Fasting Mimicking Diet Program to ImpRovE ChemoTherapy in Hormone Receptor Postive (HR+), HER2- Breast Cancer

Study Overview
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Brief Summary
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In preclinical research, short-term fasting (STF) protects tumor-bearing mice against the toxic effects of chemotherapy, improves the CD8+ effector T-cell intratumor infiltration, while enhancing the chemotherapy efficacy. Short-term use of a fasting-mimicking diet (FMD) caused a major increase in the efficacy of cancer treatment in mice comparable to STF. In humans, the investigators recently performed a multicenter randomized phase II trial showing that patients with Human Epidermal growth factor Receptor 2 (HER2) negative breast cancer treated with neoadjuvant chemotherapy and FMD displayed a better radiological response and a better pathological response (90-100% vs <90% tumor cell reduction) than patients treated with chemotherapy without FMD (de Groot, Nat Commun 2020; NCT02126449). Therefore these findings will be validated in a phase 3 trial with the underlying hypothesis that FMD during neoadjuvant chemotherapy for breast cancer improves clinical outcomes, potentially due to improved local immunity.

Detailed Description
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STF during neadjuvant chemotherapy aiming to improve the chemotherapy efficacy and decline the side effects in patients with stage II-III HR+, HER2- breast cancer

Official Title
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DIRECT-2: Fasting Mimicking Diet Program to ImpRovE ChemoTherapy in HR+, HER2- Breast Cancer

Conditions
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Fasting Mimicking Diet, HER2-negative Breast Cancer, Hormone Receptor-positive Breast Cancer, Pathological Complete Response, Objective Response Rate, Neoadjuvant Chemotherapy

Intervention / Treatment
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* Other: Fasting Mimicking diet program


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical stage II-III (cT1cN+ or ≥T2 any cN, cM0), HR+, HER2- breast cancer Detectable and measurable disease (breast and/or lymph nodes) World Health Organization (WHO) performance status 0-2 Adequate organ function assessed by standard pre-treatment assessment: Adequate bone marrow function: white blood cells (WBCs) ≥3.0 x 109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l Adequate liver function: bilirubin ≤1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL Adequate renal function: the calculated creatinine clearance should be ≥50 mL/min Available for treatment and follow-up Written informed-consent Willing to fill in Quality Of Life and Cognition questionnaires Ability to read and understand Dutch language, accessibility to a computer with internet connection and independent use of computer Exclusion Criteria: Patient history of invasive or ipsilateral non-invasive breast cancer Active malignancy in the last 5 years, with the exclusion of basal cell carcinoma or pre-invasive cervical neoplasia/dysplasia. Body mass index (BMI) < 18.5 kg/m2 Pregnancy or lactating Food allergy for ingredients of FMD (nuts, soy, honey) A metabolic condition affecting gluconeogenesis or adaptation to periodic fasting. (Diabetes Mellitus for example)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fasting Mimicking Diet group<br>Fasting Mimicking Diet 3 days before and the day of neoadjuvant chemotherapy (ddAC, T) | Other: Fasting Mimicking diet program<br>* Fasting mimicking diet by L-Nutra, a 4-day low caloric, low protein, vegetarian diet 3 days prior to and the day of neoadjuvant chemotherapy administration. The FMD will take place every 4 weeks, thus in total 5 times (2x during ddAC, 3x during Paclitaxel) during the neoadjuvant chemotherapy.<br>* Other names: Xentigen™;|
| No Intervention: Normal Diet group<br>Standard neoadjuvant chemotherapy (ddAC, T) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological response rate (pCR). Both percentage of pCR and 90-100% tumor loss according to Miller & Payne |  | 4.5 years | 
| Objective response rate assessed by MRI (RECIST1.1) after 4 ddAC cycles and at the end of chemotherapy |  | 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the effect of treatment on the 3 and 5 year Event-free survival (EFS) and Overall survival (OS) |  | 7.5 and 9.5 years | 
| Adverse events ≥grade 3 (maximum of total) difference between treatment arms during neoadjuvant chemotherapy (ddAC, paclitaxel and total). |  | 4.5 years | 
| Quality of Life assessed by online questionnaires (EORTC QLQ-C30, EORTC QLQ-BR23), burden of therapy (Distress Thermometer) and Illness Perceptions (B-IPQ) | Validated online questionnaires take place at baseline, after 4 ddAC cycles, before surgery and 6 months after surgery. | 5 years | 
| Cognition assessed by Amsterdam Cognition Scan (ACS) online battery consisting of 7 online neuropsychological tests | online questionnaires take place at baseline, before surgery and 6 months after surgery. | 5 years | 
| Determine the effect of FMD on local immunomodulation and tumor immunity | By analyzing the immune-composition and gene-expression profile using multispectral Vectra imaging and Nanostring analyses respectively, in tumor samples taken at baseline (diagnostic), after 4 cycles and resection specimen | 6 years |