Deviation 29.8	4.2 EORTC functioning scale Standard Deviation 23.2

SECONDARY outcome

Timeframe: Baseline to Cycle 2

Population: Population is everyone who had institutional glucose performed at BOTH baseline and Cycle 2 (19 metformin, 15 placebo).

Change in fasting glucose from baseline to Cycle 2

Outcome measures

Outcome measures
Measure	Metformin n=12 Participants 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 n=7 Participants 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.
Change in Fasting Glucose (mmol/L)	-0.2 mmol/L Interval -0.4 to 0.3	0 mmol/L Interval -0.15 to 0.25

SECONDARY outcome

Timeframe: Baseline to Cycle 2

Population: Population is everyone who had sufficient fasting blood available for analysis at BOTH baseline and Cycle 2 (12 metformin, 7 placebo).

Change in fasting insulin from baseline to Cycle 2

Outcome measures

Outcome measures
Measure	Metformin n=12 Participants 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 n=7 Participants 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.
Change in Fasting Insulin	-7 pmol/L Interval -14.25 to 0.5	1 pmol/L Interval -13.5 to 20.5

SECONDARY outcome

Timeframe: Baseline to Cycle 2

Population: Population is everyone who had sufficient fasting blood available for analysis at BOTH baseline and Cycle 2 (12 metformin, 7 placebo).

HOMA-IR is an index calculated from fasting insulin (pmol/L) and glucose (mmol/L) as insulin/6.9 times glucose/22.5.

Outcome measures

Outcome measures
Measure	Metformin n=12 Participants 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 n=7 Participants 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.
Change in Insulin Resistance From Baseline to Cycle 2 Measured Using Homeostatic Model Assessment (HOMA-IR)	-0.16 HOMA-IR score Interval -0.85 to 0.0	0.12 HOMA-IR score Interval -0.52 to 0.62

SECONDARY outcome

Timeframe: Baseline and 3 weeks.

Population: Data not collected

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: Data not collected

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.

Outcome measures

Outcome data not reported

Adverse Events

Metformin

Serious events: 3 serious events

Other events: 22 other events

Deaths: 19 deaths

Placebo

Serious events: 4 serious events

Other events: 15 other events

Deaths: 15 deaths

Serious adverse events

Serious adverse events
Measure	Metformin n=22 participants at risk 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 n=17 participants at risk 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.
Respiratory, thoracic and mediastinal disorders hypoxia	0.00% 0/22 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).	5.9% 1/17 • Number of events 1 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).
Gastrointestinal disorders ascites with hyponatraemia	0.00% 0/22 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).	5.9% 1/17 • Number of events 1 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).
Vascular disorders thromboembolism	0.00% 0/22 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).	5.9% 1/17 • Number of events 1 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).
Infections and infestations febrile neutropenia with respiratory infection	4.5% 1/22 • Number of events 1 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).	0.00% 0/17 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).
Infections and infestations urosepsis	4.5% 1/22 • Number of events 1 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).	0.00% 0/17 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).
Respiratory, thoracic and mediastinal disorders dyspnoea	4.5% 1/22 • Number of events 1 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).	0.00% 0/17 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).
Infections and infestations febrile neutropenia with urinary tract infection	0.00% 0/22 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).	5.9% 1/17 • Number of events 1 • The Adverse Events reporting period is defined as the time of consent signature until 30 days after date of off study treatment. 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).

Other adverse events

Additional Information

Pamela Goodwin/PI

Mount Sinai Hospital

Phone: 416 586-8211

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place