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

Breast Neoplasms Clinical Trial

— NEOLBC  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03283384
• Other study ID #: BOOG-2017-01
• Secondary ID: 2017-000676-29
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 15, 2019
• Est. completion date: August 2027

Study information

• Verified date: August 2023
• Source: Borstkanker Onderzoek Groep
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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%).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: August 2027
• Est. primary completion date: March 4, 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms

Intervention

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

Locations

Country	Name	City	State
Netherlands	Jeroen Bosch Ziekenhuis	's-Hertogenbosch
Netherlands	Ziekenhuisgroep Twente	Almelo
Netherlands	Ziekenhuis Amstelland	Amstelveen
Netherlands	Nederlands Kanker Instituut - Antoni van Leeuwenhoek	Amsterdam
Netherlands	Onze Lieve Vrouwe Gasthuis	Amsterdam
Netherlands	Gelre Ziekenhuizen	Apeldoorn
Netherlands	Amphia Ziekenhuis	Breda
Netherlands	Stichting Reinier Haga Groep (Reinier de Graaf Gasthuis)	Delft
Netherlands	Haaglanden Medisch Centrum	Den Haag
Netherlands	HAGA Ziekenhuis	Den Haag
Netherlands	Stichting Deventer Ziekenhuisgroep	Deventer
Netherlands	Catharina Ziekenhuis	Eindhoven
Netherlands	Maxima Medisch Centrum	Eindhoven
Netherlands	Groene Hart Ziekenhuis	Gouda
Netherlands	Spaarne Gasthuis	Haarlem
Netherlands	Ziekenhuis St. Jansdal	Harderwijk
Netherlands	Tergooi Ziekenhuizen	Hilversum
Netherlands	Westfriesgasthuis	Hoorn
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Academisch Ziekenhuis Maastricht	Maastricht
Netherlands	Canisius-Wilhelmina Ziekenhuis	Nijmegen
Netherlands	Laurentius Ziekenhuis	Roermond
Netherlands	Bravis Ziekenhuis	Roosendaal
Netherlands	Antonius Ziekenhuis	Sneek
Netherlands	Ziekenhuis Rivierenland	Tiel
Netherlands	Elisabeth Tweesteden Ziekenhuis	Tilburg
Netherlands	VieCuri Medisch Centrum	Venlo
Netherlands	Streekziekenhuis Koningin Beatrix	Winterswijk
Netherlands	Isala	Zwolle

Sponsors (3)

Lead Sponsor	Collaborator
Borstkanker Onderzoek Groep	Novartis, Philips Healthcare

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in ERa DNA binding signatures (Chip-seq) between baseline and after 2 weeks letrozole.	ERa DNA binding will be determined in the primary core biopsy and two weeks biopsy, where after the change in these measurements over time can be determined.	ERa 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).
Other	Change in gene expression profiles (RNA-seq) between baseline and after 2 weeks letrozole.	Gene expression profiling will be determined in the primary core biopsy and two weeks biopsy, where after the change in these measurements over time can be determined.	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).
Primary	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	Correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ® 3) and Ki67 mRNA.	The correlation between the different Ki67 measurements will be determined in the primary core biopsy, two weeks biopsy and surgical specimen.	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).
Secondary	Correlation between ER pathway activity at baseline, after two weeks letrozole and at surgery and clinical outcome.	The ER pathway activity will be determined in the primary core biopsy, two weeks biopsy and surgical specimen and then correlated with clinical outcome.; Activity will be determined using 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.	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).
Secondary	Difference in pathologic response (pCR and response according to Miller and Payne) between the randomized study arms.	The pathologic response will be determined in the surgical specimen of the patients in the randomized study arms where after the difference between the two groups can be determined.	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.
Secondary	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 determined in the primary core biopsy, two weeks biopsy and surgical specimen, where after the change in tumor biology and biomarkers over time can be determined.	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).
Secondary	Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV.	Toxicities are graded according to NCI CTCAE v4.03.	Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
Secondary	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.	The correlation of tumor measurements between MRI and palpation will be determined at three different time points.	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).
Secondary	Descriptive analysis of event free survival (EFS) at 3 and 5 years.	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.	EFS will be determined after 3 and 5 years.
Secondary	Descriptive analysis of overall survival (OS) at 3 and 5 years.	OS is defined as the time from randomization to date of death.	Time Frame: OS will be determined after 3 and 5 years.

External Links

•   Information NEOLBC study on BOOG website (sponsor).