NCT02126449

Brief Summary

Preclinical studies provide strong support for the concept that fasting evokes resistance to multiple forms of stress. Fasting reduces plasma levels of growth factors and modulates intracellular nutrient sensing systems, thereby diverting energy from growth to maintenance. Accordingly, the currently available preclinical evidence suggests that short-term fasting protects normal cells against the perils of chemotherapy. In contrast, cancer cells are not protected, as a result of their self-sufficiency in growth signals. This phenomenon is termed Differential Stress Resistance (DSR). DSR reduces the severity of toxic side-effects of chemotherapy and interestingly, it simultaneously renders cancer cells more vulnerable to chemotherapeutics. Importantly, extensive preclinical evidence and preliminary clinical data indicate that a specifically designed very low calorie, low amino acid substitution diet ("Fasting Mimicking Diet, FMD") has effects on cancer therapy that are very similar to those of fasting. This study aims to evaluate the impact of the FMD on tolerance to and efficacy of neoadjuvant chemotherapy in women with stage II or III breast cancer.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
131

participants targeted

Target at P75+ for phase_2

Timeline
Completed

Started Feb 2014

Longer than P75 for phase_2

Geographic Reach
1 country

15 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

February 1, 2014

Completed
13 days until next milestone

First Submitted

Initial submission to the registry

February 14, 2014

Completed
3 months until next milestone

First Posted

Study publicly available on registry

April 30, 2014

Completed
4.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

November 1, 2018

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

November 1, 2018

Completed
Last Updated

October 24, 2019

Status Verified

October 1, 2019

Enrollment Period

4.8 years

First QC Date

February 14, 2014

Last Update Submit

October 22, 2019

Conditions

Fasting Mimicking DietBreast CancerNeoadjuvant ChemotherapyPathological Complete Response

Outcome Measures

Primary Outcomes (2)

  • The percentage of patients with grade III/IV toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version (NCI CTCAE) v4.03.

    Phase II

    2 years

  • The percentage of pCR.

    Phase III

    4 years

Secondary Outcomes (8)

  • Clinical response measured by MRI (RECIST1.1) after 4 cycles chemotherapy.

    4 years

  • Grade I/II side effects of chemotherapy according to NCI CTCAE v4.03.

    4 years

  • Metabolic (Glucose, insulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein 3 (IGF-BP3), free thyroxin (FT4), triiodothyronine (T3) and thyroid-stimulating hormone (TSH)) and inflammatory response (CRP) to chemotherapy.

    4 years

  • DNA damage, apoptosis, immunology and nutrient sensing system activity in the tumor.

    5 years

  • Patient's quality of life (using EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires), burden of therapy noted by a visual analogue scale (VAS) (Distress Thermometer) and differences of Illness Perceptions (B-IPQ).

    4 years

  • +3 more secondary outcomes

Other Outcomes (3)

  • Protein profiles and cytokines used as biomarker to predict treatment outcome

    4 years

  • Quantification of chemotherapy-induced DNA damage in leukocytes (with γ-H2AX modification and comet assay).

    3years

  • Quantification of nutrient sensing system gene expression (with western blot).

    3 years

Study Arms (2)

Fasting mimicking diet

EXPERIMENTAL

Short term fasting using Fasting mimicking diet around neoadjuvant chemotherapy (AC\>T)

Other: Fasting mimicking diet

regular diet

NO INTERVENTION

Standard neoadjuvant chemotherapy (AC\>T)

Interventions

Fasting mimicking dietOTHER
Fasting mimicking diet

Eligibility Criteria

Age18 Years - 70 Years
Sexfemale
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Female patients with stage II or III (cT1cN+ or ≥T2 any cN, cM0) breast cancer receiving neoadjuvant AC-T
  • Measurable disease (breast and/or lymph nodes)
  • HER2 negative core biopsy Age ≥18 years
  • WHO performance status 0-2
  • 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
  • Patients must be accessible for treatment and follow-up
  • Written informed consent according to the local Ethics Committee requirements
  • Willing to fill in quality of life questionnaires
  • Able to read and write in Dutch

You may not qualify if:

  • History of breast cancer (invasive or non-invasive)
  • Previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix.
  • Serious other diseases such as recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias
  • Diabetes Mellitus
  • Body mass index (BMI) \< 19 kg/m2
  • Pregnancy or lactating
  • Significant food allergies which would make the subject unable to consume the food provided (ex: nuts or soy)
  • Any metabolic disorders that may affect gluconeogenesis or adaptation to short fasting periods.
  • Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (15)

Leids Universitair Medisch Centrum

Leiden, South Holland, 2333ZA, Netherlands

Location

Medisch Centrum Alkmaar

Alkmaar, Netherlands

Location

OLVG

Amsterdam, Netherlands

Location

Alexander Monro hospital

Bilthoven, Netherlands

Location

Amphia Hospital

Breda, Netherlands

Location

Deventer Hospital

Deventer, Netherlands

Location

Ziekenhuis Gelderse Valei

Ede, Netherlands

Location

, Catharina ziekenhuis Hospital

Eindhoven, Netherlands

Location

Kennemer gasthuis

Haarlem, Netherlands

Location

Medisch Centrum Leeuwarden

Leeuwarden, Netherlands

Location

Bronovo Hospital

The Hague, Netherlands

Location

Haga Hospital

The Hague, Netherlands

Location

VieCurie Hospital

Venlo, Netherlands

Location

Lange Land Hospital

Zoetermeer, Netherlands

Location

Isala

Zwolle, Netherlands

Location

Related Publications (2)

  • 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.

    PMID: 33179154DERIVED

  • 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.

    PMID: 32576828DERIVED

Related Links

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by SiteNeoplasmsBreast DiseasesSkin DiseasesSkin and Connective Tissue Diseases

Study Officials

  • Judith R Kroep, MD, PhD

    Leiden University Medical Center

    PRINCIPAL INVESTIGATOR

  • Hanno Pijl, MD PhD

    Leiden University Medical Center

    PRINCIPAL INVESTIGATOR

  • Koos JM van der Hoeven, MD PhD Ir

    Leiden University Medical Center

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
MD, PhD

Study Record Dates

First Submitted

February 14, 2014

First Posted

April 30, 2014

Study Start

February 1, 2014

Primary Completion

November 1, 2018

Study Completion

November 1, 2018

Last Updated

October 24, 2019

Record last verified: 2019-10

Locations

NL(15)