- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05023967
Metformin and Nightly Fasting in Women With Early Breast Cancer
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.
Study Overview
Status
Conditions
Detailed Description
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
-
Genoa, Italy, 16128
- Recruiting
- Galliera Hospital
-
Principal Investigator:
- Andrea De Censi
-
Contact:
- Andrea De Censi
- Phone Number: 39-0105634501
- Email: andrea.decensi@galliera.it
-
Milano, Italy, 20141
- Not yet recruiting
- European Institute of Oncology
-
Contact:
- Bernardo Bonanni
- Phone Number: 39-0257489022
- Email: bernardo.bonanni@ieo.it
-
Principal Investigator:
- Bernardo Bonanni
-
-
-
-
Texas
-
Houston, Texas, United States, 77030
- Recruiting
- M D Anderson Cancer Center
-
Principal Investigator:
- Parijatham Thomas, MD
-
Contact:
- Parijatham Thomas, MD
- Phone Number: 713-745-1075
- Email: psthomas@mdanderson.org
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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).
|
Undergo collection of blood and tissue samples
Other Names:
Given PO
Other Names:
Receive nutritional counseling
Other Names:
Use continuous glucose monitoring system
Other Names:
Perform intermittent fasting
Other Names:
|
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).
|
Undergo collection of blood and tissue samples
Other Names:
Use continuous glucose monitoring system
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
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)
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).
|
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
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).
|
Post-treatment (4-6 weeks)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Baseline up to 4-6 weeks
|
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.
|
Baseline up to 4-6 weeks
|
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.
|
Baseline up to 4-6 weeks
|
Difference of M30
Time Frame: Post-treatment
|
Will be assessed between arms.
Will be assessed using IHC.
|
Post-treatment
|
Difference of phosphorylated S6
Time Frame: Post-treatment
|
Will be assessed between arms.
Will be assessed using IHC.
|
Post-treatment
|
Physiological distress
Time Frame: Up to 4-6 weeks
|
Will be correlated with response biomarkers.
|
Up to 4-6 weeks
|
Eating habits
Time Frame: Up to 4-6 weeks
|
Will be correlated with response biomarkers.
|
Up to 4-6 weeks
|
Tobacco
Time Frame: Up to 4-6 weeks
|
Will be correlated with response biomarkers.
|
Up to 4-6 weeks
|
Alcohol consumption
Time Frame: Up to 4-6 weeks
|
Will be correlated with response biomarkers.
|
Up to 4-6 weeks
|
Incidence of adverse events
Time Frame: Up to 4-6 weeks
|
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
Time Frame: Up to 4-6 weeks
|
Will be assessed between arms.
|
Up to 4-6 weeks
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Andrea De Censi, M.D. Anderson Cancer Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Adenocarcinoma
- Neoplasms, Glandular and Epithelial
- Breast Diseases
- Neoplasms, Ductal, Lobular, and Medullary
- Breast Carcinoma In Situ
- Carcinoma in Situ
- Breast Neoplasms
- Carcinoma
- Carcinoma, Ductal
- Carcinoma, Intraductal, Noninfiltrating
- Carcinoma, Ductal, Breast
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Metformin
Other Study ID Numbers
- 2021-0901
- UG1CA242609 (U.S. NIH Grant/Contract)
- 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)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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