Metformin and Nightly Fasting in Women With Early Breast Cancer
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| ClinicalTrials.gov Identifier: NCT05023967 |
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Recruitment Status :
Recruiting
First Posted : August 27, 2021
Last Update Posted : May 6, 2023
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Anatomic Stage I Breast Cancer AJCC v8 Anatomic Stage II Breast Cancer AJCC v8 Breast Ductal Carcinoma In Situ Invasive Breast Carcinoma | Procedure: Biospecimen Collection Drug: Extended Release Metformin Hydrochloride Other: Monitoring Other: Nutritional Assessment Other: Short-Term Fasting | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 120 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Prevention |
| 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. |
| Actual Study Start Date : | April 4, 2023 |
| Estimated Primary Completion Date : | November 17, 2025 |
| Estimated Study Completion Date : | November 17, 2025 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Breast cancer
MedlinePlus related topics:
Breast Cancer
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (fasting, glucose monitoring, counseling, metformin)
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).
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Procedure: Biospecimen Collection
Undergo collection of blood and tissue samples
Other Names:
Drug: Extended Release Metformin Hydrochloride Given PO
Other Names:
Other: Monitoring Use continuous glucose monitoring system
Other Name: monitor Other: Nutritional Assessment Receive nutritional counseling
Other Names:
Other: Short-Term Fasting Perform intermittent fasting
Other Names:
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Active Comparator: Arm II (glucose monitoring)
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).
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Procedure: Biospecimen Collection
Undergo collection of blood and tissue samples
Other Names:
Other: Monitoring Use continuous glucose monitoring system
Other Name: monitor |
Primary Outcome Measures :
- Frequency of occurrence of dose limiting toxicity [ Time Frame: Up to 4-6 weeks ]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.
- Change in pre-post treatment Ki67 labeling index in invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) (in the absence of IBC) [ Time Frame: Baseline up to 4-6 weeks ]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).
- Difference in post-treatment adjacent DCIS (in the presence of IBC), if present, or intraepithelial neoplasia Ki67 between arms [ Time Frame: Post-treatment (4-6 weeks) ]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).
Secondary Outcome Measures :
- Change in circulating biomarkers [ Time Frame: Baseline up to 4-6 weeks ]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.
- Change of CIP2A-PP2A-GSK3beta-MCL-1 axis in cancer tissue [ Time Frame: Baseline up to 4-6 weeks ]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.
- Change of Ki67 in cancer tissue [ Time Frame: Baseline up to 4-6 weeks ]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.
- Difference of M30 [ Time Frame: Post-treatment ]Will be assessed between arms. Will be assessed using IHC.
- Difference of phosphorylated S6 [ Time Frame: Post-treatment ]Will be assessed between arms. Will be assessed using IHC.
- Physiological distress [ Time Frame: Up to 4-6 weeks ]Will be correlated with response biomarkers.
- Eating habits [ Time Frame: Up to 4-6 weeks ]Will be correlated with response biomarkers.
- Tobacco [ Time Frame: Up to 4-6 weeks ]Will be correlated with response biomarkers.
- Alcohol consumption [ Time Frame: Up to 4-6 weeks ]Will be correlated with response biomarkers.
- Incidence of adverse events [ Time Frame: Up to 4-6 weeks ]Evaluated according to the Common Terminology Criteria for Adverse Events version 5.0.
- Difference of the area under the curve of glucose levels [ Time Frame: Up to 4-6 weeks ]Will be assessed between arms.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Criteria
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05023967
Locations
| United States, Texas | |
| M D Anderson Cancer Center | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Powel H. Brown 713-792-4509 phbrown@mdanderson.org | |
| Principal Investigator: Powel H. Brown | |
| Italy | |
| Galliera Hospital | Not yet recruiting |
| Genoa, Italy, 16128 | |
| Contact: Andrea De Censi 39-0105634501 andrea.decensi@galliera.it | |
| Principal Investigator: Andrea De Censi | |
| European Institute of Oncology | Not yet recruiting |
| Milano, Italy, 20141 | |
| Contact: Bernardo Bonanni 39-0257489022 bernardo.bonanni@ieo.it | |
| Principal Investigator: Bernardo Bonanni | |
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Andrea De Censi | M.D. Anderson Cancer Center |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT05023967 |
| Other Study ID Numbers: |
NCI-2021-08921 NCI-2021-08921 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) B115UCS2019 2021-000134-34 2021-09-01 Pending3 ( Other Identifier: M D Anderson Cancer Center ) MDA20-02-01 ( Other Identifier: DCP ) P30CA016672 ( U.S. NIH Grant/Contract ) UG1CA242609 ( U.S. NIH Grant/Contract ) |
| First Posted: | August 27, 2021 Key Record Dates |
| Last Update Posted: | May 6, 2023 |
| Last Verified: | May 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | 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. |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Carcinoma Breast Neoplasms Carcinoma in Situ Carcinoma, Ductal Carcinoma, Intraductal, Noninfiltrating Carcinoma, Ductal, Breast Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms |
Neoplasms by Site Breast Diseases Skin Diseases Adenocarcinoma Neoplasms, Ductal, Lobular, and Medullary Breast Carcinoma In Situ Metformin Hypoglycemic Agents Physiological Effects of Drugs |