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

HER2-negative Breast Cancer Clinical Trial

— DIRECT-2  

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT05503108
• Other study ID #: NL80749.058.22 DIRECT 2
• Secondary ID: P22.028BOOG 2022
• Status: Suspended
• Phase: Phase 3
• Start date: March 17, 2023
• Est. completion date: January 1, 2024

Study information

• Verified date: November 2023
• Source: Leiden University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 10
• Est. completion date: January 1, 2024
• Est. primary completion date: January 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

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

Intervention

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.

Locations

Country	Name	City	State
Netherlands	Noordwest Ziekenhuisgroep	Alkmaar
Netherlands	Rode Kruis ziekenhuis	Beverwijk
Netherlands	Alexander Monro Ziekenhuis	Bilthoven
Netherlands	Reinier de Graaf ziekenhuis	Delft
Netherlands	Deventer Ziekenhuis	Deventer
Netherlands	Ziekenhuis Gelderse Vallei	Ede
Netherlands	Leiden University Medical Center	Leiden

Sponsors (7)

Lead Sponsor	Collaborator
Leiden University Medical Center	Borstkanker Onderzoek Groep, Comprehensive Cancer Centre The Netherlands, Koningin Wilhelmina Fonds, L-Nutra Inc, The Netherlands Cancer Institute, World Cancer Research Fund International

Country where clinical trial is conducted

Netherlands, 

References & Publications (4)

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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Primary	Pathological response rate (pCR). Both percentage of pCR and 90-100% tumor loss according to Miller & Payne		4.5 years
Primary	Objective response rate assessed by MRI (RECIST1.1) after 4 ddAC cycles and at the end of chemotherapy		4.5 years
Secondary	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
Secondary	Adverse events =grade 3 (maximum of total) difference between treatment arms during neoadjuvant chemotherapy (ddAC, paclitaxel and total).		4.5 years
Secondary	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
Secondary	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
Secondary	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

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