A Phase 2 interventional study of Letrozole and Chemotherapy in Breast Neoplasms, sponsored by Borstkanker Onderzoek Groep. Active, not recruiting at 29 sites in Netherlands. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-09-19.
Sponsored by Borstkanker Onderzoek Groep · Phase 2, Interventional, and Treatment
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.
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%).
Inclusion Criteria:
Inclusion criteria randomization specific:
In order to be eligible to be randomized in this study, a subject must meet all of the following criteria:
Exclusion Criteria:
Currently receiving any of the following substances and cannot be discontinued 7 days prior to randomisation:
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
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
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
Letrozole 2.5 mg daily.
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 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks).
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.
Time frame: CCCA will be determined in the surgical specimen, which is around 7 months after start of initial letrozole treatment.
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.
Time frame: 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.
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.
Time frame: 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.
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.
Time frame: 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 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.
Time frame: 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.
Toxicities are graded according to NCI CTCAE v4.03.
Time frame: Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
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.
Time frame: 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).
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.
Time frame: EFS will be determined after 3 and 5 years.
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: Time Frame: OS will be determined after 3 and 5 years.
Change in ERα DNA binding signatures (Chip-seq) between baseline and after 2 weeks letrozole.
ERα 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.
Time frame: 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 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.
Time frame: 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).
Plan to share: Undecided
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Borstkanker Onderzoek Groep