Calorie Restriction With or Without Metformin in Triple Negative Breast Cancer

NCT04248998 | Unknown Phase 2 DMC

• 2 other identifiers: INT 192/192019-003093-13
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Glucose starvation and metformin have synergistic antitumor effects that are mediated through the concomitant inhibition of glycolysis and mitochondrial oxidative phosphorylation. The BREAKFAST trial will evaluate the antitumor activity of combining cyclic fasting-mimicking diet (FMD), which reproduces the in vitro effects of glucose starvation, plus/minus metformin with standard preperative anthracycline-taxane chemotherapy in patients with stage I-III TNBC

Conditions

Triple-negative Breast Cancer

Keywords

Triple-negative breast cancer; Fasting-Mimicking Diet; Metformin; Tumor Metabolism; Cytotoxic Chemotherapy

Outcome Measures

Primary Outcomes (1)

• pCR rate

  Rate of pathologic complete responses (pCRs)

  36 months

Secondary Outcomes (19)

• Severe adverse events

  36 months

• Safety of the experimental treatments

  36 months

• Compliance with the experimental treatment

  36 months

• RFS

  60 months

• DMFS

  60 months

Study Arms (2)

Chemotherapy plus Fasting-Mimicking Diet (FMD)

EXPERIMENTAL

Experimental Arm A will consist of 6 months of standard anthracycline-taxane preoperative chemotherapy in combination with triweekly cycles of 5-day FMD. Chemotherapy will consist of: * four triweekly cycles of doxorubicin 60 mg/mq plus cyclophosphamide 600 mg/mq, followed by * twelve consecutive cycles of weekly paclitaxel 80 mg/mq The FMD will consist of a triweekly 5-day regimen of a plant-based, calorie-restricted (600 KCal on day 1; 300 KCal on days 2-5), low-carbohydrate, low-protein diet. The FMD will be repeated up to a maximum of eight consecutive cycles.

Dietary Supplement: Fasting-mimicking diet; Drug: Preoperative chemotherapy

Fasting-mimicking diet plus metformin plus chemotherapy

EXPERIMENTAL

Experimental Arm B will consist of 6 months of standard anthracycline-taxane preoperative chemotherapy in combination with triweekly cycles of 5-day FMD and daily metformin Chemotherapy will consist of: * four triweekly cycles of doxorubicin 60 mg/mq plus cyclophosphamide 600 mg/mq, followed by * twelve consecutive cycles of weekly paclitaxel 80 mg/mq The FMD will consist of a triweekly 5-day regimen of a plant-based, calorie-restricted (600 KCal on day 1; 300 KCal on days 2-5), low-carbohydrate, low-protein diet. The FMD will be repeated up to a maximum of eight consecutive cycles. Metformin will be administered at an initial dosage of 850 mg/dya, and then escalated to the maximum dosage of 1700/day (two 850 mg tablets) if well tolerated. Metformin will be interrupted 7 days before surgery.

Dietary Supplement: Fasting-mimicking diet; Drug: Metformin; Drug: Preoperative chemotherapy

Interventions

Fasting-mimicking diet DIETARY_SUPPLEMENT

Cyclic, 5-day, calorie-restricted (600 KCal on day 1; 300 KCal on days 2-5), low-carbohydrate, low protein diet every three weeks

Chemotherapy plus Fasting-Mimicking Diet (FMD); Fasting-mimicking diet plus metformin plus chemotherapy

Metformin DRUG

Metformin 850 mg twice a day

Also known as: Metforal

Fasting-mimicking diet plus metformin plus chemotherapy

Preoperative chemotherapy DRUG

Chemotherapy will consist of: * four triweekly cycles of doxorubicin 60 mg/mq plus cyclophosphamide 600 mg/mq, followed by * twelve consecutive cycles of weekly paclitaxel 80 mg/mq

Also known as: doxorubicin+cyclophosphamide and paclitaxel

Chemotherapy plus Fasting-Mimicking Diet (FMD); Fasting-mimicking diet plus metformin plus chemotherapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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:
• ANC ≥ 1.5 x 103/l
• platelets ≥ 100 x 103/l
• hemoglobin ≥ 9.0 g/dl
• calcium (corrected for serum albumin) within normal limits or ≤ grade 1 according to NCI-CTCAE version 5.0 if not clinically significant
• potassium within the normal limits, or corrected with supplements
• creatinine \< 1.5 ULN
• blood uric acid \< 10 mg/dl

You may not qualify if:

• Patients eligible for this study must not meet any of the following 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/m2.
• History of alcohol abuse.
• Non-intentional weight loss ≥ 5% in the previous 3 months, unless the patient has a BMI \> 22 kg/m2 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/m2 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.

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead
• IFOM ETS - The AIRC Institute of Molecular Oncology: collaborator
• European Institute of Oncology: collaborator
• University of Milan: collaborator

Study Sites (1)

Fondazione IRCCS Istituto Nazionale Tumori

Milan, 20133, Italy

Location

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• Ligorio F, Vingiani A, Torelli T, Sposetti C, Drufuca L, Iannelli F, Zanenga L, Depretto C, Folli S, Scaperrotta G, Capri G, Bianchi GV, Ferraris C, Martelli G, Maugeri I, Provenzano L, Nichetti F, Agnelli L, Lobefaro R, Fuca G, Fotia G, Mariani L, Morelli D, Ladisa V, De Santis MC, Lozza L, Trecate G, Belfiore A, Brich S, Bertolotti A, Lorenzini D, Ficchi A, Martinetti A, Sottotetti E, Arata A, Corsetto P, Sorrentino L, Rediti M, Salvadori G, Minucci S, Foiani M, Apolone G, Pagani M, Pruneri G, de Braud F, Vernieri C. Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients. Cell Metab. 2025 Feb 4;37(2):330-344.e7. doi: 10.1016/j.cmet.2024.11.004. Epub 2024 Dec 17.

  PMID: 39694040 DERIVED

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

Metformin; AC protocol; Paclitaxel

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Officials

• Filippo de Braud, Professor

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

• Claudio Vernieri, M.D. PhD

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 27, 2020
• First Posted: January 30, 2020
• Study Start: May 5, 2020
• Primary Completion: May 1, 2024
• Study Completion: May 1, 2024
• Last Updated: January 18, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)