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12 consecutive cycles of weekly paclitaxel plus carboplatin (PCb) combined with 4 triweekly cycles of Pembrolizumab, followed by 4 consecutive cycles of triweekly anthracycline (doxorubicin or epirubicin)-cyclophosphamide (AC or EC) chemotherapy combined with 4 triweekly cycles of Pembrolizumab.

Standard treatment (12 consecutive cycles of weekly paclitaxel plus carboplatin (PCb) combined with 4 triweekly cycles of Pembrolizumab, followed by 4 consecutive cycles of triweekly anthracycline (doxorubicin or epirubicin)-cyclophosphamide (AC or EC) chemotherapy combined with 4 triweekly cycles of Pembrolizumab) in combination with up to a maximum of 8 consecutive triweekly cycles of 5-day Fasting-Like Approach

Each FLA cycle will consist of 5 consecutive days of a specific FLA scheme, which will be repeated with a three-week interval. The FLA will consist of a plant-based, low-calorie (about 600 Kcal on day 1; about 300 Kcal on day 2 to 5), low-protein, low-carbohydrate diet. The first FLA cycle will start two days prior to the day of first chemo-immunotherapy cycle administration and will continue for two more days after chemotherapy. In the absence of significant contraindications or severe adverse events, subsequent FLA cycles will recur with three-week intervals and will maintain the same timing with respect to chemo-immunotherapy administration.

Control diet (ARM A) or Fasting-Like Approach (FLA, ARM B)

Claudio Vernieri, MD, PhD

Francesca Ligorio, MD

Claudio Vernieri

Francesca Ligorio

Maria Vittoria Dieci, MD

Matteo Lambertini, MD

Sabino De Placido, MD

Monica Iorfida, MD

Alberto Zambelli, MD

Andrea Botticelli, MD

Carla Strina, MD

Italian, multicenter, open-label, two-arm, comparative, randomized phase II study investigating if the addition of the experimental metabolic intervention consisting in cycles of Fasting-Like Approach, as administered every three weeks up to a maximum of 8 consecutive cycles, is able to increase the anticancer activity of standard preoperative chemo-immunotherapy in patients with localized invasive Triple Negative Breast Cancer.

TNBC is the most aggressive subtype of breast cancer. TNBC patients who achieve pCR during neoadjuvant chemo-immunotherapy have significantly lower rates of disease recurrence or death. Preclinical studies indicate that combining nutrient starvation, in the form of cycles of FLA, with anthracycline- or platinum-based chemotherapy remarkably increases the therapeutic index of chemotherapy against murine and human models of breast cancer, including models of TNBC. In particular, the chemotherapy-fasting/FLA combination increases the anticancer activity of chemotherapy, while reducing treatment-related adverse events (AEs). Moreover, the FLA has demonstrated potent and desirable immunomodulatory effects both in in vivo studies and in patients with cancer, and the activation of antitumor immunity is a crucial mediator of the anticancer effects of the FLA, either alone or in combination with chemotherapy. Therefore, there is a strong biological rationale to combine cyclic FLA with ICIs in cancer therapy.

Based on these data, we hypothesize that combining the FLA with standard-of-care, preoperative, anthracycline-taxane-carboplatin chemotherapy plus Pembrolizumab can increase the rate of pCR in a population of patients with stage II-III TNBC.

This is an Italian, multicenter, open-label, two-arm, comparative, randomized phase II study. This study is designed to investigate if the addition if the experimental metabolic intervention consisting in cycles of FLA, as administered every three weeks up to a maximum of 8 consecutive cycles, is able to increase the anticancer activity of standard preoperative chemo-immunotherapy consisting of antracycline-taxane-carboplatin-based chemotherapy plus pembrolizumab in patients with treatment naïve, localized (tumor stage T1c AND nodal stage N1-2, or tumor stage T2-4 AND nodal stage N0-2) invasive Triple Negative Breast Cancer (HER2 negative, ER \<1%, PgR \<1%). Bilateral and/or multifocal primary tumor is allowed, as well as inflammatory breast cancer, and the tumor with the most advanced T stage should be used to assess the eligibility. If multi-focal/multi-centric disease, TNBC needs to be confirmed for each focus. The primary study endpoint is pathologic complete response (pCR).

Patients will be randomly allocated to one of the following treatment arms:

* Arm A (control arm): 12 consecutive cycles of weekly paclitaxel plus carboplatin (PCb) combined with 4 triweekly cycles of Pembrolizumab, followed by 4 consecutive cycles of triweekly anthracycline (doxorubicin or epirubicin)-cyclophosphamide (AC or EC) chemotherapy combined with 4 triweekly cycles of Pembrolizumab. This combination treatment will be further referred to as "standard treatment".
* Arm B (experimental arm): standard treatment in combination with up to a maximum of 8 consecutive triweekly cycles of 5-day FLA.

Enrolled patients will be randomized in a 1:1 ratio and stratified according to a) disease stage: stage II (T1N1, T2N0, T2N1, T3N0) vs. stage III (T3N1; any T4; any N2); b) patient body mass index (BMI ≥25 kg/m2 vs \<25 kg/m2).

After completion of the experimental preoperative protocol, patients will undergo surgery between 14 and 28 days after the last chemotherapy administration.

After surgery, patients will receive 9 additional triweekly pembrolizumab administration at the same dosage, and regardless of the pathologic tumor response (pCR yes vs. no). After surgery, patients may receive local radiotherapy, depending on the pathological stage and according to local and international guidelines.

Multicenter, open-label, two-arm, comparative, randomized phase II study

Targeting Triple Negative BREAst Cancer Metabolism With a Combination of Chemoimmunotherapy and a FASTing-like Approach in the Preoperative Setting: the BREAKFAST 2 Trial

Role of key DNA repair, metabolic, autophagy and immunologic pathways in the efficacy of the experimental treatments, defined as the rate of pCR

Absence of residual tumor cells in both breast tissue and axillary lymph nodes (ypT0/ypTis ypN0)

Time from surgery to tumor recurrence, either local or distant, or patient death from any cause, assessed up to 36 months

Time from the date of randomization to the first documentation of progressive disease, or patient death from any cause, assessed up to 36 months

Time from surgery to the occurrence of distant metastases or patient death from any cause, assessed up to 36 months

Time from randomization to the date of death (patients alive at the time of data cut-off and analysis will be censored at their last contact date), assessed up to 60 months

Dose of effective drug administrated per unit of time (e.g., mg/m2/week)

Percentage of patients with drug dose and/or time modifications

Percentage of patients with experimental dietary regimen modifications

Incidence, nature, severity and seriousness of AEs, according of NCI-CTCAE, version 5.0

Maximum toxicity grade experienced by each patient for each specific toxicity

Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Targeting Triple Negative BREAst Cancer Metabolism With a Combination of Chemoimmunotherapy and a FASTing-like Approach in the Preoperative Setting: the BREAKFAST 2 Trial	NCT05763992	Breast Cancer Triple Negative... Dietary Exposur... Fasting	Control diet (A...	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Targeting Triple Negative BREAst Cancer Metabolism With a Combination of Chemoimmunotherapy and a FASTing-like Approach in the Preoperative Setting: the BREAKFAST 2 Trial	NCT05763992	Breast Cancer Triple Negative... Dietary Exposur... Fasting	Control diet (A...	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Spots Global Cancer Trial Database for dietary exposure