Evaluation of Time-Restricted Eating and Metformin Hydrochloride in Luminal Invasive Breast Cancer and Ductal Carcinoma In Situ: A Phase IIb Randomized Trial
- Trial ID
- 2024-518402-40-00
Trial statistics
Objectives
The primary objective of this study is to assess the effect of the combination of prolonged nightly fasting (≥16 hours) and **Metformin** on the change of Ki67 labeling index (LI) in cancer tissue, specifically in **invasive breast cancer** (IBC) or ductal carcinoma in situ (DCIS), if IBC is absent. This is evaluated by comparing the Ki67 LI between pre-treatment biopsy and post-treatment surgical specimen. The clinical relevance of this objective lies in its potential to provide insights into the efficacy of this combined intervention in reducing cancer cell proliferation, as indicated by changes in the Ki67 LI, which is a marker of cellular proliferation. Additionally, a co-primary objective is to evaluate the difference in post-treatment Ki67 LI in cancer-adjacent DCIS (in the presence of IBC) or intraepithelial neoplasia (IEN), defined as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS), between the active treatment and the control group. The primary interim objective is 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.
Participants
The clinical trial involves a total of **30 participants** who are exclusively female, as the study focuses on women with histologically confirmed **luminal (ER+ve and/or PgR+ve >=1%) invasive breast cancer** or ductal carcinoma in situ. The age range of participants is 18 years and older, with an ECOG performance status of 0 or 1, indicating that they are in relatively good health with normal organ and marrow function. Participants were selected based on their eligibility for elective surgery and not for neo-adjuvant treatment, although those with larger tumors who refuse neo-adjuvant chemotherapy before surgery are also eligible. The study population does not include any vulnerable groups. Lifestyle considerations include the requirement for female participants of child-bearing potential to use contraception or abstain from sexual activity during the study. The trial does not include male participants, and the sponsor has not provided information on specific lifestyle factors such as diet or physical activity.
Plans and Procedures
The clinical trial is designed as a **randomized**, phase IIb, window of opportunity presurgical trial, focusing on the effects of prolonged nightly fasting combined with **metformin hydrochloride** in patients with luminal invasive breast cancer or ductal carcinoma in situ. The trial aims to assess the safety and efficacy of the intervention, with a primary objective of evaluating changes in the Ki67 labeling index in cancer tissue. The study is expected to run until October 2025, with recruitment having commenced in April 2023.
Participants will be randomly assigned to either the experimental treatment arm or the control group. The trial is **double-blind** and controlled, ensuring that neither the participants nor the investigators are aware of the group assignments, thus minimizing bias. The study involves a series of visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and organ function. Participants must be women with histologically confirmed ER+ve and/or PgR+ve operable invasive breast cancer or ductal carcinoma in situ, among other criteria.
Following the screening, participants will undergo a baseline visit where initial assessments and measurements are taken. The treatment period will last for a maximum of 42 days, during which participants will receive the study medication, **GLUCOPHAGE UNIDIE 750 mg** prolonged-release tablets, administered orally. Follow-up visits will be scheduled to monitor safety and efficacy, with particular attention to any dose-limiting toxicities, such as hypoglycemic events or grade 3 or greater adverse events related to the study drug.
The end-of-study visit will involve a comprehensive evaluation of the participants' health status and the collection of final data for analysis. The expected length of participant involvement is approximately 42 days, with conditions for early termination including the occurrence of dose-limiting toxicities or withdrawal of consent. The trial's primary endpoints include the frequency of dose-limiting toxicities and changes in the Ki67 labeling index, while secondary endpoints are not specified in the provided data.
Treatment
The clinical trial involves the administration of **Metformin Hydrochloride** as the experimental medication. The specific product used is "GLUCOPHAGE UNIDIE 750 mg compresse a rilascio prolungato," which is a **prolonged-release tablet**. This formulation is designed for oral administration. The dosage regimen for participants involves a maximum daily dose of 1500 mg, with the treatment period extending up to 42 days. The active substance, Metformin Hydrochloride, is of chemical origin and is provided by BRUNO FARMACEUTICI. The administration of the medication is intended to be consistent with the study's objective of evaluating its effect in combination with prolonged nightly fasting on the Ki67 labeling index in cancer tissue.
In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The primary interim objective is to assess the safety of the experimental intervention, particularly focusing on the occurrence of dose-limiting toxicities, such as hypoglycemic events or significant adverse events related to the study drug.
Efficacy
Efficacy in this clinical trial will be assessed through the evaluation of the **Ki67 labeling index (LI)** in cancer tissue. The primary objective is to measure the change in Ki67 LI between pre-treatment biopsy and post-treatment surgical specimen in patients with invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS). The co-primary objective involves evaluating the difference in post-treatment Ki67 LI in cancer-adjacent DCIS or intraepithelial neoplasia (IEN), defined as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS), between the active treatment and control groups.
The primary endpoint includes the change in pre- and post-treatment immunohistochemical Ki67 LI in IBC or DCIS, and the difference in post-treatment Ki67 LI in adjacent DCIS or IEN between the treatment arms. The efficacy parameters will be collected and analyzed using validated immunohistochemical techniques to ensure accurate and reliable measurement of the Ki67 LI. The schedule for these assessments will align with the trial's design, focusing on pre-treatment and post-treatment timepoints to capture the necessary data for evaluating the treatment's impact on the Ki67 LI.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Women with histologically confirmed ER+ve and/or 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. ER+ve and/or PgR+ve ≥1% , HER2+ve (cT1, cN0) IBC and DCIS are also eligible.
- Age ≥ 18 years
- ECOG performance status ≤1 (Karnofsky ≥70%)
- Participants must have normal organ and marrow function as defined below: Leukocytes ≥3,000/microliter Absolute neutrophil count ≥1,500/microliter Platelets ≥100,000/microliter AST (SGOT)/ALT (SGPT) ≤1.5 × institutional upper limit of normal Creatinine clearance estimated > 45 mL/min with Cockcroft-Gault formula
- 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
- BMI < 18.5 Kg/m2.
- 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 BC.
- Patients with history of cancer within the last year. NOTE: Non melanoma skin cancer 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 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 IUDs.
- Concomitant use of Topiramate or other carbonic anhydrase inhibitors (e.g., Zonisamide, Acetazolamide or Dichlorphenamide)
- Concomitant use of GLP-1 medications (e.g. liraglutide, semaglutide, etc.).
- 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 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 Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Yet Recruiting | 04 Apr 2023 | 90 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GLUCOPHAGE UNIDIE 750 mg compresse a rilascio prolungato | Test | COMPRESSE A RILASCIO PROLUNGATO | ORAL | 1500 | 42 | PRD1663568 |