<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03283384</url>
  </required_header>
  <id_info>
    <org_study_id>BOOG-2017-01</org_study_id>
    <secondary_id>2017-000676-29</secondary_id>
    <nct_id>NCT03283384</nct_id>
  </id_info>
  <brief_title>Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.</brief_title>
  <acronym>NEOLBC</acronym>
  <official_title>Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Borstkanker Onderzoek Groep</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Philips Healthcare</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Borstkanker Onderzoek Groep</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this prospective, randomized, multicenter, open-label, phase II study is to test&#xD;
      if chemotherapy can be replaced by the combination of ribociclib plus letrozole as a&#xD;
      neo-adjuvant therapy for patients with non-metastatic primary luminal breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Based on Ki67 levels after two weeks of initial letrozole treatment in postmenopausal&#xD;
      patients with hormone receptor positive, HER2 negative, stage II/III breast cancer, patients&#xD;
      are either advised to continue letrozole treatment (if Ki67 &lt;1%) or will be randomized&#xD;
      between standard chemotherapy (AC-T) or ribociclib in combination with letrozole (if Ki67&#xD;
      ≥1%).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 15, 2019</start_date>
  <completion_date type="Anticipated">August 2027</completion_date>
  <primary_completion_date type="Anticipated">March 4, 2026</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Difference in complete cell cycle arrest (CCCA; defined as Ki67 IHC &lt;1%) between ribociclib plus letrozole and chemotherapy in the surgical specimen.</measure>
    <time_frame>CCCA will be determined in the surgical specimen, which is around 7 months after start of initial letrozole treatment.</time_frame>
    <description>Determine if ribociclib plus letrozole gives a ≥100% improvement in CCCA as compared to chemotherapy in the surgical specimen.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation between Ki67 IHC scored manually, IHC scored automatically (Vectra ® 3) and Ki67 mRNA.</measure>
    <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).</time_frame>
    <description>The correlation between the different Ki67 measurements will be determined in the primary core biopsy, two weeks biopsy and surgical specimen.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between ER pathway activity at baseline, after two weeks letrozole and at surgery and clinical outcome.</measure>
    <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).</time_frame>
    <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.&#xD;
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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in pathologic response (pCR and response according to Miller and Payne) between the randomized study arms.</measure>
    <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.</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in tumor biology and biomarkers (ER, PR, HER2, Rb, Ki67) at baseline, after 2 weeks letrozole and at surgery.</measure>
    <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).</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV.</measure>
    <time_frame>Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.</time_frame>
    <description>Toxicities are graded according to NCI CTCAE v4.03.</description>
  </secondary_outcome>
  <secondary_outcome>
    <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.</measure>
    <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).</time_frame>
    <description>The correlation of tumor measurements between MRI and palpation will be determined at three different time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Descriptive analysis of event free survival (EFS) at 3 and 5 years.</measure>
    <time_frame>EFS will be determined after 3 and 5 years.</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Descriptive analysis of overall survival (OS) at 3 and 5 years.</measure>
    <time_frame>Time Frame: OS will be determined after 3 and 5 years.</time_frame>
    <description>OS is defined as the time from randomization to date of death.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in ERα DNA binding signatures (Chip-seq) between baseline and after 2 weeks letrozole.</measure>
    <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).</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in gene expression profiles (RNA-seq) between baseline and after 2 weeks letrozole.</measure>
    <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).</time_frame>
    <description>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.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Breast Neoplasms</condition>
  <arm_group>
    <arm_group_label>Advise letrozole, treatment choice free.</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>All patients initially start with two weeks of letrozole treatment. Patients with a Ki67 of &lt;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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chemotherapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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)).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ribociclib plus letrozole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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)).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Letrozole</intervention_name>
    <description>Letrozole 2.5 mg daily.</description>
    <arm_group_label>Advise letrozole, treatment choice free.</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chemotherapy</intervention_name>
    <description>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).</description>
    <arm_group_label>Chemotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ribociclib plus letrozole</intervention_name>
    <description>Ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks).</description>
    <arm_group_label>Ribociclib plus letrozole</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Postmenopausal women presenting with histological proven (core biopsy material)&#xD;
             hormone receptor positive (ER≥50%, PR any), HER2 negative, stage II/ III breast&#xD;
             cancer.&#xD;
&#xD;
          -  Measurable disease (breast and/or lymph nodes)&#xD;
&#xD;
          -  WHO 0-2&#xD;
&#xD;
          -  Adequate bone marrow function (within 4 weeks prior to registration): WBC≥3.0x109/l,&#xD;
             neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l&#xD;
&#xD;
          -  Adequate liver function (within 4 weeks prior to registration): bilirubin ≤1.5 x upper&#xD;
             limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x&#xD;
             UNL&#xD;
&#xD;
          -  Adequate renal function (within 4 weeks prior to registration): the calculated&#xD;
             creatinine clearance should be ≥50 ml/min&#xD;
&#xD;
          -  Accessible for treatment and follow-up&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Inclusion criteria randomization specific:&#xD;
&#xD;
        In order to be eligible to be randomized in this study, a subject must meet all of the&#xD;
        following criteria:&#xD;
&#xD;
          -  Registration in the NEOLBC trial before 2 weeks biopsy&#xD;
&#xD;
          -  Use of letrozole&#xD;
&#xD;
          -  Outcome central Ki67 determination in two weeks biopsy available.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Evidence of distant metastases (M1)&#xD;
&#xD;
          -  Previous invasive breast cancer&#xD;
&#xD;
          -  Prior chemotherapy, radiation therapy or hormonal therapy with the exception of&#xD;
             patients who received letrozole ≤ 14 days (+ max. 4 days) prior to registration and&#xD;
             who are still on letrozole.&#xD;
&#xD;
          -  Previous malignancy within 5 years, with exception of a history of a previous basal&#xD;
             cell carcinoma of the skin or pre-invasive carcinoma of the cervix.&#xD;
&#xD;
          -  Peripheral neuropathy &gt; grade 2, whatever the cause&#xD;
&#xD;
          -  Serious other diseases as infections (hepatitis B, C and HIV), recent myocardial&#xD;
             infarction, clinical signs of cardiac failure or clinically significant arrhythmias or&#xD;
             on screening, any of the following cardiac parameters: bradycardia (heart rate &lt;50 at&#xD;
             rest) or QTcF ≥450 msec.&#xD;
&#xD;
          -  Known hypersensitivity reaction to any of the components of the treatment (peanuts,&#xD;
             soy)&#xD;
&#xD;
          -  Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment,&#xD;
             prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH),&#xD;
             or fondaparinux is allowed.&#xD;
&#xD;
          -  Currently receiving any of the following substances and cannot be discontinued 7 days&#xD;
             prior to randomisation:&#xD;
&#xD;
               -  Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit&#xD;
                  hybrids, pummelo's, star-fruit, pomegranate and Seville oranges.&#xD;
&#xD;
               -  That have a known risk to prolong the QT interval or induce Torsades de Pointes.&#xD;
&#xD;
               -  That have a narrow therapeutic window and are predominantly metabolized through&#xD;
                  CYP3A4/5.&#xD;
&#xD;
               -  Herbal preparations/medications, dietary supplements.&#xD;
&#xD;
          -  Medical or psychological condition which in the opinion of the investigator would not&#xD;
             permit the patient to complete the study or sign meaningful informed consent.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Judith R Kroep, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Leiden University Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sabine C Linn, Prof. MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NKI-AvL</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gerrit-Jan Liefers, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Leiden University Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>A. E van Leeuwen-Stok, PhD</last_name>
    <role>Study Director</role>
    <affiliation>BOOG Study Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Jeroen Bosch Ziekenhuis</name>
      <address>
        <city>'s-Hertogenbosch</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ziekenhuisgroep Twente</name>
      <address>
        <city>Almelo</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ziekenhuis Amstelland</name>
      <address>
        <city>Amstelveen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nederlands Kanker Instituut - Antoni van Leeuwenhoek</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Onze Lieve Vrouwe Gasthuis</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gelre Ziekenhuizen</name>
      <address>
        <city>Apeldoorn</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Amphia Ziekenhuis</name>
      <address>
        <city>Breda</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stichting Reinier Haga Groep (Reinier de Graaf Gasthuis)</name>
      <address>
        <city>Delft</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Haaglanden Medisch Centrum</name>
      <address>
        <city>Den Haag</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HAGA Ziekenhuis</name>
      <address>
        <city>Den Haag</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stichting Deventer Ziekenhuisgroep</name>
      <address>
        <city>Deventer</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Catharina Ziekenhuis</name>
      <address>
        <city>Eindhoven</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maxima Medisch Centrum</name>
      <address>
        <city>Eindhoven</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Groene Hart Ziekenhuis</name>
      <address>
        <city>Gouda</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spaarne Gasthuis</name>
      <address>
        <city>Haarlem</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ziekenhuis St. Jansdal</name>
      <address>
        <city>Harderwijk</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tergooi Ziekenhuizen</name>
      <address>
        <city>Hilversum</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Westfriesgasthuis</name>
      <address>
        <city>Hoorn</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leiden University Medical Center</name>
      <address>
        <city>Leiden</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Academisch Ziekenhuis Maastricht</name>
      <address>
        <city>Maastricht</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Canisius-Wilhelmina Ziekenhuis</name>
      <address>
        <city>Nijmegen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Laurentius Ziekenhuis</name>
      <address>
        <city>Roermond</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bravis Ziekenhuis</name>
      <address>
        <city>Roosendaal</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Antonius Ziekenhuis</name>
      <address>
        <city>Sneek</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ziekenhuis Rivierenland</name>
      <address>
        <city>Tiel</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Elisabeth Tweesteden Ziekenhuis</name>
      <address>
        <city>Tilburg</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VieCuri Medisch Centrum</name>
      <address>
        <city>Venlo</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Streekziekenhuis Koningin Beatrix</name>
      <address>
        <city>Winterswijk</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isala</name>
      <address>
        <city>Zwolle</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <link>
    <url>https://www.boogstudycenter.nl/studie/286/neolbc.html</url>
    <description>Information NEOLBC study on BOOG website (sponsor).</description>
  </link>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>August 28, 2017</study_first_submitted>
  <study_first_submitted_qc>September 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <last_update_submitted>August 16, 2023</last_update_submitted>
  <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Breast cancer</keyword>
  <keyword>Ribociclib</keyword>
  <keyword>Letrozole</keyword>
  <keyword>Chemotherapy</keyword>
  <keyword>CDK4</keyword>
  <keyword>CDK6</keyword>
  <keyword>Ki67</keyword>
  <keyword>NEOLBC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Letrozole</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03283384
org study id: BOOG-2017-01
secondary id: 2017-000676-29
nct id: NCT03283384
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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%).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
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.
description: Determine if ribociclib plus letrozole gives a ≥100% improvement in CCCA as compared to chemotherapy in the surgical specimen.
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).
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).
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.
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).
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.
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).
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.
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.
description: OS is defined as the time from randomization to date of death.
measure: Change in ERα DNA binding signatures (Chip-seq) between baseline and after 2 weeks letrozole.
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).
description: 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.
measure: Change in gene expression profiles (RNA-seq) between baseline and after 2 weeks letrozole.
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).
description: 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.
arm group label: Advise letrozole, treatment choice free.
arm group type: Other
description: 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.
arm group label: Chemotherapy
arm group type: Active Comparator
description: 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)).
arm group label: Ribociclib plus letrozole
arm group type: Experimental
description: 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)).
intervention type: Drug
intervention name: Letrozole
description: Letrozole 2.5 mg daily.
arm group label: Advise letrozole, treatment choice free.
intervention type: Drug
intervention name: Chemotherapy
description: 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).
arm group label: Chemotherapy
intervention type: Drug
intervention name: Ribociclib plus letrozole
description: Ribociclib 600 mg/day (days 1-21, q4 weeks) plus letrozole 2.5 mg daily (days 1-28, q4 weeks).
arm group label: Ribociclib plus letrozole
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Judith R Kroep, MD PhD
role: Principal Investigator
affiliation: Leiden University Medical Center
last name: Sabine C Linn, Prof. MD
role: Principal Investigator
affiliation: NKI-AvL
last name: Gerrit-Jan Liefers, MD PhD
role: Principal Investigator
affiliation: Leiden University Medical Center
last name: A. E van Leeuwen-Stok, PhD
role: Study Director
affiliation: BOOG Study Center
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country: Netherlands
url: https://www.boogstudycenter.nl/studie/286/neolbc.html
description: Information NEOLBC study on BOOG website (sponsor).
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Letrozole
sharing ipd: Undecided