Studieoverzicht - 2017-01 NEOLBC

 
Number 2017-01 NEOLBC
Nickname NEOLBC
Status Open Date: 08-03-2018
Inclusion closed
Other study number(s)
Participating parties/groups
Full title ‘Tailoring NEOadjuvant therapy in hormone receptor positive, HER2 negative, Luminal BC (NEOLBC)’
Phase and type Randomized Phase II
Age ≥18
Menopausal status Postmenopausal
Indication Neoadjuvant
Subindication HER2- HR+
Target sample size 100
Actual accrual 5 Date: 01-03-2019
Estimated study completion date 30-08-2020
CCMO approval Yes Date: 01-11-2017 Nr: NL58504
EudraCT nr. 2017-000676-29
Trial Register NCT03283384
METC approval Yes Date: 12-01-2018 METC: Leiden Universitair Medisch Centrum Nr: NL58504.058.17
Amendments Yes Date: 07-08-2018
KWF-CKS approval Not applicable Date: 01-01-1970 Nr: nvt
News item
Website , voor patienten: https://www.kanker.nl/trials/905-boog-2017-01---neolbc-studie-borstkanker
Sponsor BOOG
Principal Investigator(s) Dr. J.R. Kroep (Leids Universitair Medisch Centrum)
Study manager Drs. A.F. de Groot, LUMC (studiecoördinator)
T.W. Volker, MSc, BOOG Study Center (Project medewerker)
Dr. A. E. van Leeuwen-Stok, BOOG Study Center (Clinical Study Manager)
Central datamanagement and randomization Datacenter Heelkunde, LUMC,
Postbus 9600
2300 RC Leiden, The Netherlands
datacenter@lumc.nl | 071-5263500
Monitoring IKNL
Local datamanagement IKNL or site
Funding Novartis, Philips
Extra Coordinating investigator/project leader: A.F. de Groot (Leids Universitair Medisch Centrum)

Design:
Objectives:

Primary objective:

  • Determine if ribociclib plus letrozole gives a >50% improvement in complete cell cycle arrest (CCCA; defined as Ki67 IHC <1%) as compared to chemotherapy in the surgical specimen*.

 

Secondary objective

  • Study the correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ® 3) and Ki67 mRNA.
  • Correlate ER pathway activity at baseline, after two weeks letrozole and at surgery with clinical outcome (collaboration with Philips Netherlands). If sufficient material is available additional pathway activities (such as PI3K and others) can be determined.
  • Study the difference in pathologic response (pCR and response according to Miller and Payne) between the randomized study arms*.
  • Determine the change in tumor biology and biomarkers (ER, PR, HER2, Rb, Ki67) at baseline, after 2 weeks letrozole and at surgery.
  • Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV*.
  • Study the correlation of tumor measurements between standard MRI and palpation at baseline, after 12 weeks of therapy and pre-surgery.
  • Descriptive analysis of event free survival (EFS) and overall survival (OS) at 3 and 5 years.   

 

Side study objective:

  • Determine the change in ERα DNA binding and gene expression profiling between baseline and after 2 weeks letrozole.

 

* Indicates that the objective is not applicable to the group with a Ki67 of <1% (explained later in this protocol).

Endpoints:

Main study parameter/endpoint

  • Difference in CCCA (defined as Ki67 IHC <1%)) between ribociclib plus letrozole and chemotherapy in the surgical specimen*.
    • Analysis will be done on the core biopsy, 2 week biopsy and surgical specimen. We have built a Bayesian network model of the ER transcriptional program, which interprets the pathway target genes’ mRNA levels (from Affymetrix HG-U133Plus2.0 arrays) and infers a probability that the ER pathway is active in a certain sample (11). To be able to measure ER activity in FFPE samples we translated the original Affymetrix based model to be used with RT-qPCR data, using 12 most discriminating target genes and  minimal 4 reference genes. For all other pathways measured on the multi-pathway PCR plate similar models have been built. Philips developed one PCR plate for measuring multiple pathways which also includes a PCR assay for Ki67 mRNA.
    • EFS is defined as the time from randomization to the first date of local, regional, or distant relapse, second primary invasive breast cancer including contralateral breast cancer, progression according to RECIST 1.1 or death due to any cause which ever occurred first.
    • A ductal carcinoma in situ (DCIS) or a lobular carcinoma in situ (LCIS) will not be considered a recurrence.
    • A new non-breast primary cancer will not be considered an event.
    • OS is defined as the time from randomization to date of death.

 

Secondary study parameters/endpoints

  • Correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ® 3) and Ki67 mRNA.
  • Correlation between ER pathway activity (and possible additional pathway activities) at baseline, after two weeks letrozole and at surgery and clinical outcome.
  • Difference in pathologic response (pCR and response according to Miller and Payne) between the randomized study arms*.
  • Change in tumor biology and biomarkers (ER, PR, HER2, Rb, Ki67) at baseline, after 2 weeks letrozole and at surgery
  • Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV*.
  • Correlation of tumor measurements between standard MRI (using RECIST 1.1) and palpation (largest diameter in cm) at baseline, after 12 weeks of therapy and pre-surgery.
  • Descriptive analysis  of  event free survival (EFS) and overall survival (OS) at 3 and 5 years.

 

Other study parameters

  • Change in ERα DNA binding signatures (Chip-seq), and gene expression profiles (RNA-seq) between baseline and after 2 weeks letrozole.

 

* Indicates that the objective is not applicable to the group with a Ki67 of <1%.

Main eligibility criteria:

Inclusion criteria

     In order to be eligible to participate in this study, a subject must meet all of the following criteria:

  • Postmenopausal women presenting with histological proven (core biopsy material) hormone receptor positive (ER>50%, PR any), HER2 negative, stage II/ III breast cancer.
  • Measurable disease (breast and/or lymph nodes)
  • WHO 0-2
  • Adequate bone marrow function (within 4 weeks prior to registration): WBC≥3.0x109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l
  • Adequate liver function (within 4 weeks prior to start treatment): 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
  • Accessible for treatment and follow-up
  • Written informed consent

    

Inclusion criteria – randomization specific          

In order to be eligible to be randomized in this study, a subject must meet all of the following criteria:

  • Registration in the NEOLBC trial before start of letrozole
  • Use of letrozole
  • Outcome central Ki67 determination in two weeks biopsy available.

 

Exclusion criteria

  • Evidence of distant metastases (M1)
  • Previous invasive breast cancer
  • Prior chemotherapy, hormonal therapy or radiation therapy
  • 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.
  • Peripheral neuropathy > grade 2, whatever the cause
  • Serious other diseases as infections (hepatitis B, C and HIV), recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias or on screening, any of the following cardiac parameters: bradycardia (heart rate <50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec.
  • Known hypersensitivity reaction to any of the components of the treatment
  • Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment,

prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.

  • Currently receiving any of the following substances and cannot be discontinued 7 days prior to randomisation:
    • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges.
    • That have a known risk to prolong the QT interval or induce Torsades de Pointes.
    • That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
    • Herbal preparations/medications, dietary supplements.
    • 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.
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