Exercise and Metformin in Colorectal and Breast Cancer Survivors

Study Overview
=================
Brief Summary
-----------------
Metformin is a medication that is commonly used in the treatment of diabetes. Recently small studies in cancer patients without diabetes suggest that metformin may benefit in lowering insulin levels. In those studies of patients with cancer but not diabetes, glucose (or sugar) levels in the blood are generally no lowered. Insulin and insulin-like growth factors affect the growth of cancer cells. This randomized study will compare different interventions; exercise, exercise and metformin, metformin alone, or a control arm. The investigators are not directly testing how either exercise or metformin affects your disease. The investigators are testing how they affect insulin levels in your body as well as other blood markers. The investigators believe that these blood tests may either be related to cancer recurrences or be an early sign of cancer recurrences and they are testing how both exercise and metformin may change those markers.

Detailed Description
-----------------
Subjects will be randomized into one of four groups: exercise training, exercise training and metformin, metformin alone, or control arm. All subjects will have lifestyle measurements, interviews regarding activity level, diet questionnaires, and blood tests. Subjects randomized to exercise training will participate in two supervised exercise sessions per week with an exercise physiologist for 3 months. They will also be asked to exercise on their own for up to an additional 120 minutes each week. Subjects randomized to exercise training and metformin will participate in two supervised exercise sessions per week and will take metformin. Metformin will be taken once daily for the first two weeks and then twice daily for 3 months. Subjects randomized to metformin will take metformin once daily for the first two weeks and then twice daily. Subjects on the control arm will receive a packet of educational information on nutrition and physical activity developed by the National Cancer Institute and American Cancer Society. In addition to education information, they will be offered two supervised sessions with an exercise physiologist as well as a pedometer 3 months after enrollment in the study.

Official Title
-----------------
Randomized Phase II Study of Exercise and Metformin in Colorectal and Breast Cancer Survivors

Conditions
-----------------
Colorectal Cancer, Breast Cancer

Intervention / Treatment
-----------------
* Behavioral: Exercise training
* Drug: Metformin
* Other: Educational information


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed stage I-III colorectal or breast cancer Undergone curative-intent complete surgical resection and completed all adjuvant therapy (if indicated) at least 2 months prior to enrollment Note: Breast cancer subjects on hormonal therapy or trastuzumab only therapy and colorectal cancer subjects on adjunctive therapies not considered cytotoxic chemotherapy (including those participating in CALGB 80702 receiving only celecoxib/placebo) are eligible. Participants will be allowed to receive concomitant adjuvant endocrine therapy for breast cancer; however, all endocrine agents must be initiated at least 1 month prior to enrollment in the study and continued throughout the duration of study participation. Less than 120 minutes of exercise per week Approval by oncologist or surgeon English speaking and able to read English No planned surgery anticipated in the 3 month intervention period At least one month from any major surgery to start of intervention including colostomy reversal Exclusion Criteria: Concurrent other malignancy or history of other malignancy treated within the past 3 years (other than non-melanoma skin cancer or in-situ cervical cancer) Metastatic disease Scheduled to receive any form of further adjuvant cancer therapy Currently on medication for diabetes treatment Pregnant or breast-feeding Any condition associated with increased risk of metformin-associated lactic acidosis (prior renal failure or liver failure, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day) Known hypersensitivity or intolerance to metformin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Exercise training<br>Exercise training with exercise physiologist | Behavioral: Exercise training<br>* Two supervised exercise sessions per week<br>|
| Active Comparator: Exercise training with metformin<br>Exercise training with exercise physiologist with oral metformin | Behavioral: Exercise training<br>* Two supervised exercise sessions per week<br>Drug: Metformin<br>* Oral metformin QD for two weeks, then BID<br>* Other names: Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet;|
| Active Comparator: Metformin<br>Metformin | Drug: Metformin<br>* Oral metformin QD for two weeks, then BID<br>* Other names: Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet;|
| Active Comparator: Control<br>Educational information | Other: Educational information<br>* educational information<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Insulin Level | Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting insulin level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting insulin levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 0 and 3 months (change between 0 and 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Other Insulin-Related Biomarkers | Markers related to insulin and insulin-like growth factors (including insulin-like growth factor 1 [IGF-1], IGF binding protein-1 [IGFBP-1], IGF binding protein-3 [IGFBP-3], leptin) will be measured by a blood draw at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 0 and 3 months (change between 0 and 3 months) | 
| Change in Fasting Glucose Level | Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting Glucose level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting Glucose levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 0 and 3 months (change between 0 and 3 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Colorectal, Breast, Insulin, Exercise