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DIetary REstriction as an Adjunct to Neoadjuvant ChemoTherapy for HER2 Negative Breast Cancer (DIRECT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02126449
Recruitment Status : Completed
First Posted : April 30, 2014
Last Update Posted : October 24, 2019
Borstkanker Onderzoek Groep
Pink Ribbon Inc.
Information provided by (Responsible Party):
J.R. Kroep, Leiden University Medical Center

Tracking Information
First Submitted Date  ICMJE February 14, 2014
First Posted Date  ICMJE April 30, 2014
Last Update Posted Date October 24, 2019
Actual Study Start Date  ICMJE February 2014
Actual Primary Completion Date November 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2014)
  • 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. [ Time Frame: 2 years ]
    Phase II
  • The percentage of pCR. [ Time Frame: 4 years ]
    Phase III
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2014)
  • Clinical response measured by MRI (RECIST1.1) after 4 cycles chemotherapy. [ Time Frame: 4 years ]
  • Grade I/II side effects of chemotherapy according to NCI CTCAE v4.03. [ Time Frame: 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. [ Time Frame: 4 years ]
  • DNA damage, apoptosis, immunology and nutrient sensing system activity in the tumor. [ Time Frame: 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). [ Time Frame: 4 years ]
  • Long term efficacy of treatment (DFS, OS). [ Time Frame: 4years ]
  • Hormone receptor percentage, Ki67 and immunologic tumor profile and tumor/stroma ratio as predictive biomarker [ Time Frame: 4 years ]
  • SNPs used as biomarker to predict treatment outcome. [ Time Frame: 5 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 28, 2014)
  • Protein profiles and cytokines used as biomarker to predict treatment outcome [ Time Frame: 4 years ]
  • Quantification of chemotherapy-induced DNA damage in leukocytes (with γ-H2AX modification and comet assay). [ Time Frame: 3years ]
  • Quantification of nutrient sensing system gene expression (with western blot). [ Time Frame: 3 years ]
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE DIetary REstriction as an Adjunct to Neoadjuvant ChemoTherapy for HER2 Negative Breast Cancer
Official Title  ICMJE DIetary REstriction as an Adjunct to Neoadjuvant ChemoTherapy for HER2 Negative Breast Cancer
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Fasting Mimicking Diet
  • Breast Cancer
  • Neoadjuvant Chemotherapy
  • Pathological Complete Response
Intervention  ICMJE Other: Fasting mimicking diet
Study Arms  ICMJE
  • Experimental: Fasting mimicking diet
    Short term fasting using Fasting mimicking diet around neoadjuvant chemotherapy (AC>T)
    Intervention: Other: Fasting mimicking diet
  • No Intervention: regular diet
    Standard neoadjuvant chemotherapy (AC>T)
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 29, 2018)
Original Estimated Enrollment  ICMJE
 (submitted: April 28, 2014)
Actual Study Completion Date  ICMJE November 2018
Actual Primary Completion Date November 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02126449
Other Study ID Numbers  ICMJE NL44684.058.13
BOOG2013-04 ( Other Identifier: BOOG )
p13.135 ( Other Identifier: CME LUMC )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party J.R. Kroep, Leiden University Medical Center
Study Sponsor  ICMJE Leiden University Medical Center
Collaborators  ICMJE
  • Borstkanker Onderzoek Groep
  • Pink Ribbon Inc.
  • Amgen
Investigators  ICMJE
Principal Investigator: 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
PRS Account Leiden University Medical Center
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP