Evaluation of Anthracycline-Taxane Chemotherapy Combined with Fasting-Mimicking Diet and Metformin in Triple Negative Breast Cancer Patients

Trial ID: 2023-508920-37-00
Protocol: BREAKFAST
Sponsor: Fondazione IRCCS Istituto Nazionale Dei Tumori

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Diseases & Conditions

Triple negative breast cancer

Objectives

The primary objective of the study is to investigate whether the experimental treatments, which consist of a combination of triweekly anthracycline-taxane chemotherapy with cyclic **fasting-mimicking diet (FMD)**, with or without daily metformin, can increase the rate of pathological complete response (pCR) in patients with **triple negative breast cancer** compared to historical results with standard anthracycline-taxane chemotherapy. This is clinically relevant as achieving a higher pCR rate is associated with improved long-term outcomes in this aggressive subtype of breast cancer.

Secondary objectives include:

Assessing the tolerability of the experimental arms, particularly the occurrence of severe (grade 3/4) adverse events.
Evaluating the safety of each experimental treatment, focusing on treatment-related adverse events.
Studying patient compliance with the prescribed FMD regimen and pharmacological treatment.
Estimating clinical tumor responses using imaging evaluations according to RECIST 1.1 criteria before surgery.
Estimating patient relapse-free survival and distant metastasis-free survival in both experimental arms.
Evaluating overall survival in both experimental arms.
Studying the short-term and long-term effects of the experimental treatments on systemic metabolism by evaluating blood metabolites.
Correlating experimental treatment-induced modifications of systemic metabolism and immunity with treatment activity.
Correlating tumor gene expression profiles with the efficacy of the experimental arms.
Correlating the tumor mutational status of genes involved in specific pathways with the efficacy of the experimental treatments.

Participants

The clinical trial focuses on **triple negative breast cancer** and involves a study population exclusively composed of female participants, aged between 18 and 75 years. The trial does not include male subjects or vulnerable populations. Participants are required to have a histologically confirmed diagnosis of invasive triple negative breast cancer, be candidates for neoadjuvant chemotherapy and subsequent curative surgery, and have localized disease at clinical stage I-III. The trial population was selected based on specific inclusion criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate bone marrow and organ function. Participants must also demonstrate a willingness and ability to comply with the prescribed fasting-mimicking diet regimen, metformin intake, and other study procedures. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as sexual abstinence or the use of two highly effective methods of contraception are required for female patients of childbearing potential throughout the study and for at least six months after the end of the fasting-mimicking diet. The trial aims to investigate the efficacy of experimental treatments in increasing the rate of pathological complete response compared to historical results with standard chemotherapy.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of combining triweekly anthracycline-taxane chemotherapy with a cyclic fasting-mimicking diet (FMD), with or without the addition of **metformin hydrochloride**, in patients with **triple negative breast cancer**. This is a randomized, double-blind, controlled trial conducted in a therapeutic exploratory phase II setting. The trial aims to assess whether the experimental treatments can increase the rate of pathologic complete response (pCR) compared to historical results with standard chemotherapy. The trial is expected to run until December 31, 2027, with recruitment having commenced on May 20, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, sex, and health status. Following successful screening, participants will be randomized to receive either the experimental treatment or control. Study visits will occur at each chemotherapy cycle to monitor metabolic biomarkers and assess treatment efficacy and safety. The end-of-study visit will evaluate the primary endpoint of pCR, defined as the absence of residual tumor cells in both breast tissue and axillary lymph nodes.

The expected length of participant involvement is approximately three months, corresponding to the maximum treatment period. Participants may be withdrawn from the study early due to adverse events, non-compliance with the study protocol, or withdrawal of consent. Secondary endpoints include relapse-free survival, distant metastasis-free survival, and overall survival, along with the assessment of metabolic biomarkers and the role of specific molecular pathways in treatment efficacy. The trial will also monitor the incidence and severity of adverse events according to NCI-CTCAE version 5.0.

Treatment

The clinical trial involves the use of **METFORAL 850 mg** film-coated tablets, which contain the active substance **metformin hydrochloride**. This medication is administered orally and is designed to be taken daily. The maximum daily dose is 850 mg, with a total maximum dose of 1700 mg over the course of the treatment period. The treatment duration is set for a maximum of three months. Metformin hydrochloride is a chemical compound, also known by its synonyms 2-(N,N-dimethylcarbamimidoyl)guanidine hydrochloride and 3-(diaminomethylidene)-1,1-dimethyl-guanidine hydrochloride. The pharmaceutical form of the medication is a film-coated tablet, ensuring ease of administration and patient compliance.

In addition to the experimental treatment with metformin, the study includes a combination of triweekly anthracycline-taxane chemotherapy. This standard-of-care therapy is administered in conjunction with a cyclic fasting-mimicking diet (FMD). The trial aims to evaluate the efficacy of these combined treatments in increasing the rate of pathological complete response (pCR) in patients with triple-negative breast cancer, compared to historical results with standard chemotherapy alone. The study does not utilize a placebo or comparator treatment, as the focus is on the combination of chemotherapy and dietary intervention with or without metformin. Participant compliance with the dosing schedule and administration of the treatments is monitored throughout the trial to ensure adherence to the protocol.

Efficacy

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **pathologic complete response (pCR)**, defined as the absence of residual tumor cells in both breast tissue and axillary lymph nodes. This endpoint will be evaluated to determine the effectiveness of the experimental treatments, which include a combination of chemotherapy and a diet mimicking fasting, with or without the addition of metformin, in patients with triple-negative breast cancer.

Secondary endpoints include several measures: **relapse-free survival (RFS)**, defined as the time from surgery to tumor recurrence; **distant metastasis-free survival (DMFS)**, defined as the time from surgery to the occurrence of distant metastases; and **overall survival (OS)**, defined as the time from randomization to the date of death. Additionally, metabolic biomarkers such as plasma glucose, insulin, insulin-like growth factor 1 (IGF-1) levels, and lipid profiles will be assessed at baseline and at each chemotherapy cycle. The role of DNA repair, mTORC 1, PP2A, autophagy, and Beclin 1 pathways in the efficacy of the treatments will also be evaluated, specifically in relation to the rate of pCRs.

Other secondary endpoints include dose-intensity, percentage of patients with drug dose and/or time modifications, percentage of patients with dietary regimen modifications, and percentage of premature withdrawals. The incidence, nature, severity, and seriousness of adverse events (AEs) will be recorded according to NCI-CTCAE version 5.0, along with the maximum toxicity grade experienced by each patient and the percentage of patients experiencing grade 3-4 toxicity. The percentage of patients experiencing at least one serious adverse event (SAE) will also be documented.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Female sex
Age ≥ 18 and ≤ 75 years.
Evidence of a personally signed and dated informed consent document (ICD) indicating that the patient has been informed of all pertinent aspects of the study before enrollment
Willingness and ability to comply with the prescribed FMD regimen, metformin intake, the scheduled visits, treatment plans, laboratory tests and other procedures
Histologically confirmed diagnosis of invasive TNBC candidate to neoadjuvant chemotherapy and subsequent curative surgery. On the basis of International Guidelines, TNBC is defined by absent or minimal (<1%) expression of oestrogen and progesterone receptors at IHC, and absence of HER2 over-expression or amplification, as defined as an IHC score of 0, 1+, or an IHC score of 2+ with in situ hybridization (ISH) analysis excluding HER2 gene amplification
Patients with localized disease (clinical stage I-III according to TNM). Patients with Stage I TNBC will be included only if the primary tumor is at least 10 mm in greatest dimension (clinical T1c as determined through baseline CESM and CE-MRI assessment).
Presence of an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
Presence of adequate bone marrow and organ function as defined by the following laboratory values: a. ANC ≥ 1.5 x 10^3/lb. platelets ≥ 100 x 10^3/l c. hemoglobin ≥ 9.0 g/dl d. calcium (corrected for serum albumin) within normal limits or ≤ grade 1 according to NCI-CTCAE version 5.0 if not clinically significant e. potassium within the normal limits, or corrected with supplements f. creatinine < 1.5 ULN g. blood uric acid < 10 mg/dl h. ALT and AST ≤ 2 x ULN i. total bilirubin < 1.5 ULN except for patients with Gilbert syndrome who may only be included if the total bilirubin is < 3.0 x ULN or direct bilirubin < 1.5 x ULN j. Fasting glucose ≤ 250 mg/dl.
Female patients of childbearing potential must agree to sexual abstinence or to use two highly effective methods of contraception throughout the study and for at least six months after the end of the FMD. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide. A patient is of childbearing potential if, in the opinion of the Investigator, she is biologically capable of having children and is sexually active.
Female patients are not of childbearing potential if they meet at least one of the following criteria: a. Have undergone a documented hysterectomy and/or bilateral oophorectomy b. Have medically confirmed ovarian failure c. Achieved post-menopausal status, defined as: ≥ 12 months of non-therapy-induced amenorrhea or surgically sterile (absence of ovaries) and have a serum FSH level within the laboratory’s reference range for postmenopausal females.

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Exclusion Criteria

Prior systemic treatment for breast cancer or other malignancies within 5 years of treatment enrollment.
Prior treatment with anthracyclines
Diagnosis of other malignancies in advanced stages (unresectable, locally advanced or metastatic), or that required systemic (neo)adjuvant chemotherapy in the previous 5 years. Other malignancies diagnosed more than 5 years before the diagnosis of breast cancer must have been radically treated without evidence of relapse at the moment of patient enrollment in the trial
Body mass index (BMI) < 20 kg/m^2.
History of alcohol abuse.
Non-intentional weight loss ≥ 5% in the previous 3 months, unless the patient has a BMI > 22 kg/m^2 and weight loss has been lower than 10% at the time of enrollment in the study; or non-intentional weight loss of ≥ 10% in the previous 3 months, unless the patients has a BMI > 25 kg/m^2 and weight loss has been lower than 15% at the time of the enrollment in the study. In both cases, weight must have been stable for at least one month before study enrollment
Active pregnancy or breast feeding.
Known active B or C hepatitis or human immunodeficiency virus (HIV) infection, or occasional finding of active hepatitis B/C infection during screening tests before chemotherapy initiation, as defined as positive polymerase chain reaction (PCR) testing for HBV-DNA and HCV-RNA and qualitative PCR for HIV-RNA, or requiring active treatment at study enrollment.
Serious infections in the previous 4 weeks before the FMD initiation, including, but not limited to, potential hospitalizations for complications of infections, bacteriemia or serious pneumonitis.
Active autoimmune diseases requiring systemic treatments (e.g. systemic steroids or immune suppressants).
Active chronic therapy with systemic steroids at a dose ≥ 10 mg per day of prednisone or equivalent at study enrollment
Known recent diagnosis of hypothyroidism requiring systemic replacement hormonal therapy and without stabilization of hormonal profile (fT3, fT4 and TSH within the normal range).
Diagnosis of type 1 or 2 diabetes mellitus requiring pharmacologic therapy (including, but not limited to, insulin, secretagogues and metformin). A diagnosis of type 2 diabetes mellitus not requiring pharmacological treatments based on the judgment of a diabetologist, is compatible with patient enrollment in the trial.
Active gastric or intestinal ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small intestine resection.
Anamnesis of clinically significant heart disease including: a. angina pectoris, coronary bypass, symptomatic pericarditis, myocardial infarction in the previous 12 months from the beginning of experimental therapy; b. congestive heart failure (NYHA III-IV).
Anamnesis of clinically meaningful cardiac arrhythmias, such as ventricular tachycardia, chronic atrial fibrillation, complete bundle branch block, high grade atrio-ventricular block like bi-fascicular block, type II Mobitz and third grade atrio-ventricular block, nodal arrhythmias, supra-ventricular arrhythmia.
Left ventricular ejection fraction lower than 50% at the cardiac scan with radionuclides or at echocardiography.
Previous episodes of symptomatic hypotension leading to loss of consciousness.
Baseline plasma fasting glucose ≤ 60 mg/dL.
Medical or psychiatric comorbidities rendering the patient not candidate to the clinical trial, according to the investigator’s judgement.
Other cardiac, liver, lung or renal comorbidities, not specified in the previous inclusion or exclusion criteria, but potentially exposing the patient to a high risk of lactic acidosis.