Metformin and Nightly Fasting in Women With Early Breast Cancer

Study Overview
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Brief Summary
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This phase IIb trial studies the combined effect of prolonged nightly fasting and metformin hydrochloride extended release in decreasing breast tumor cell proliferation and other biomarkers of breast cancer. Preventing invasive breast cancer or DCIS. Metformin is widely used to treat type II diabetes and is associated with a decreased risk of cancer and death in diabetic individuals. Intermittent fasting may protect cancer patients from the toxic effects of chemotherapy agents without causing chronic weight loss. The combination of intermittent fasting and metformin may reduce breast cancer growth and may be used in women at risk for breast cancer or other cancers associated with being overweight.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the safety of the experimental intervention based on the frequency of occurrence of a dose limiting toxicity (DLT) in the first 14 participants assigned to the experimental treatment arm. II. Evaluate the difference in post-treatment Ki67 labeling index (LI) in cancer adjacent ductal carcinoma in situ (DCIS) (in the presence of invasive breast cancer [IBC]), if present, or intraepithelial neoplasia (IEN) (defined as atypical ductal hyperplasia [ADH] or atypical lobular hyperplasia [ALH] or lobular carcinoma in situ [LCIS]) between the active treatment and the control group. SECONDARY OBJECTIVES: I. To explore the effect of intervention on the change of expression of PP2A-GSK3beta-MCL-1 axis in pre-post treatment cancer tissue levels. II. To measure the change in circulating biomarkers: Homeostatic model assessment (HOMA) index, highly sensitive C-reactive protein (CRP) (hsCRP), C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, Hb1Ac, lipid profile, adipokines (leptin and adiponectin). III. To correlate a customized next generation sequencing (NGS) mutational profile panel focused on estrogen receptor (ER) positive (+ve) with the response of Ki67. IV. To measure the difference of cell death by immunohistochemistry (IHC) for M30 in post- treatment cancer samples between arms. V. To measure the difference of phosphorylated (p)S6 by IHC in post- treatment cancer samples between arms. VI. To assess safety and toxicities according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0. VII. To correlate physiological distress, eating habits, tobacco and alcohol consumption with the response of Ki67 between arms. VIII. To compare the area under the curve (AUC) of glucose levels between arms and within the experimental arm according to different doses of metformin hydrochloride extended release (0 mg, 750 mg and 1500 mg). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients fast for >= 16 hours every night and use the continuous glucose monitoring system for 4-6 weeks. Patients also receive nutritional counseling sessions on days 0 and 10. Beginning week 2, patients also receive metformin hydrochloride extended release orally (PO) once daily (QD) until the day of surgery. Treatment continues for 4-6 weeks (until surgery) in the absence of disease progression or unacceptable toxicity. Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43). ARM II: Patients continue their usual dietary pattern and use the continuous glucose monitoring system for 4-6 weeks (until surgery). Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43). After completion of study intervention, patients are followed up at 30 days.

Official Title
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Time Restricted Eating And Metformin (TEAM) in Invasive Breast Cancer (IBC) or Ductal Carcinoma in Situ (DCIS). A Randomized, Phase IIb, Window of Opportunity Presurgical Trial.

Conditions
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Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Breast Ductal Carcinoma In Situ, Invasive Breast Carcinoma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Drug: Extended Release Metformin Hydrochloride
* Other: Monitoring
* Other: Nutritional Assessment
* Other: Short-Term Fasting


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with histologically confirmed luminal (ER+ve and/or progesterone [PgR]+ve >= 1%) operable IBC (cT1-2, cN0-1, Mx) candidate to elective surgery and not to neo-adjuvant treatment. Women with larger tumors who refuse neo-adjuvant chemotherapy before surgery can also be eligible. Luminal HER2+ve (cT1, cN0) IBC and DCIS are also eligible Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) Leukocytes >= 3,000/microliter Absolute neutrophil count >= 1,500/microliter Platelets >= 100,000/microliter Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal Creatinine within normal institutional limits Creatinine clearance estimated with Cockcroft-Gault formula > 45 mL/min Female participants of child-bearing potential must agree to use contraception such as barrier method of birth control or abstinence, prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she has to inform her study physician immediately. The effects of metformin hydrochloride extended release on the developing human fetus at the recommended therapeutic dose are unknown Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Body mass index (BMI) < 18.5 Kg/m^2 Previous treatment for breast cancer including chemotherapy and endocrine therapy Women who are planned to receive neoadjuvant therapy (HER2+ve T2 or N+ve IBC or women < 50 years with luminal B IBC) Triple negative breast cancer (BC) Documented history of symptomatic hypoglycemia Diabetic patients or participants with fasting glucose level >= 126 mg/dL Known hypersensitivity or intolerance to metformin hydrochloride extended release Participants should not be receiving any other investigational agents Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements History of lactic acidosis Liver dysfunction including chronic active hepatitis and cirrhosis not compensated History of vitamin B12 deficiency or megaloblastic anemia Chronic use of large doses of diuretics (e.g., > 80 mg furosemide) Current use of oral hormonal contraceptives or female hormones in the last four weeks or 5 half-lives, excluding vaginal creams and intrauterine devices (IUDs) Concomitant use of topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) Pregnant women are excluded from this study because even though published data from post-marketing studies have not reported a clear association between metformin hydrochloride extended release and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin hydrochloride extended release was used during pregnancy, these studies cannot definitely establish the absence of any metformin hydrochloride extended release associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with metformin hydrochloride extended release, breastfeeding should be discontinued if the mother is treated with metformin hydrochloride extended release. Moreover, prolonged fasting is not recommended in pregnant woman Women who practice any type of intermittent fasting program Women who will not have anyone available to assist them in case of need

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (fasting, glucose monitoring, counseling, metformin)<br>Patients fast for >= 16 hours every night and use the continuous glucose monitoring system for 4-6 weeks. Patients also receive nutritional counseling sessions on days 0 and 10. Beginning week 2, patients also receive metformin hydrochloride extended release PO QD until the day of surgery. Treatment continues for 4-6 weeks (until surgery) in the absence of disease progression or unacceptable toxicity. Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43). | Procedure: Biospecimen Collection<br>* Undergo collection of blood and tissue samples<br>* Other names: Specimen Collection;Drug: Extended Release Metformin Hydrochloride<br>* Given PO<br>* Other names: Metformin Hydrochloride Extended Release;Other: Monitoring<br>* Use continuous glucose monitoring system<br>* Other names: monitor;Other: Nutritional Assessment<br>* Receive nutritional counseling<br>* Other names: nutritional counseling;Other: Short-Term Fasting<br>* Perform intermittent fasting<br>* Other names: Short-term Intermittent Fasting;|
| Active Comparator: Arm II (glucose monitoring)<br>Patients continue their usual dietary pattern and use the continuous glucose monitoring system for 4-6 weeks (until surgery). Patients undergo the collection of blood samples at baseline and at the final study visit (days 28-43), and the collection of tissue at the time of surgery (days 28-43). | Procedure: Biospecimen Collection<br>* Undergo collection of blood and tissue samples<br>* Other names: Specimen Collection;Other: Monitoring<br>* Use continuous glucose monitoring system<br>* Other names: monitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of occurrence of dose limiting toxicity | Defined as a hypoglycemic event requiring permanent discontinuation of study treatment or any grade 3 or greater adverse event possibly, probably, or definitely related to the study drug. | Up to 4-6 weeks | 
| Change in pre-post treatment Ki67 labeling index in invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) (in the absence of IBC) | Generalized linear models will be used to assess differences between treatment arms for Ki67. Log transformation will be considered to obtain normal distribution of residuals. Will also evaluate the need to adjust for baseline characteristics and significant confounders (such as body mass index [BMI] and HER2 status). | Baseline up to 4-6 weeks | 
| Difference in post-treatment adjacent DCIS (in the presence of IBC), if present, or intraepithelial neoplasia Ki67 between arms | Generalized linear models will be used to assess differences between treatment arms for Ki67. Log transformation will be considered to obtain normal distribution of residuals. Will also evaluate the need to adjust for baseline characteristics and significant confounders (such as BMI and HER2 status). | Post-treatment (4-6 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in circulating biomarkers | Will include Homeostatic model assessment index, highly sensitive C-reactive protein, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, Hb1Ac, lipid profile, leptin and adiponectin. Will present full distributions and median values of circulating biomarkers, Ki67, at baseline, after treatment, and of changes and percentage changes (with interquartile ranges) of all continuous variables, by arms. Analysis of covariance (ANCOVA) models will evaluate the associations of post values (after treatment) and changes from baseline by study arms adjusting for baseline values, explanatory variables and possible confounders (such as age and BMI). Normal distribution of residuals from full models will be checked and, if needed, a transformation will be considered. | Baseline up to 4-6 weeks | 
| Change of CIP2A-PP2A-GSK3beta-MCL-1 axis in cancer tissue | Will present full distributions and median values of circulating biomarkers, Ki67, at baseline, after treatment, and of changes and percentage changes (with interquartile ranges) of all continuous variables, by arms. ANCOVA models will evaluate the associations of post values (after treatment) and changes from baseline by study arms adjusting for baseline values, explanatory variables and possible confounders (such as age and BMI). Normal distribution of residuals from full models will be checked and, if needed, a transformation will be considered. | Baseline up to 4-6 weeks | 
| Change of Ki67 in cancer tissue | Will depend upon next generation sequencing mutational profile obtained in post-treatment surgical specimens. Will present full distributions and median values of circulating biomarkers, Ki67, at baseline, after treatment, and of changes and percentage changes (with interquartile ranges) of all continuous variables, by arms. ANCOVA models will evaluate the associations of post values (after treatment) and changes from baseline by study arms adjusting for baseline values, explanatory variables and possible confounders (such as age and BMI). Normal distribution of residuals from full models will be checked and, if needed, a transformation will be considered. | Baseline up to 4-6 weeks | 
| Difference of M30 | Will be assessed between arms. Will be assessed using IHC. | Post-treatment | 
| Difference of phosphorylated S6 | Will be assessed between arms. Will be assessed using IHC. | Post-treatment | 
| Physiological distress | Will be correlated with response biomarkers. | Up to 4-6 weeks | 
| Eating habits | Will be correlated with response biomarkers. | Up to 4-6 weeks | 
| Tobacco | Will be correlated with response biomarkers. | Up to 4-6 weeks | 
| Alcohol consumption | Will be correlated with response biomarkers. | Up to 4-6 weeks | 
| Incidence of adverse events | Evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. | Up to 4-6 weeks | 
| Difference of the area under the curve of glucose levels | Will be assessed between arms. | Up to 4-6 weeks |