LifEStyle Intervention to Enhance Efficacy of Neoadjuvant Therapy in Patients With Triple Negative Breast Cancer

Leslie is a 2-arms randomized (2:1) Phase IIb clinical trial including 356 patients that will investigate whether combining a cyclic FMD-based intervention with exercise concomitant with neoadjuvant systemic therapy may have a beneficial effect on treatment response, survival, treatment tolerability and compliance, as well as quality of life of patients with TNBC. The neoadjuvant treatment will last for 21 weeks in both arms. Visits to the day clinic will be scheduled for administration of Standard of Care (SOC) in combination with 2-weekly visits to physiotherapists and online support of onco-dietician for patients from arm B.

The control group (arm A): SOC neoadjuvant therapy is based on the systemic treatment regimen described in the Keynote 522 trial, apart from some minor changes. It consists of four cycles of an intravenous infusion of pembrolizumab (200 mg) once every 3 weeks plus paclitaxel (80 mg per square meter of body-surface area once weekly) plus carboplatin (at a dose based on an area under the concentration-time curve of 1.5 mg per milliliter per minute) once weekly in the first 12 weeks, followed by four cycles of epirubicin (90 mg per square meter) plus cyclophosphamide (600 mg per square meter) once every 2 weeks plus pembrolizumab 400mg every 6 weeks or pembrolizumab 200mg every 3 weeks in the subsequent 8 weeks. All treatments after surgery will be administered according to the institutional guidelines.

The interventional group (arm B): Next to the SOC, the lifestyle intervention (cyclic FMD and exercise) will be part of the treatment. The FMD is a plant-based, low-carbohydrate, low-caloric diet of 4 days , with the fourth day being the day of chemo/immunotherapy. A total of 6 FMD cycles will be administered over the treatment period of 20 weeks. The exercise regimen consists of a non-linear aerobic exercise program of 3-4 sessions per week. During days of FMD no exercise will be prescribed.

Inclusion criteria

• The patient has a biopsy-confirmed diagnosis of stage II-III TNBC

• Patients with tumor stage T1cN1-2, T2N0-N2, T3N0-N2, T4N0-N2
• ER and PR negative is defined as an absent or minimal (≤10%) expression of oestrogen and progesterone receptors and absence of HER2 protein over-expression per ASCO/CAP-guidelines
• All histological subtypes are eligible, including but not limited to invasive breast cancer of no special type (NST) , invasive lobular carcinoma (ILC) etc
• WHO/ECOG performance status of grade 0-1
• The participant is able to perform a CPET test (cardiopulmonary exercise testing)
• Body mass index ≥ 18.5 kg/m²
• Pregnant or breastfeeding women
• Presence of adequate bone marrow and organ function
• HbA1c <10%

Exclusion criteria

• had a treatment with any of the following:

• any other chemotherapy, immunotherapy or anticancer agents within 5 years of the first dose of study treatment
• injectable hypoglycemics 2. have not have recovered adequately from the toxicity and/or complications from a surgical intervention prior to starting therapy
• prior systemic treatment for breast cancer or other malignancies within 5 years of treatment enrollment, except for adequately treated basal cell or squamous skin cancer or in situ cervical cancer. 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.
• has a history of an additional malignancy that is progressing or that has required active treatment in the 5 years prior to breast cancer diagnosis. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Prior treatment with anthracyclines
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
• Has any disorder, which in the Investigator's opinion might jeopardize the participant's safety or compliance with the protocol
• Has, as judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV). Screening for chronic conditions is not required
• Active autoimmune diseases requiring systemic treatments
• Patients with type 1 diabetes mellitus
• History of alcohol use disorder (DSM-5)
• History of eating disorder (DSM-5)