Clinical trial NCT05503108: Fasting Mimicking Diet Program to ImpRovE ChemoTherapy in Hormone Receptor Postive (HR+), HER2- Breast Cancer
Official title: DIRECT-2: Fasting Mimicking Diet Program to ImpRovE ChemoTherapy in HR+, HER2- Breast Cancer
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE3
Conditions: Fasting Mimicking Diet
HER2-negative Breast Cancer
Hormone Receptor-positive Breast Cancer
Pathological Complete Response
Objective Response Rate
Neoadjuvant Chemotherapy
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: The Netherlands Cancer Institute
name: Borstkanker Onderzoek Groep
name: Comprehensive Cancer Centre The Netherlands
name: Koningin Wilhelmina Fonds
name: World Cancer Research Fund International
name: L-Nutra Inc
First posted: 2022-08-16
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: 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)

Primary outcomes:
measure: Pathological response rate (pCR). Both percentage of pCR and 90-100% tumor loss according to Miller & Payne
timeFrame: 4.5 years
measure: Objective response rate assessed by MRI (RECIST1.1) after 4 ddAC cycles and at the end of chemotherapy
timeFrame: 4.5 years
Secondary outcomes:
measure: Determine the effect of treatment on the 3 and 5 year Event-free survival (EFS) and Overall survival (OS)
timeFrame: 7.5 and 9.5 years
measure: Adverse events ≥grade 3 (maximum of total) difference between treatment arms during neoadjuvant chemotherapy (ddAC, paclitaxel and total).
timeFrame: 4.5 years
measure: Quality of Life assessed by online questionnaires (EORTC QLQ-C30, EORTC QLQ-BR23), burden of therapy (Distress Thermometer) and Illness Perceptions (B-IPQ)
timeFrame: 5 years
measure: Cognition assessed by Amsterdam Cognition Scan (ACS) online battery consisting of 7 online neuropsychological tests
timeFrame: 5 years
measure: Determine the effect of FMD on local immunomodulation and tumor immunity
timeFrame: 6 years
Other outcomes:
measure: Biomarker analysis to predict treatment outcome
timeFrame: 6 years
measure: 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.
timeFrame: 4.5 years
Locations:
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep
city: Beverwijk
country: Netherlands
facility: Rode Kruis ziekenhuis
city: Bilthoven
country: Netherlands
facility: Alexander Monro Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf ziekenhuis
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
Study officials:
affiliation: Leiden University Medical Center
name: Judith R Kroep, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.