Metformin and Nightly Fasting in Women With Early Breast Cancer

• Primary Interim Objective

The primary interim objective will be 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. A DLT is defined as a hypoglycemic event requiring permanent discontinuation of study treatment or any grade 3 or greater adverse event (AE) possibly, probably, or definitely related to the study drug.

Hypoglycemia AEs that require permanent discontinuation of study treatment are:

• ≥ 1 grade 2 or higher neuroglycopenic symptoms and grade 2 hypoglycemia;
• occurrence ≥ 3 times of grade 2 symptoms (≥ 2 autonomic or ≥ 1 neuroglycopenic symptoms) and grade 1 or higher hypoglycemia;
• symptomatic or asymptomatic grade 3 hypoglycemia.

In the first 14 participants enrolled in the experimental arm (combination of prolonged nightly fasting and Metformin Hydrochloride Extended-Release) we can accept at most 3 participants with a DLT. If 4 or more of the first 14 participants assigned to the treatment arm experience the above-mentioned DLTs, the trial will be definitively stopped.

In order to early identify any DLT, participants will be instructed to contact study staff in case of occurrence of any symptoms regardless of their grade and a review of the occurrence of any AE will be performed every 10 days. The early detection of symptoms related to the study treatment will help us to avoid worsening of symptoms to grade 3 and thus prevent any DLT. Moreover, the glucose trends of the first 14 participants enrolled in the experimental arm will be downloaded and immediately evaluated to identify any asymptomatic hypoglycemia.

Hypoglycemia will be assessed through the evaluation of glucose reports and fingersticks results in case of symptoms.

• Primary and Co-primary Objective

We have recently shown that the combination of hypoglycemia and Metformin reduces tumor growth in animal models (1). Moreover, Metformin alone was able to reduce breast cancer cell proliferation in women with insulin resistance in a randomized presurgical trial (2,3).

Breast carcinogenesis may be present in three components in surgical specimens and more rarely in biopsy specimens: invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) and intraepithelial neoplasia (IEN), defined as atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS). We propose to assess the effect of the combination of prolonged nightly fasting (≥16 hours) and Metformin Hydrochloride Extended-Release on the change of Ki67 labeling index (LI) in cancer tissue (IBC or DCIS, if IBC is absent) between pre-treatment biopsy and post treatment surgical specimen. As co-primary objective, we will also evaluate the difference in post-treatment Ki67 LI in cancer adjacent DCIS (in the presence of IBC), if present, or IEN (defined as ADH or ALH or LCIS) between the active treatment and the control group. IBC and DCIS strata will be based on the post-treatment pathology. If DCIS is the primary lesion because of the absence of invasive disease, adjacent IEN will be counted only if ADH/ALH/LCIS is present.

The change (pre/post treatment) of Ki67 LI in IEN will be evaluated only if present in the pretreatment biopsy specimen.

Secondary Objectives

• to explore the effect of intervention on the change of expression of PP2A-GSK3ß-MCL-1 axis in pre-post treatment cancer tissue levels;
• to measure the change in circulating biomarkers: HOMA index, Hb1Ac;
• to measure the difference of cell death by IHC for M30 in post- treatment cancer samples between arms;
• to measure the difference of pS6 by IHC in post- treatment cancer samples between arms;
• to compare the area under the curve (AUC) of glucose levels between arms according to insulin resistance biomarker levels and WCRF score;
• to assess safety and toxicities according to NCI-CTC AE v. 5.0.
• Exploratory Objectives
• to correlate a customized NGS mutational profile panel focused on ER+ve with the response of Ki67;
• to measure the change in circulating biomarkers: highly sensitive CRP (hsCRP), C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, lipid profile, adipokines (leptin and adiponectin);
• to correlate psychological distress, eating habits, tobacco and alcohol consumption with the response of Ki67 and insulin resistance biomarkers between arms;
• to compare the slow ramp up schedule of metformin to the quick ramp up schedule to metformin in the treatment group on the area under the curve (AUC) of glucose levels

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 within the last 12 months
• Women who are planned to receive neoadjuvant therapy
• Triple negative breast cancer (BC)
• Patients with a history of cancer within the last year. NOTE: Non melanoma skin cancer is allowed.
• 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 or lactating women. 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