PrimaryDoes a peri-chemotherapeutic FMD ameliorate grade III or IV toxicity (Phase II part) and increase pathologic complete response (pCR) in patients with HER2 negative early breast cancer treated with neoadjuvant chemotherapy (Phase III part).…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* The percentage of patients with grade III/IV toxicity to the National Cancer
Institute Common Terminology Criteria for Adverse Events version 4.03 (phase
II).
* The percentage of pathological complete response according Miller and Payne
(phase III).
Secondary outcome
Secondary endpoints:
* To determine the effect of FMD on the clinical response measured by MRI
(RECIST1.1) halfway therapy.
* To determine the effect of FMD on grade I/II side effects of chemotherapy
according to NCI CTCAE v4.03.
* Metabolic (Glucose, insulin, insulin-like growth factor-I (IGF-I),
insulin-like growth factor binding protein 3 (IGF-BP3), free thyroxin (FT4), T3
and thyroid-stimulating hormone (TSH)) and inflammatory response (CRP) to
chemotherapy.
* DNA damage, apoptosis, immunology and nutrient sensing system activity in the
tumor.
* 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).
* Long term efficacy of treatment (DFS, OS).
* Hormone receptor percentage, Ki67 and immunologic tumor profile and
tumor/stroma ratio as predictive biomarker.
* SNPs used as biomarker to predict treatment outcome.
Side study endpoints:
* Protein profiles and cytokines used as biomarker to predict treatment outcome
* Quantification of chemotherapy-induced DNA damage in leukocytes (with *-H2AX
modification and comet assay).
* Quantification of nutrient sensing system gene expression (with western
blot).
Background summary
Evidence from experimental animals provides strong support for the concept that
fasting evokes resistance to multiple forms of stress. Fasting reduces plasma
levels of growth factors (e.g. insulin-like growth factor-I) 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 (high dose)
chemotherapy. In contrast, cancer cells are not (or less) 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. A recent report of a case
series of 10 cancer patients suggests that short term fasting protects against
the side effects of chemotherapy in humans. Indeed, the majority of patients
preferred fasting to feeding in preparation of their therapy.
Obviously, fasting is not an easy thing to do for most of us. 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 further evaluate the impact of
the FMD on tolerance to and efficacy of neo-adjuvant chemotherapy in women with
stage II or III breast cancer.
Study objective
Primary
Does a peri-chemotherapeutic FMD ameliorate grade III or IV toxicity (Phase II
part) and increase pathologic complete response (pCR) in patients with HER2
negative early breast cancer treated with neoadjuvant chemotherapy (Phase III
part).
Secondary
* Does a peri-chemotherapeutic FMD reduce
* grade I/II side effects of chemotherapy
* the metabolic and inflammatory response to chemotherapy.
* Does a peri-chemotherapeutic FMD increase
* Clinical response
* DNA damage, apoptosis, immunology and nutrient sensing
pathways in the tumor.
* the patient*s quality of life.
* long term efficacy of treatment (disease-free survival (DFS) and overall
survival (OS)).
* Study predictive biomarkers (hormone receptor percentage, Ki67,
immunologic tumor profile and tumor/stroma ratio) of the tumor.
* Determine single nucleotide polymorphisms (SNPs) that can be
used as biomarker to predict treatment outcome in these patients
using a FMD.
Side studies
* Determine protein profiles (proteomics) and cytokines that can be
used as biomarker to predict treatment outcome in these patients
using a FMD.
* Does a peri-chemotherapeutic FMD reduce
chemotherapy-induced DNA damage in leukocytes.
* Does a peri-chemotherapeutic FMD increase
activation of energy sensing pathways in leukocytes.
Study design
Prospective, open, multicenter, randomized phase II/III intervention study
Intervention
Chemolieve* for 3 days prior to and the day of chemotherapy and 3 days prior to
surgery versus regular diet.
Study burden and risks
There are potential risks and discomforts associated with low calorie and low
protein diets like Chemolieve*, such as hunger, drowsiness, dizziness,
headache, muscle aches, fatigue and low blood pressure. Bodyweight will be
monitored in the course of the trial to detect *10% weight loss, which will be
a reason for withdrawal from further participation. The benefits obviously
remain to be established, but they are potentially substantial.
There is a possibility that patients experience more nausea because of leaving
out dexamethasone as an anti-emetic in the intervention group during the AC or
FEC cycles. To reduce this risk, patients will receive metoclopramide instead
and if they experience serious nausea, dexamethasone will be given the next
cycles.
Plesmanlaan 125
Amsterdam 1066 CX
NL
Plesmanlaan 125
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
* Female patients with stage II or III breast cancer receiving neoadjuvant 4AC>4T or 3FEC>3T
* 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
10^9/l, platelets *100 x 10^9/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 invasive breast cancer or ipsilateral non-invasive breast cancer
* 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
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL44684.058.13 |