Metformin and Nightly Fasting in Women With Early Breast Cancer

Last updated: November 6, 2025
Sponsor: M.D. Anderson Cancer Center
Overall Status: Active - Not Recruiting

Phase

2

Condition

Carcinoma

Precancerous Condition

Ductal Carcinoma In Situ (Dcis)

Treatment

Extended Release Metformin Hydrochloride

Biospecimen Collection

Short-Term Fasting

Clinical Study ID

NCT05023967
2021-0901
P30CA016672
B115UCS2019
2021-000134-34
MDA20-02-01
NCI-2021-08921
UG1CA242609
Pending3
2021-09-01
  • Ages > 18
  • Female

Study Summary

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.

Eligibility Criteria

Inclusion

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 toneo-adjuvant treatment. Women with larger tumors who refuse neo-adjuvantchemotherapy before surgery can also be eligible. Luminal HER2+ve (cT1, cN0) IBC andDCIS 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 suchas barrier method of birth control or abstinence, prior to study entry and for theduration of study participation. Should a woman become pregnant or suspect she ispregnant while participating in this study, she has to inform her study physicianimmediately. The effects of metformin hydrochloride extended release on thedeveloping human fetus at the recommended therapeutic dose are unknown

  • Ability to understand and the willingness to sign a written informed consentdocument

Exclusion

Exclusion Criteria:

  • Body mass index (BMI) < 18.5 Kg/m^2

  • Previous treatment for breast cancer including chemotherapy and endocrine therapywithin 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 skincancer 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 activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith 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 fourweeks 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 becauseeven though published data from post-marketing studies have not reported a clearassociation between metformin hydrochloride extended release and major birthdefects, miscarriage, or adverse maternal or fetal outcomes when metforminhydrochloride extended release was used during pregnancy, these studies cannotdefinitely establish the absence of any metformin hydrochloride extended releaseassociated risk because of methodological limitations, including small sample sizeand inconsistent comparator groups. Because there is an unknown but potential riskfor adverse events (AEs) in nursing infants secondary to treatment of the motherwith metformin hydrochloride extended release, breastfeeding should be discontinuedif 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

Study Design

Total Participants: 37
Treatment Group(s): 5
Primary Treatment: Extended Release Metformin Hydrochloride
Phase: 2
Study Start date:
April 04, 2023
Estimated Completion Date:
December 16, 2026

Study Description

  • 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

Connect with a study center

  • Galliera Hospital

    Genoa, 16128
    Italy

    Site Not Available

  • Galliera Hospital

    Genoa 3176219, 16128
    Italy

    Site Not Available

  • European Institute of Oncology

    Milan 6951411, 20141
    Italy

    Site Not Available

  • European Institute of Oncology

    Milano, 20141
    Italy

    Site Not Available

  • M D Anderson Cancer Center

    Houston, Texas 77030
    United States

    Site Not Available

  • M D Anderson Cancer Center

    Houston 4699066, Texas 4736286 77030
    United States

    Site Not Available

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