Clinical Trials /

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

NCT03283384

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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.

Clinical Trial IDs

  • ORG STUDY ID: BOOG-2017-01
  • SECONDARY ID: 2017-000676-29
  • NCT ID: NCT03283384

Conditions

  • Breast Neoplasms

Interventions

DrugSynonymsArms
LetrozoleAdvise letrozole, treatment choice free.
ChemotherapyChemotherapy
Ribociclib plus letrozoleRibociclib plus letrozole

Purpose

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%).
    

Trial Arms

NameTypeDescriptionInterventions
Advise letrozole, treatment choice free.OtherAll 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.
  • Letrozole
ChemotherapyActive ComparatorAll 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)).
  • Chemotherapy
Ribociclib plus letrozoleExperimentalAll 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)).
  • Ribociclib plus letrozole

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Difference in complete cell cycle arrest (CCCA; defined as Ki67 IHC <1%) between ribociclib plus letrozole and 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.
Safety Issue:
Description:Determine if ribociclib plus letrozole gives a ≥100% improvement in CCCA as compared to chemotherapy in the surgical specimen.

Secondary Outcome Measures

Measure:Correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ® 3) and Ki67 mRNA.
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).
Safety Issue:
Description:The correlation between the different Ki67 measurements will be determined in the primary core biopsy, two weeks biopsy and surgical specimen.
Measure:Correlation between ER pathway activity at baseline, after two weeks letrozole and at surgery and clinical outcome.
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).
Safety Issue:
Description: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.
Measure:Difference in pathologic response (pCR and response according to Miller and Payne) between the randomized study arms.
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.
Safety Issue:
Description: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.
Measure:Change in tumor biology and biomarkers (ER, PR, HER2, Rb, Ki67) at baseline, after 2 weeks letrozole and at surgery.
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).
Safety Issue:
Description: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.
Measure:Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV.
Time Frame:Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
Safety Issue:
Description:Toxicities are graded according to NCI CTCAE v4.03.
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.
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).
Safety Issue:
Description:The correlation of tumor measurements between MRI and palpation will be determined at three different time points.
Measure:Descriptive analysis of event free survival (EFS) at 3 and 5 years.
Time Frame:EFS will be determined after 3 and 5 years.
Safety Issue:
Description: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.
Measure:Descriptive analysis of overall survival (OS) at 3 and 5 years.
Time Frame:Time Frame: OS will be determined after 3 and 5 years.
Safety Issue:
Description:OS is defined as the time from randomization to date of death.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Borstkanker Onderzoek Groep

Trial Keywords

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

Last Updated

January 16, 2020