Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.

NCT03283384 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: BOOG-2017-012017-000676-29
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 29

Brief Summary

The aim of this prospective, randomized, multicenter, open-label, phase II study is to test if chemotherapy can be replaced by the combination of ribociclib plus letrozole as a neo-adjuvant therapy for patients with non-metastatic primary luminal breast cancer.

Conditions

Breast Neoplasms

Keywords

Breast cancer; Ribociclib; Letrozole; Chemotherapy; CDK4; CDK6; Ki67; NEOLBC

Outcome Measures

Primary Outcomes (1)

• Difference in complete cell cycle arrest (CCCA; defined as Ki67 IHC <1%) between ribociclib plus letrozole and chemotherapy in the surgical specimen.

  Determine if ribociclib plus letrozole gives a ≥100% improvement in CCCA as compared to chemotherapy in the surgical specimen.

  CCCA will be determined in the surgical specimen, which is around 7 months after start of initial letrozole treatment.

Secondary Outcomes (8)

• Correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ® 3) and Ki67 mRNA.

  Ki67 measurements will be done in the primary core biopsy (baseline), two weeks biopsy (done after two weeks of initial letrozole treatment) and the surgical specimen (which is around 7 months after start of initial letrozole treatment).

• Correlation between ER pathway activity at baseline, after two weeks letrozole and at surgery and clinical outcome.

  ER pathway activity will measured in the primary core biopsy (baseline), two weeks biopsy (done after two weeks of initial letrozole treatment) and the surgical specimen (which is around 7 months after start of initial letrozole treatment).

• Difference in pathologic response (pCR and response according to Miller and Payne) between the randomized study arms.

  pCR and response according to Miller and Payne will be determined in the surgical specimen, which is around 7 months after start of initial letrozole treatment.

• Change in tumor biology and biomarkers (ER, PR, HER2, Rb, Ki67) at baseline, after 2 weeks letrozole and at surgery.

  Tumor biology and biomarkers will be assessed in the primary core biopsy (baseline), two weeks biopsy (done after two weeks of initial letrozole treatment) and the surgical specimen (which is around 7 months after start of initial letrozole treatment).

• Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV.

  Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.

Other Outcomes (2)

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

  ERα DNA binding signatures will be assessed in the primary core biopsy (baseline) and the two weeks biopsy (done after two weeks of initial letrozole treatment).

• Change in gene expression profiles (RNA-seq) between baseline and after 2 weeks letrozole.

  Gene expression profiles will be assessed in the primary core biopsy (baseline) and the two weeks biopsy (done after two weeks of initial letrozole treatment).

Study Arms (3)

Advise letrozole, treatment choice free.

OTHER

All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of \<1% in the biopsy taken after those two weeks of treatment are advised to stay on letrozole treatment until surgery. However, treatment choice is free.

Drug: Letrozole

Chemotherapy

ACTIVE COMPARATOR

All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of ≥1% in the biopsy taken after those two weeks of treatment are randomized between chemotherapy (standard AC-T chemotherapy) or ribociclib plus letrozole (ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks)).

Drug: Chemotherapy

Ribociclib plus letrozole

EXPERIMENTAL

All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of ≥1% in the biopsy taken after those two weeks of treatment are randomized between chemotherapy (standard AC-T chemotherapy) or ribociclib plus letrozole (ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks)).

Drug: Ribociclib plus letrozole

Interventions

Letrozole DRUG

Letrozole 2.5 mg daily.

Advise letrozole, treatment choice free.

Chemotherapy DRUG

Dose dense AC-T chemotherapy: consisting of 4 cycles of AC (doxorubicin and cyclophosphamide at a dose of 60 and 600 mg/m² as an i.v. bolus, respectively) 2-weekly, plus G-CSF (6 mg once per cycle) 24-48 hr after chemotherapy, followed by cycles of T (4 cycles docetaxel 100 mg/m² 3-weekly or 12 cycles paclitaxel 80 mg/m2 weekly).

Chemotherapy

Ribociclib plus letrozole DRUG

Ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks).

Ribociclib plus letrozole

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 registration): 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 (within 4 weeks prior to registration): the calculated creatinine clearance should be ≥50 ml/min
• Accessible for treatment and follow-up
• Written informed consent
• 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 2 weeks biopsy
• Use of letrozole
• Outcome central Ki67 determination in two weeks biopsy available.

You may not qualify if:

• Evidence of distant metastases (M1)
• Previous invasive breast cancer
• Prior chemotherapy, radiation therapy or hormonal therapy with the exception of patients who received letrozole ≤ 14 days (+ max. 4 days) prior to registration and who are still on letrozole.
• 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) or QTcF ≥450 msec.
• Known hypersensitivity reaction to any of the components of the treatment (peanuts, soy)
• 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, pummelo's, star-fruit, pomegranate 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.

Sponsors & Collaborators

• Borstkanker Onderzoek Groep: lead
• Novartis: collaborator
• Philips Healthcare: collaborator

Study Sites (29)

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, Netherlands

Location

Ziekenhuisgroep Twente

Almelo, Netherlands

Location

Ziekenhuis Amstelland

Amstelveen, Netherlands

Location

Nederlands Kanker Instituut - Antoni van Leeuwenhoek

Amsterdam, Netherlands

Location

Onze Lieve Vrouwe Gasthuis

Amsterdam, Netherlands

Location

Gelre Ziekenhuizen

Apeldoorn, Netherlands

Location

Amphia Ziekenhuis

Breda, Netherlands

Location

Stichting Reinier Haga Groep (Reinier de Graaf Gasthuis)

Delft, Netherlands

Location

Stichting Deventer Ziekenhuisgroep

Deventer, Netherlands

Location

Catharina Ziekenhuis

Eindhoven, Netherlands

Location

Maxima Medisch Centrum

Eindhoven, Netherlands

Location

Groene Hart Ziekenhuis

Gouda, Netherlands

Location

Spaarne Gasthuis

Haarlem, Netherlands

Location

Ziekenhuis St. Jansdal

Harderwijk, Netherlands

Location

Tergooi Ziekenhuizen

Hilversum, Netherlands

Location

Westfriesgasthuis

Hoorn, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Academisch Ziekenhuis Maastricht

Maastricht, Netherlands

Location

Canisius-Wilhelmina Ziekenhuis

Nijmegen, Netherlands

Location

Laurentius Ziekenhuis

Roermond, Netherlands

Location

Bravis Ziekenhuis

Roosendaal, Netherlands

Location

Antonius Ziekenhuis

Sneek, Netherlands

Location

Haaglanden Medisch Centrum

The Hague, Netherlands

Location

HAGA Ziekenhuis

The Hague, Netherlands

Location

Ziekenhuis Rivierenland

Tiel, Netherlands

Location

Elisabeth Tweesteden Ziekenhuis

Tilburg, Netherlands

Location

VieCuri Medisch Centrum

Venlo, Netherlands

Location

Streekziekenhuis Koningin Beatrix

Winterswijk, Netherlands

Location

Isala

Zwolle, Netherlands

Location

Related Links

• Information NEOLBC study on BOOG website (sponsor).

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Letrozole; Drug Therapy; ribociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics

Study Officials

• Judith R Kroep, MD PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• Sabine C Linn, Prof. MD

  NKI-AvL

  PRINCIPAL INVESTIGATOR

• Gerrit-Jan Liefers, MD PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• A. E van Leeuwen-Stok, PhD

  BOOG Study Center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 28, 2017
• First Posted: September 14, 2017
• Study Start: June 15, 2019
• Primary Completion: December 6, 2022
• Study Completion (Estimated): August 1, 2027
• Last Updated: September 19, 2025

Record last verified: 2025-09

Locations

NL (29)