Metformin for the Treatment of Insulin Resistance in Women With Stage I-III Breast Cancer Completing Chemotherapy

Phase 3

Recruiting

• Conditions: Anatomic Stage I Breast Cancer AJCC v8; Anatomic Stage II Breast Cancer AJCC v8; Anatomic Stage III Breast Cancer AJCC v8; Invasive Breast Carcinoma
• Interventions: Procedure: Biospecimen Collection; Other: Educational Intervention; Drug: Extended Release Metformin Hydrochloride; Other: Questionnaire Administration

• Registration Number: NCT06763328
• Lead Sponsor: City of Hope Medical Center

Brief Summary

This phase III trial evaluates how often women develop insulin resistance and type-2 diabetes and compares metformin with usual care to usual care alone in treating insulin resistance in women with stage I-III breast cancer after chemotherapy. Insulin resistance occurs when cells stop responding to insulin and is a risk factor for developing diabetes and heart disease. Higher levels of insulin have been shown to be associated with aggressive breast cancer. Metformin hydrochloride decreases the amount of glucose (a type of sugar) released into the bloodstream from the liver and increases the body's use of the glucose. Metformin as well as standard of care diet and exercise education is known to lower blood sugar. However, chemotherapy may accelerate metabolic disorders, such as high blood sugar, and the impact of metformin in these breast cancer survivors is not known. Giving metformin with usual care may be more effective than usual care alone in preventing or reversing insulin resistance in women with stage I-III breast cancer after chemotherapy.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if extended release metformin hydrochloride (metformin) can normalize glycosylated hemoglobin (HgbA1c) (\< 5.7%) for women breast cancer survivors with HgbA1c between 5.7-6.4%.

EXPLORATORY OBJECTIVES:

I. To investigate whether metformin treatment of insulin resistance (versus standard of care alone) alters epigenetic changes (chromatin acetylation, chromatin opening, and methylation) and the level of inflammatory cytokines. (Pilot) II. To investigate whether normalization of HgbA1c alters epigenetic changes (chromatin acetylation, chromatin opening, and methylation) and the level of inflammatory cytokines. (Pilot)

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive standard of care healthy diet and exercise handouts and extended release metformin orally (PO) once daily (QD) for 12 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.

ARM II: Patients receive standard of care healthy diet and exercise handouts on study. Additionally, patients undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days and in 12 months.

Study Timeline

• Study Start: 2024-12-16
• Status Verified: 2025-01
• Study First Submitted: 2025-01-02
• Study First Submitted QC: 2025-01-02
• Last Update Submitted: 2025-01-02
• Study First Posted: 2025-01-08
• Last Update Posted: 2025-01-08
• Primary Completion: 2029-06-16
• Study Completion: 2029-06-16

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 200

Inclusion Criteria

• Documented informed consent of the participant and/or legally authorized representative

• Agreement to allow lab draw of approximately 26 mL of blood (less than 3 tablespoons)

  • To check blood counts, organ function and disease at baseline and 12 months
  • Clinical labs at baseline, 3 months, 6 months,12 months, and 24 months
  • Research labs at baseline, 6 months,12 months, and 24 months

• Age: ≥ 18 years

• Female sex assigned at birth

• Ability to read and understand English or Spanish for questionnaires

• Diagnosis of estrogen receptor (ER)-negative /HER2-wild type or -amplified invasive mammary carcinoma stages I-III

• Receive systemic treatment for breast cancer treatment

• Completed treatment for stage 1-3 breast cancer within 30 days to 3 years and are disease free

• Women who receive drugs for weight loss - e.g. semaglutide - prior to diagnosis are eligible for this protocol and can continue the drug during the intervention

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Exclusion Criteria

• Currently taking metformin or any other oral antidiabetic medications. Weight loss medications are permitted - e.g. semaglutide
• Taking tamoxifen or aromatase inhibitor
• Contraindication to metformin prevention such as acute hypersensitivity or allergic reaction to metformin
• Participants with acute or chronic renal insufficiency (a glomerular filtration rate [GFR] < 30 mL/min/1.73m^2) or those with acute renal insufficiency of any severity due to hepato-renal syndrome or in the peri-operative liver transplantation period
• Previously diagnosed type 1 or type 2 diabetes
• Patients pregnant or within 1 year of pregnancy and completion of lactation (pregnancy tests are standard of care [SOC] for initiation of chemotherapy)
• Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• An employee who is under the direct/indirect supervision of the principal investigator (PI)/a co-investigator/the study manager and/or a direct study team member
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (standard of care, metformin)	Biospecimen Collection	Patients receive standard of care healthy diet and exercise handouts and extended release metformin PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.
Arm I (standard of care, metformin)	Educational Intervention	Patients receive standard of care healthy diet and exercise handouts and extended release metformin PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.
Arm I (standard of care, metformin)	Extended Release Metformin Hydrochloride	Patients receive standard of care healthy diet and exercise handouts and extended release metformin PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.
Arm I (standard of care, metformin)	Questionnaire Administration	Patients receive standard of care healthy diet and exercise handouts and extended release metformin PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.
Arm II (standard of care)	Biospecimen Collection	Patients receive standard of care healthy diet and exercise handouts on study. Additionally, patients undergo blood sample collection throughout the study.
Arm II (standard of care)	Educational Intervention	Patients receive standard of care healthy diet and exercise handouts on study. Additionally, patients undergo blood sample collection throughout the study.
Arm II (standard of care)	Questionnaire Administration	Patients receive standard of care healthy diet and exercise handouts on study. Additionally, patients undergo blood sample collection throughout the study.

Primary Outcome Measures

Name	Time	Method
Hemoglobin A1c (Hgb A1c) normalization	Up to 12 months	Will be defined as Hgb A1c \< 5.7%. Will be compared across groups (metformin + standard of care/usual medical care versus standard of care/usual medical care alone) using chi-square statistics. Data will be summarized using counts and percentages.

Secondary Outcome Measures

Name	Time	Method
HgbA1c normalization	At 3, 6, 12 and 24 months	Will compare HgbA1c normalization as well as pairwise t-tests across treatment groups to examine the magnitude of change in HgbA1c.

Trial Locations

Locations (3)

City of Hope Medical Center; 🇺🇸 Duarte, California, United States

UC San Diego Moores Cancer Center; 🇺🇸 La Jolla, California, United States

University of California-Riverside; 🇺🇸 Riverside, California, United States