Studieoverzicht - 2022-01 DIRECT-2

Number 2022-01 DIRECT-2
Nickname DIRECT-2
Status Active, not recruiting Date: 13-09-2023
Inclusion closed 07-09-2023
Other study number(s)
Participating parties/groups
Full title DIRECT-2: Fasting mimicking Diet to ImpRovE ChemoTherapy in HR+, HER2- primary breast cancer.
Phase and type Randomized Phase III
Age ≥18 years
Menopausal status Both pre- and postmenopausal
Indication Neoadjuvant
Subindication HER2- HR+
Target sample size 240
Actual accrual 10 Date: 07-09-2023
Estimated study completion date
CCMO approval Yes Date: Nr: NL80749.058.22
EudraCT nr. n.a.
Trial Register
METC approval Yes Date: 05-01-2023 METC: METC Zuidwest Holland Nr: P22.028
Amendments Date:
KWF-CKS approval Yes Date: 21-12-2021 Nr: 13820
News item
Sponsor LUMC
Principal Investigator(s) Dr. J.R. Kroep (LUMC), Dr. G.J. Liefers (LUMC), Prof. dr. H. Pijl (LUMC), Prof. dr. S. Schagen (NKI-AvL) en Prof. dr. S.H. van der Burg (LUMC)
Study manager Studiecoördinator:
Drs. N. de Gruil

BOOG Study Center:
CSM: Dr. A.E. van Leeuwen-Stok
PM: Ilse Schilderinck (MSc)
Central datamanagement and randomization LUMC Clinical Research Center
Monitoring LUMC Clinical Research Center
Local datamanagement Centrum zelf of IKNL
Funding KWF
Extra Open voor inclusie: Alexander Monro Ziekenhuis, Amphia Ziekenhuis, Antonius Zorggroep, Deventer Ziekenhuis, Diakonessenhuis Utrecht, Jeroen Bosch Ziekenhuis, Leids Universitair Medisch Centrum, Medisch Centrum Leeuwarden, Noordwest Ziekenhuisgroep, Reinier de Graaf Gasthuis, Rode Kruis Ziekenhuis, Streekziekenhuis Koningin Beatrix, VieCuri Medisch Centrum, Ziekenhuis Gelderse Vallei,


Multicenter, randomized, open-label phase III trial 


The overall aim of this study is to test the capacity of fasting mimicking diet (FMD) during neoadjuvant chemotherapy in patients with breast cancer to improve the pathological response rate and quality of life including cognition and to assess how local immunity is modulated by FMD.


Primary objectives:

- Improve the pathological response rate according to Miller and Payne (score 4-5 indicating 90-100% tumor-cell loss) scored on surgical resection samples, by adding FMD to neoadjuvant chemotherapy as compared to a regular diet.
- Improve clinical response rate according to RECIST1.1 using MRI evaluation after 4 ddAC cycles and at the end of chemotherapy.


Secondary objectives: 

- Determine the effect of the FMD on the 3 and 5 year event free survival (EFS).
- Determine adverse events ≥grade 3 (maximum of total) difference between treatment arms during neoadjuvant chemotherapy. Determine the effect of the FMD on QoL evaluated by questionnaires. 
- Determine the effect of the FMD on cognition evaluated by an online battery consisting of 7 online neuropsychological tests.
- Determine the effect of the FMD on local immunomodulation and tumor immunity by analyzing the immune-composition and gene-expression profile in tumor-samples taken at baseline and after 4 cycles using for example multispectral Vectra imaging and Nanostring analyses.


Primary endpoints: 

- Pathologic response according to Miller & Payne (increase in 90-100% tumor-cell loss) scored in the tumor resection sample taken at surgery by pathologist in participating center. After study completion, central revision will take place, where study staff pathologist evaluating Miller & Payne will be blinded to the nature of the intervention.
- Clinical response evaluation measured by MRI according to RECIST 1.1. 


Secondary endpoints: 

- 3 and 5 year EFS difference between treatment arms.
- Adverse events ≥grade 3 (maximum of total) difference between treatment arms during neoadjuvant chemotherapy.
- QoL change in questionnaire scores from T0 to T1, T2 and T3.
- Cognitive test performance difference between treatment arms at T2 and T3 adjusted for baseline (T0).
- Change in local tumor immunity assessed by VECTRA imaging with 7-plex panels for T-cell populations (CD8+ , CD3+ , Treg by FOXp3, Tbet), myeloid cells (CD57 for Natural killer cells; CD68, CD33, CD163 for Macrophages; CD14, CD33, HLA-DR isotype for Monocytic myeloid-derived suppressor cells (mMDSC); CD66 for neutrophils; CD303 for plasmacytoid dendritic cells). This will be studied on the diagnostic biopsy and extra tumor biopsy taken after 4th cycle ddAC.
- Change in Immune cell properties/signaling assessed by RNA copy numbers per gene generated by the RNA nanostring IO360 PanCancer panel experiment. This will be studied on the diagnostic biopsy and extra tumor biopsy taken after 4th cycle ddAC. 

Main eligibility criteria:

Inclusion criteria: 
- Clinical stage II-III (cT1cN+ or ≥T2 any cN, cM0), HR+, HER2- breast cancer. 
- Detectable and measurable disease (breast and/or lymph nodes).
- Age ≥18 years old.
- WHO performance status 0-2. 
- Adequate organ function assessed by standard pre-treatment assessment:
  a. Adequate bone marrow function : white blood cells (WBCs) ≥3.0 x 109 /l, neutrophils ≥1.5 x 109 /l,     platelets ≥100 x 109 /l
  b. 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
  c. Adequate renal function: the calculated creatinine clearance should be ≥50 mL/min. 
- Available for treatment and follow-up. 
- Written informed-consent. 
- Willing to fill in Quality Of Life questionnaires
- Ability to read and understand Dutch language, accessibility to a computer with internet connection and independent use of computer

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