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

Primary Purpose

Fasting Mimicking Diet, HER2-negative Breast Cancer, Hormone Receptor-positive Breast Cancer

Status
Recruiting
Phase
Phase 3
Locations
Netherlands
Study Type
Interventional
Intervention
Fasting Mimicking diet program
Sponsored by
Leiden University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fasting Mimicking Diet

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Noordwest Ziekenhuisgroep
  • Alexander Monro Ziekenhuis
  • Amphia Ziekenhuis
  • Reinier de Graaf ziekenhuis
  • Jeroen Bosch Ziekenhuis
  • Deventer Ziekenhuis
  • Ziekenhuis Gelderse Vallei
  • Beatrixziekenhuis
  • Groene Hart Ziekenhuis
  • Martini Hospital
  • Medisch Centrum Leeuwarden
  • Leiden University Medical CenterRecruiting
  • Alrijne Ziekenhuis
  • Sint Antonius Ziekenhuis
  • Diakonessenhuis
  • Viecuri Medisch Centrum
  • Streekziekenhuis Koningin Beatrix Winterswijk
  • Isala Ziekenhuis

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Fasting Mimicking Diet group

Normal Diet group

Arm Description

Fasting Mimicking Diet 3 days before and the day of neoadjuvant chemotherapy (ddAC, T)

Standard neoadjuvant chemotherapy (ddAC, T)

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Determine the effect of treatment on the 3 and 5 year Event-free survival (EFS) and Overall survival (OS)
Adverse events ≥grade 3 (maximum of total) difference between treatment arms during neoadjuvant chemotherapy (ddAC, paclitaxel and total).
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.
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.
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

Full Information

First Posted
July 24, 2022
Last Updated
March 24, 2023
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
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1. Study Identification

Unique Protocol Identification Number
NCT05503108
Brief Title
Fasting Mimicking Diet Program to ImpRovE ChemoTherapy in Hormone Receptor Postive (HR+), HER2- Breast Cancer
Acronym
DIRECT-2
Official Title
DIRECT-2: Fasting Mimicking Diet Program to ImpRovE ChemoTherapy in HR+, HER2- Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 1, 2023 (Anticipated)
Primary Completion Date
May 1, 2027 (Anticipated)
Study Completion Date
May 1, 2032 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the 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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fasting Mimicking Diet, HER2-negative Breast Cancer, Hormone Receptor-positive Breast Cancer, Pathological Complete Response, Objective Response Rate, Neoadjuvant Chemotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
240 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Fasting Mimicking Diet group
Arm Type
Experimental
Arm Description
Fasting Mimicking Diet 3 days before and the day of neoadjuvant chemotherapy (ddAC, T)
Arm Title
Normal Diet group
Arm Type
No Intervention
Arm Description
Standard neoadjuvant chemotherapy (ddAC, T)
Intervention Type
Other
Intervention Name(s)
Fasting Mimicking diet program
Other Intervention Name(s)
Xentigen™
Intervention Description
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.
Primary Outcome Measure Information:
Title
Pathological response rate (pCR). Both percentage of pCR and 90-100% tumor loss according to Miller & Payne
Time Frame
4.5 years
Title
Objective response rate assessed by MRI (RECIST1.1) after 4 ddAC cycles and at the end of chemotherapy
Time Frame
4.5 years
Secondary Outcome Measure Information:
Title
Determine the effect of treatment on the 3 and 5 year Event-free survival (EFS) and Overall survival (OS)
Time Frame
7.5 and 9.5 years
Title
Adverse events ≥grade 3 (maximum of total) difference between treatment arms during neoadjuvant chemotherapy (ddAC, paclitaxel and total).
Time Frame
4.5 years
Title
Quality of Life assessed by online questionnaires (EORTC QLQ-C30, EORTC QLQ-BR23), burden of therapy (Distress Thermometer) and Illness Perceptions (B-IPQ)
Description
Validated online questionnaires take place at baseline, after 4 ddAC cycles, before surgery and 6 months after surgery.
Time Frame
5 years
Title
Cognition assessed by Amsterdam Cognition Scan (ACS) online battery consisting of 7 online neuropsychological tests
Description
online questionnaires take place at baseline, before surgery and 6 months after surgery.
Time Frame
5 years
Title
Determine the effect of FMD on local immunomodulation and tumor immunity
Description
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
Time Frame
6 years
Other Pre-specified Outcome Measures:
Title
Biomarker analysis to predict treatment outcome
Description
Genetic and/or epigenetic analysis will be performed on blood samples by for example PCR and/or GWAS technique.
Time Frame
6 years
Title
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.
Time Frame
4.5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Judith R Kroep
Phone
+3171-5263464
Email
J.R.kroep@lumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Nadia de Gruil, Msc
Phone
+3171-5263464
Email
N.de_gruil@lumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Judith R Kroep, PhD
Organizational Affiliation
Leiden University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Noordwest Ziekenhuisgroep
City
Alkmaar
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
S. Vrijaldenhoven
Facility Name
Alexander Monro Ziekenhuis
City
Bilthoven
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
D. Ten Bokkel Huinink
Facility Name
Amphia Ziekenhuis
City
Breda
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
J. Heijns
Facility Name
Reinier de Graaf ziekenhuis
City
Delft
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A. Vulink
Facility Name
Jeroen Bosch Ziekenhuis
City
Den Bosch
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
J. Tol
Facility Name
Deventer Ziekenhuis
City
Deventer
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
L. Kessels
Facility Name
Ziekenhuis Gelderse Vallei
City
Ede
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A. Baars
Facility Name
Beatrixziekenhuis
City
Gorinchem
ZIP/Postal Code
4204 AA
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A.S.A. van Brussel
Facility Name
Groene Hart Ziekenhuis
City
Gouda
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
M. Cloos van Balen
Facility Name
Martini Hospital
City
Groningen
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A van der Velden
Facility Name
Medisch Centrum Leeuwarden
City
Leeuwarden
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
L. Hamming
Facility Name
Leiden University Medical Center
City
Leiden
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nadia de Gruil, Msc
Phone
+3171-5263464
Email
N.de_gruil@lumc.nl
First Name & Middle Initial & Last Name & Degree
Judith R Kroep, PhD
Phone
+3171-5263464
Email
J.R.kroep@lumc.nl
First Name & Middle Initial & Last Name & Degree
Judith R Kroep, PhD
Facility Name
Alrijne Ziekenhuis
City
Leiderdorp
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
F.A.J. Toonen
Facility Name
Sint Antonius Ziekenhuis
City
Nieuwegein
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
G.J. Veldhuis
Facility Name
Diakonessenhuis
City
Utrecht
ZIP/Postal Code
3582 KE
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
T Oostergo
Facility Name
Viecuri Medisch Centrum
City
Venlo
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A.J. van de Wouw
Facility Name
Streekziekenhuis Koningin Beatrix Winterswijk
City
Winterswijk
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
M. Duizer
Facility Name
Isala Ziekenhuis
City
Zwolle
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A. Honkoop

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32576828
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.
Results Reference
background
PubMed Identifier
33179154
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.
Results Reference
background
PubMed Identifier
31113478
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.
Results Reference
background
PubMed Identifier
27411588
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.
Results Reference
background
Links:
URL
https://www.boogstudycenter.nl/studie/299/direct-2.html
Description
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Fasting Mimicking Diet Program to ImpRovE ChemoTherapy in Hormone Receptor Postive (HR+), HER2- Breast Cancer

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