Clinical trial NCT02126449: DIetary REstriction as an Adjunct to Neoadjuvant ChemoTherapy for HER2 Negative Breast Cancer
Official title: DIetary REstriction as an Adjunct to Neoadjuvant ChemoTherapy for HER2 Negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Fasting Mimicking Diet
Breast Cancer
Neoadjuvant Chemotherapy
Pathological Complete Response
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Borstkanker Onderzoek Groep
name: Pink Ribbon Inc.
name: Amgen
First posted: 2014-04-30
Enrollment: 131
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 2 years
measure: The percentage of pCR.
timeFrame: 4 years
Secondary outcomes:
measure: Clinical response measured by MRI (RECIST1.1) after 4 cycles chemotherapy.
timeFrame: 4 years
measure: Grade I/II side effects of chemotherapy according to NCI CTCAE v4.03.
timeFrame: 4 years
measure: 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.
timeFrame: 4 years
measure: DNA damage, apoptosis, immunology and nutrient sensing system activity in the tumor.
timeFrame: 5 years
measure: 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).
timeFrame: 4 years
measure: Long term efficacy of treatment (DFS, OS).
timeFrame: 4years
measure: Hormone receptor percentage, Ki67 and immunologic tumor profile and tumor/stroma ratio as predictive biomarker
timeFrame: 4 years
measure: SNPs used as biomarker to predict treatment outcome.
timeFrame: 5 years
Other outcomes:
measure: Protein profiles and cytokines used as biomarker to predict treatment outcome
timeFrame: 4 years
measure: Quantification of chemotherapy-induced DNA damage in leukocytes (with γ-H2AX modification and comet assay).
timeFrame: 3years
measure: Quantification of nutrient sensing system gene expression (with western blot).
timeFrame: 3 years
Locations:
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
state: Zuid-holland
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar
city: Amsterdam
country: Netherlands
facility: OLVG
city: Bilthoven
country: Netherlands
facility: Alexander Monro hospital
city: Breda
country: Netherlands
facility: Amphia Hospital
city: Deventer
country: Netherlands
facility: Deventer Hospital
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Valei
city: Eindhoven
country: Netherlands
facility: , Catharina ziekenhuis Hospital
city: Haarlem
country: Netherlands
facility: Kennemer gasthuis
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: The Hague
country: Netherlands
facility: Bronovo Hospital
city: The Hague
country: Netherlands
facility: Haga Hospital
city: Venlo
country: Netherlands
facility: VieCurie Hospital
city: Zoetermeer
country: Netherlands
facility: Lange Land Hospital
city: Zwolle
country: Netherlands
facility: Isala
Study officials:
affiliation: Leiden University Medical Center
name: Judith R Kroep, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Hanno Pijl, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Koos JM van der Hoeven, MD PhD Ir
role: PRINCIPAL_INVESTIGATOR
References:
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, 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.