Fasting Mimicking Diet Program to ImpRovE ChemoTherapy in Hormone Receptor Postive (HR+), HER2- Breast Cancer (DIRECT-2)

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

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.

Study Overview

• Status: Suspended
• Conditions: HER2-negative Breast Cancer; Hormone Receptor-positive Breast Cancer; Neoadjuvant Chemotherapy; Fasting Mimicking Diet; Pathological Complete Response; Objective Response Rate
• Intervention / Treatment: Other: Fasting Mimicking diet program

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Alkmaar, Netherlands
    • Noordwest Ziekenhuisgroep
  • Beverwijk, Netherlands, 1942 LE
    • Rode Kruis Ziekenhuis
  • Bilthoven, Netherlands
    • Alexander Monro Ziekenhuis
  • Delft, Netherlands
    • Reinier de Graaf Ziekenhuis
  • Deventer, Netherlands
    • Deventer Ziekenhuis
  • Ede, Netherlands
    • Ziekenhuis Gelderse Vallei
  • Leiden, Netherlands
    • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fasting Mimicking Diet group; Fasting Mimicking Diet 3 days before and the day of neoadjuvant chemotherapy (ddAC, T)	Other: Fasting Mimicking diet program; 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.; Other Names: Xentigen™
No Intervention: Normal Diet group; Standard neoadjuvant chemotherapy (ddAC, T)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker analysis to predict treatment outcome	Genetic and/or epigenetic analysis will be performed on blood samples by for example PCR and/or GWAS technique.	6 years
Optional Bioelectrical Impedance Analysis (BIA) for participants at the Leiden University Medical Center (LUMC) to investigate the change in body composition in both treatment arms.		4.5 years

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: The Netherlands Cancer Institute; Borstkanker Onderzoek Groep; Comprehensive Cancer Centre The Netherlands; Koningin Wilhelmina Fonds; World Cancer Research Fund International; L-Nutra Inc
• Investigators: Principal Investigator: Judith R Kroep, PhD, Leiden University Medical Center

Publications and helpful links

General Publications

• Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, Cacciottolo M, Martin-Montalvo A, de Cabo R, Wei M, Morgan TE, Longo VD. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell. 2016 Jul 11;30(1):136-146. doi: 10.1016/j.ccell.2016.06.005.
• de Groot S, Lugtenberg RT, Cohen D, Welters MJP, Ehsan I, Vreeswijk MPG, Smit VTHBM, de Graaf H, Heijns JB, Portielje JEA, van de Wouw AJ, Imholz ALT, Kessels LW, Vrijaldenhoven S, Baars A, Kranenbarg EM, Carpentier MD, Putter H, van der Hoeven JJM, Nortier JWR, Longo VD, Pijl H, Kroep JR; Dutch Breast Cancer Research Group (BOOG). Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat Commun. 2020 Jun 23;11(1):3083. doi: 10.1038/s41467-020-16138-3.
• Lugtenberg RT, de Groot S, Kaptein AA, Fischer MJ, Kranenbarg EM, Carpentier MD, Cohen D, de Graaf H, Heijns JB, Portielje JEA, van de Wouw AJ, Imholz ALT, Kessels LW, Vrijaldenhoven S, Baars A, Fiocco M, van der Hoeven JJM, Gelderblom H, Longo VD, Pijl H, Kroep JR; Dutch Breast Cancer Research Group (BOOG). Quality of life and illness perceptions in patients with breast cancer using a fasting mimicking diet as an adjunct to neoadjuvant chemotherapy in the phase 2 DIRECT (BOOG 2013-14) trial. Breast Cancer Res Treat. 2021 Feb;185(3):741-758. doi: 10.1007/s10549-020-05991-x. Epub 2020 Nov 11.
• de Groot S, Pijl H, van der Hoeven JJM, Kroep JR. Effects of short-term fasting on cancer treatment. J Exp Clin Cancer Res. 2019 May 22;38(1):209. doi: 10.1186/s13046-019-1189-9.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2023
• Primary Completion (Estimated): January 1, 2024
• Study Completion (Estimated): January 1, 2024

Study Registration Dates

• First Submitted: July 24, 2022
• First Submitted That Met QC Criteria: August 15, 2022
• First Posted (Actual): August 16, 2022

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: NL80749.058.22 DIRECT 2; P22.028 (Other Identifier: Leiden University Medical Center (LUMC)); BOOG 2022-01 (Other Identifier: BOrstkanker Onderzoek Groep (BOOG))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No