Abstract OT3-1-03: DIRECT: A phase II/III randomized trial with dietary restriction as an adjunct to neoadjuvant chemotherapy for HER2-negative breast cancer

Background: Preclinical evidence shows that short-term fasting protects normal cells, while cancer cells are sensitized to chemotherapy. Furthermore, a specifically designed very low calorie, low amino acid substitution diet (“Fasting Mimicking Diet”, FMD) has similar effects on chemotherapy as short-term fasting. This trial evaluates the impact of FMD on tolerance to and efficacy of neoadjuvant chemotherapy in women with HER2-negative early breast cancer. Trial design: DIRECT is a Dutch, randomized, open-label multicenter phase II/III trial. Women receiving neoadjuvant TAC courses (docetaxel/adriamycin/cyclophosphamide; day 1, q 3 weeks with G-CSF support at day 2) will be randomized with or without FMD for 3 days prior to and the day of chemotherapy and 3 days prior to surgery. Eligibility criteria: Eligible women are WHO 0-2, age ≥18 years, HER2-negative, stage II or III breast cancer and adequate bone marrow, liver and renal function, BMI > 19kg/m 2 and absence of diabetes mellitus. Study endpoints: The primary endpoints are grade III/IV toxicity (phase II) and the pathologic complete response rate (pCR) (phase III). Secondary endpoints are grade I/II toxicity, metabolic and inflammatory response to chemotherapy, DNA damage, apoptosis, immunology and nutrient sensing pathways in the tumor, biomarkers as single nucleotide polymorphisms, Ki67 and tumor stroma/ratio, patient9s quality of life and (disease free) survival. Optional side studies include chemotherapy-induced DNA damage and nutrient sensing pathways in leukocytes and proteomics. Statistical Methods: Using a 5% significance level based on the two-sided Fisher9s exact test with a power of 80%, 128 patients (64/arm) will be enrolled to show a 50% decrease of grade III/IV adverse events in the experimental arm (phase II) and 250 patients (125/arm) are needed to show an improvement of the pCR rate from 18% to 36% (phase III). Target accrual: Recruitment will start in September 2013. The expected end of accrual of 250 patients from multiple centers in the Netherlands will be the last quarter of 2015. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-03.