Studieoverzicht - 2013-04 DIRECT

 
Number 2013-04 DIRECT
Nickname DIRECT
Status Follow up Date: 15-01-2018
Inclusion closed 15-01-2018
Other study number(s)
Participating parties/groups
Full title DIetary REstriction as an adjunct to neoadjuvant ChemoTherapy for HER2 negative breast cancer
Phase and type Randomized Phase II/III
Age ≥18
Menopausal status Both pre- and postmenopausal
Indication Neoadjuvant
Subindication HER2-, any HR
Target sample size 250
Actual accrual 131 Date: 01-02-2018
Estimated study completion date 01-09-2017
CCMO approval Not applicable Date: Nr: NL44684.058.13
EudraCT nr. Not applicable
Trial Register
METC approval Yes Date: 12-09-2013 METC: Leiden Universitair Medisch Centrum Nr: P13-135
Amendments Yes Date: 23-01-2015
KWF-CKS approval Not applicable Date: Nr:
News item
Website http://www.boogstudycenter.nl
Sponsor BOOG Study Center
Principal Investigator(s) J.R. Kroep, H. Pijl, J.J.M van der Hoeven
Study manager R. Lugtenberg (studiecoördinator LUMC), A.E. van Leeuwen-Stok (BOOG SC)
Central datamanagement and randomization Leiden University Medical Center
Datacenter Surgery K6-R
Phone +31 71 526 3500
Fax +31 71 526 6744
E-mail datacenter@lumc.nl
Monitoring LUMC datacenter, Department of Surgery
Local datamanagement IKNL / Centrum zelf
Funding Logo Pink Ribbon.jpgPink Ribbon
Amgen
Extra

Design:

Objectives:

Primary Objective(s):

  • Phase II part: To determine the effect of FMD on grade III/IV toxicity of patients with HER2 negative early breast cancer treated with neoadjuvant chemotherapy.
  • Phase III part: To determine the effect of the FMD on the pCR.

 

Secondary Objectives:

  • To determine the effect of FMD on clinical response measured with MRI halfway the neoadjuvant chemotherapy.
  • To determine the effect of FMD on grade I/II side effects of chemotherapy.
  • To determine the effect of FMD on the body’s metabolic and inflammatory response to chemotherapy.
  • To determine the effect of FMD on DNA damage, immunology, apoptosis and nutrient sensing pathways in the tumor.
  • To determine the effect of FMD on the patient’s quality of life (EORTC QLQ-C30, EORTC QLQ-BR23, VAS (Distress Thermometer) and patient’s perceptions (B-IPQ).
  • To determine the effect of FMD on treatment efficacy (DFS and OS).
  • To study predictive biomarkers (hormone receptor percentage, Ki67, immunologic tumor profile and tumor/stroma ratio) in the tumor.
  • To identify SNPs that can be used as biomarkers to predict the effect of FMD on treatment outcome (efficacy and toxicity) after chemotherapy.

 

Optional Secondary Objectives:

  • To identify protein profiles (proteomics) and cytokines that can be used as biomarkers to predict the effect of FMD on treatment outcome (efficacy and toxicity) after chemotherapy.
  • To determine the effect of FMD on chemotherapy-induced DNA damage in leukocytes.
  • To determine the effect of FMD on energy sensing pathways in leukocytes.
Endpoints:

Primary study endpoint 

  • Phase II part: Grade III/IV toxicity will be scored before each chemotherapeutic gift, after the last cycle and 6 months after surgery using NCI-CTCAE v4.03 (see appendix A).  
  • Phase III part: pCR at surgery will be measured using Miller and Payne (see appendix B). Study staff evaluating pCR will be blind to the nature of the intervention.

 

Secondary study endpoints 

  • Clinical response: measured by MRI after the last AC or FEC cycle of chemotherapy
  • Grade I and II side effects of chemotherapy: scoredprior to every chemotherapeutic gift according NCI-CTC v 4.03 to quantify toxicity (see Appendix A) and a list of relevant side effects will be filled out (see Appendix C).
  • The body’s metabolic and inflammatory response to chemotherapy: every cycle just before start of chemotherapy measure metabolic parameters (glucose, insulin, insulin-like growth factor-1 (IGF-1)) and the inflammatory parameter C-reactive protein (CRP) will be measured. Insulin-like growth factor binding protein 3 (IGF-BP3), free thyroxin (FT4), T3 and thyroid-stimulating hormone (TSH) will be measured before the cycles 1, the last AC or FEC cycle and the last docetaxel cycle.
  • DNA damage, apoptosis, immunology, tumor/stroma ratio and nutrient sensing pathways in the tumor after surgery:

Chemotherapy-induced DNA damage in material of the tumor will be measured using the comet assay and the phosphorylation of H2AX, a protein involved in the DNA damage response.

Caspase-3 (as a measure of apoptosis) will be measured using immunohistochemistry and mTOR, AMPK, sirtuin and IGF-1 pathways will be characterized by Western blot, microarray and polymerase chain reaction. The results of the nutrient sensing pathways of the operation specimen will be compared with the biopsy.

Tumor biology is changing. Not only the tumor itself is important, its relation with the micro-environment determines the aggressive potential. The amount of stroma present in the primary tumor has shown to be an important prognostic parameter. Patients with a high amount of stroma have a worse prognosis whereas patients with no or little stroma show good survival. The Tumor/Stroma Ratio (TSR) can be determined on routine histological sections. Preliminary results also show that stroma has a protective role and that response to therapy differs for both stroma groups. We would like to validate the stroma parameter in this prospective trial. The two stroma groups will be evaluated for outcome and response to therapy. The TSR will be evaluated on H&E slides.

  • Predictive biomarkers: after surgery material of the tumor will be used to study: hormone receptor percentage, Ki67, immunologic tumor profile and TSR as defined above. The results of the operation specimen will be compared with the biopsy.
  • Patient’s quality of life and perceptions:patients will be asked to fill out EORTC QLC-C30 and EORTC QLQ-BR23 (except the questions about arm and breast symptoms 47-53) questionnaire before start of chemotherapy (baseline), before the last AC or FEC cycle and before the last docetaxel cycle and 6 months after surgery. Patients will be asked to fill out a distress thermometer (visual analogue scale (VAS)) about experienced burden of therapy at baseline, before the last AC or FEC cycle and before the last docetaxel cycle and 6 months after      therapy. At baseline and before the last docetaxel cycle patients will be asked to fill out the B-IPQ (two different forms)  to measure illness perceptions (see appendix D).
  • DFS and OS: disease free survival and overall survival will be determined after 5 and possibly 10 years according to the national guidelines.
  • SNPs: before start therapy an extra blood samples (5ml EDTA tube) will be taken to identify and prospectively validate unique genes that can be used as biomarkers to predict treatment outcome (efficacy and toxicity) after chemotherapy.

 

Optional secondary study endpoints 

  • Proteomics and cytokines: before cycle 1 an extra blood sample (10ml gel tube) will be taken to identify protein profiles and cytokines that can be used as biomarkers to predict treatment outcome (efficacy and toxicity) after chemotherapy (see blood sampling 8.6).
  • Chemotherapy-induced DNA damage in leukocytes: at the first and the last AC or FEC chemotherapy cycle, 2 extra blood samples (10 ml heparin tube each) will be taken before chemotherapy (baseline value) and 3 hours after start of chemotherapy for quantification of chemotherapy-induced DNA damage in leukocytes. Chemotherapy induced DNA damage will be measured using the comet assay and the phosphorylation of H2AX, a protein involved in the DNA damage response (see blood sampling 8.6).
  • Nutrient sensing systems in leukocytes: at the first and the last AC or FEC cycle and before the last docetaxel cycle chemotherapy cycle, 2 extra blood samples (10 ml heparin tube each) will be taken for quantification of nutrient sensing systems in leukocytes before (baseline value) and 3 hours after start of chemotherapy. mTOR, AMPK, sirtuin and IGF-1 pathways will be characterized by Western blot, microarray and polymerase chain reaction (see blood sampling 8.6).
Main eligibility criteria:
  • Female patients with stage II or III (cT1cN+ or ≥T2 any cN, cM0) breast cancer receiving neoadjuvant AC-T or FEC-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
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