Clinical trial NCT03283384: Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.
Official title: Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Neoplasms
Keywords: Breast cancer
Ribociclib
Letrozole
Chemotherapy
CDK4
CDK6
Ki67
NEOLBC
Lead sponsor: Borstkanker Onderzoek Groep
Sponsor class: NETWORK
Collaborators: name: Novartis
name: Philips Healthcare
First posted: 2017-09-14
Enrollment: 100
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Based on Ki67 levels after two weeks of initial letrozole treatment in postmenopausal patients with hormone receptor positive, HER2 negative, stage II/III breast cancer, patients are either advised to continue letrozole treatment (if Ki67 \<1%) or will be randomized between standard chemotherapy (AC-T) or ribociclib in combination with letrozole (if Ki67 ≥1%).

Eligibility criteria: Inclusion 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 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

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 2 weeks biopsy
* 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, 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.

Primary outcomes:
measure: Difference in complete cell cycle arrest (CCCA; defined as Ki67 IHC <1%) between ribociclib plus letrozole and chemotherapy in the surgical specimen.
timeFrame: CCCA will be determined in the surgical specimen, which is around 7 months after start of initial letrozole treatment.
Secondary outcomes:
measure: Correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ® 3) and Ki67 mRNA.
timeFrame: 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).
measure: Correlation between ER pathway activity at baseline, after two weeks letrozole and at surgery and clinical outcome.
timeFrame: 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).
measure: Difference in pathologic response (pCR and response according to Miller and Payne) between the randomized study arms.
timeFrame: 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.
measure: Change in tumor biology and biomarkers (ER, PR, HER2, Rb, Ki67) at baseline, after 2 weeks letrozole and at surgery.
timeFrame: 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).
measure: Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV.
timeFrame: Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
measure: Correlation of tumor measurements between standard MRI (using RECIST 1.1) and palpation (largest diameter in cm) at baseline, after AC/before T or 8 weeks of definitive neoadjuvant therapy and pre-surgery.
timeFrame: Tumor measurements (MRI and palpation) will be performed at baseline, after AC/before T or 8 weeks of definitive neoadjuvant therapy and pre-surgery (which is around 7 months after start of initial letrozole treatment).
measure: Descriptive analysis of event free survival (EFS) at 3 and 5 years.
timeFrame: EFS will be determined after 3 and 5 years.
measure: Descriptive analysis of overall survival (OS) at 3 and 5 years.
timeFrame: Time Frame: OS will be determined after 3 and 5 years.
Other outcomes:
measure: Change in ERα DNA binding signatures (Chip-seq) between baseline and after 2 weeks letrozole.
timeFrame: 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).
measure: Change in gene expression profiles (RNA-seq) between baseline and after 2 weeks letrozole.
timeFrame: 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).
Locations:
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Almelo
country: Netherlands
facility: Ziekenhuisgroep Twente
city: Amstelveen
country: Netherlands
facility: Ziekenhuis Amstelland
city: Amsterdam
country: Netherlands
facility: Nederlands Kanker Instituut - Antoni van Leeuwenhoek
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Delft
country: Netherlands
facility: Stichting Reinier Haga Groep (Reinier de Graaf Gasthuis)
city: Den Haag
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Den Haag
country: Netherlands
facility: HAGA Ziekenhuis
city: Deventer
country: Netherlands
facility: Stichting Deventer Ziekenhuisgroep
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Haarlem
country: Netherlands
facility: Spaarne Gasthuis
city: Harderwijk
country: Netherlands
facility: Ziekenhuis St. Jansdal
city: Hilversum
country: Netherlands
facility: Tergooi Ziekenhuizen
city: Hoorn
country: Netherlands
facility: Westfriesgasthuis
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Ziekenhuis
city: Roermond
country: Netherlands
facility: Laurentius Ziekenhuis
city: Roosendaal
country: Netherlands
facility: Bravis Ziekenhuis
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis
city: Tiel
country: Netherlands
facility: Ziekenhuis Rivierenland
city: Tilburg
country: Netherlands
facility: Elisabeth Tweesteden Ziekenhuis
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum
city: Winterswijk
country: Netherlands
facility: Streekziekenhuis Koningin Beatrix
city: Zwolle
country: Netherlands
facility: Isala
Study officials:
affiliation: Leiden University Medical Center
name: Judith R Kroep, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: NKI-AvL
name: Sabine C Linn, Prof. MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Gerrit-Jan Liefers, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: BOOG Study Center
name: A. E van Leeuwen-Stok, PhD
role: STUDY_DIRECTOR
References: