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Anatomic Stage I Breast Cancer AJCC v8Phase 2NCT05023967

Metformin and Nightly Fasting in Women With Early Breast Cancer

A Phase 2 study testing Biospecimen Collection, Extended Release Metformin Hydrochloride and Monitoring in people with Anatomic Stage I Breast Cancer AJCC v8 and Anatomic Stage II Breast Cancer AJCC v8, run by M.D. Anderson Cancer Center at 3 sites in 2 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
Biospecimen Collection, Extended Release Metformin Hydrochloride and Monitoring
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
120 participants
Where
3 sitesin 2 countries
Study dates
4 Apr 2023to 16 Dec 2026
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 11Show fewer
  • 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

Who cannot join

  • 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
Show all 19Show fewer
  • 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

Trial locations and contacts

3 sites in 2 countries.

3 sites in 2 countries

Italy2 sites

  • Galliera Hospital

    Genoa, 16128

  • European Institute of Oncology

    Milan, 20141

Other trials in Italy

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: 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.

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.

Read the detailed 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
Being tested
Biospecimen Collection, Extended Release Metformin Hydrochloride, Monitoring, Nutritional Assessment, Short-Term Fasting
Medical subject headings
Carcinoma, Intraductal, Noninfiltrating

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection

    Undergo collection of blood and tissue samples

  • Extended Release Metformin HydrochlorideDrug

    Also called ER Metformin Hydrochloride, Extended-release Metformin Hydrochloride, Glucophage XR, Glumetza

    Given PO

  • MonitoringOther

    Also called monitor

    Use continuous glucose monitoring system

  • Nutritional AssessmentOther

    Also called Dietary Assessment, dietary counseling, nutritional counseling

    Receive nutritional counseling

  • Short-Term FastingOther

    Also called Intermittent Fasting, Short-term Intermittent Fasting

    Perform intermittent fasting

Study groups in NCT05023967
Study groupRoleWhat they receive
Arm I (fasting, glucose monitoring, counseling, metformin)ExperimentalPatients 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).
Receives: Procedure: Biospecimen Collection; Drug: Extended Release Metformin Hydrochloride; Other: Monitoring; Other: Nutritional Assessment; Other: Short-Term Fasting
Arm II (glucose monitoring)Active comparatorPatients 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).
Receives: Procedure: Biospecimen Collection; Other: Monitoring

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 4-6 weeks

  2. 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).

    Measured: Baseline up to 4-6 weeks

  3. 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).

    Measured: Post-treatment (4-6 weeks)

Secondary outcomes (11)

  1. 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.

    Measured: Baseline up to 4-6 weeks

  2. 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.

    Measured: Baseline up to 4-6 weeks

  3. 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.

    Measured: Baseline up to 4-6 weeks

  4. Difference of M30

    Will be assessed between arms. Will be assessed using IHC.

    Measured: Post-treatment

  5. Difference of phosphorylated S6

    Will be assessed between arms. Will be assessed using IHC.

    Measured: Post-treatment

  6. Physiological distress

    Will be correlated with response biomarkers.

    Measured: Up to 4-6 weeks

  7. Eating habits

    Will be correlated with response biomarkers.

    Measured: Up to 4-6 weeks

  8. Tobacco

    Will be correlated with response biomarkers.

    Measured: Up to 4-6 weeks

  9. Alcohol consumption

    Will be correlated with response biomarkers.

    Measured: Up to 4-6 weeks

  10. Incidence of adverse events

    Evaluated according to the Common Terminology Criteria for Adverse Events version 5.0.

    Measured: Up to 4-6 weeks

  11. Difference of the area under the curve of glucose levels

    Will be assessed between arms.

    Measured: Up to 4-6 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Aug 2021
  2. Study start4 Apr 2023
  3. Primary completion9 Dec 2025
  4. Study completion16 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
120 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05023967
Sponsor's protocol ID
2021-0901
Other IDs
NCI-2021-08921, B115UCS2019, 2021-000134-34, 2021-09-01, Pending3, MDA20-02-01, UG1CA242609
Status last verified
Nov 2025
First submitted
26 Aug 2021
Last updated
5 Jan 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Publications

  • Briata IM, Spinaci S, Thomas PS, Serrano D, Buttiron Webber T, Gandolfo N, Guasone F, Rattaro A, Firpo E, D'amico M, Rutigliani M, Oliva M, Gualco M, Peresi M, Uncini S, Guerrieri-Gonzaga A, Johansson H, Gandini S, Lazzeroni M, Accornero CA, Pala O, Minucci S, Intra M, Veronesi P, Vornik LA, Garcia-Gonzalez A, Lozano MC, Heckman-Stoddard BM, Dimond E, Sauter ER, Vilar E, Bonanni B, DeCensi A. Time-Restricted Eating and Metformin in Invasive Breast Cancer or DCIS: A Randomized, Phase IIb, Presurgical Trial. Preliminary Safety Analysis. Cancer Prev Res (Phila). 2026 Jan 6;19(1):25-32. doi: 10.1158/1940-6207.CAPR-25-0104.

    PubMed 41165048

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Biospecimen Collection, Extended Release Metformin Hydrochloride and Monitoring in people with Anatomic Stage I Breast Cancer AJCC v8 and Anatomic Stage II Breast Cancer AJCC v8, run by M.D. Anderson Cancer Center at 3 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 5 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Italy, United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Frequency of occurrence of dose limiting toxicity (time frame: Up to 4-6 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05023967, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jan 2026.

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