<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/NCT03819010</url>
  </required_header>
  <id_info>
    <org_study_id>MedOPP199</org_study_id>
    <secondary_id>2018-001702-28</secondary_id>
    <nct_id>NCT03819010</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Letrozole and Palbociclib in Patients With Stage II-IIIB Breast Cancer, HR+, HER2 -</brief_title>
  <acronym>DxCARTES</acronym>
  <official_title>Neoadjuvant Letrozole + Palbociclib in Patients With II-IIIB BC,HR+, HER2-, Phenotype and Pretreatment Recurrence Score(RS):18-25 or 26-100 by Oncotype DX Breast RS Assay.Analysis of RS and Pathological Changes at Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MedSIR</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>MedSIR</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an international, multicenter, open-label, non-comparative, Simon´s two-stage design,&#xD;
      phase II clinical trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary objective:&#xD;
&#xD;
      To explore after 6 months of treatment the ability of palbociclib in combination with&#xD;
      letrozole to induce global molecular changes measured by either the Oncotype DX Breast&#xD;
      Recurrence Score® (the &quot;Assay&quot;) test result at surgery (post-treatment Recurrence Score® (RS)&#xD;
      result), or pathological Complete Response (pCR) in patients with aggressive luminal tumors&#xD;
      (pre-treatment RS result 18-25 or 26-100, and Ki67≥ 20).&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
      BIOLOGY&#xD;
&#xD;
        -  To explore the ability of palbociclib in combination with letrozole to induce global&#xD;
           molecular changes measured by post-treatment RS result, in patients with aggressive&#xD;
           luminal tumors (pre-treatment RS result 18-25 and Ki67≥ 20) after 6 months of treatment.&#xD;
&#xD;
        -  To explore the ability of palbociclib in combination with letrozole to induce global&#xD;
           molecular reduction measured by either the post-treatment RS result, and/or Residual&#xD;
           Cancer Burden (RCB), and/or Ki67 in patients with aggressive luminal tumors&#xD;
           (pre-treatment RS result 18-25 or 26-100 and Ki67 ≥ 20) after 6 months of treatment.&#xD;
&#xD;
        -  To verify the ability of palbociclib in combination with letrozole to induce global&#xD;
           molecular reduction (measured as either post-treatment RS≤25 or RCB score of 0-I) in&#xD;
           &gt;35% of patients in cohort B with pre-treatment RS 26-100;&#xD;
&#xD;
        -  To verify the ability of palbociclib in combination with letrozole to induce increase in&#xD;
           RS result (measured as post-treatment RS 26-100) in &lt;3% of patients in cohort A with&#xD;
           pre-treatment RS 18-25;&#xD;
&#xD;
        -  To evaluate the concordance rate between the RCB score (0- I vs. II-III) and the&#xD;
           post-treatment RS result in both cohorts of patients after treatment with palbociclib in&#xD;
           combination with letrozole;&#xD;
&#xD;
        -  To evaluate the concordance rate between the preoperative endocrine prognostic index&#xD;
           (PEPI) score and post-treatment RS result in both cohorts of patients after treatment&#xD;
           with palbociclib in combination with letrozole;&#xD;
&#xD;
        -  To evaluate the concordance rate between the pCR and the post-treatment RS result in&#xD;
           both cohorts of patients after treatment with palbociclib in combination with letrozole;&#xD;
&#xD;
        -  To determine the change in RS result as measured by median absolute value or median&#xD;
           percentage after 6 months of treatment: from pre-treatment RS 18-25 to post-treatment RS&#xD;
           0-17 for patients in cohort A and from pre-treatment RS 26-100 to post-treatment RS≤25&#xD;
           for patients in cohort B.&#xD;
&#xD;
      EFFICACY&#xD;
&#xD;
        -  To determine the Overall Response Rate (ORR) of patients treated with palbociclib in&#xD;
           combination with letrozole.&#xD;
&#xD;
        -  To evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole.&#xD;
&#xD;
        -  To determine the rate of breast conserving surgery.&#xD;
&#xD;
      SAFETY&#xD;
&#xD;
      • To assess the safety and tolerability of palbociclib in combination with letrozole.&#xD;
&#xD;
      A two-stage Simon's statistical design will be used for both cohorts (minimax design in&#xD;
      co-hort B and optimal design in cohort A). A total of 66 patients will be enrolled into this&#xD;
      trial, N=33 patients in cohort with high-risk tumors (Cohort B: pre-treatment RS&gt;25) and N=33&#xD;
      patients in cohort with intermediate-risk tumors (Cohort A: pre-treatment RS18-25).&#xD;
&#xD;
      The accrual goal will be of 26 patients (N=13 patients in each cohort) during the first&#xD;
      stage. The interim analysis has been planned after 15 patients (cohort B) and 9 patients&#xD;
      (cohort A) will be available for biological response evaluation, and in case of positive&#xD;
      findings, the trial will recruit additional 40 patients (N=20 patients in each cohort).&#xD;
&#xD;
        -  The study would be defined as positive at final analysis in the cohort B (pre-treatment&#xD;
           RS&gt;25), if 8 or more than 8 patients with biological signal (post-treatment RS≤25) are&#xD;
           observed (≥28.6%) among 28 evaluable patients.&#xD;
&#xD;
        -  The study would be defined as positive at final analysis in the cohort A (pre-treatment&#xD;
           RS18-25), if 25 or more than 25 patients with biological stabilization (post-treatment&#xD;
           RS≤25) are observed (≥89.3%) among 28 evaluable patients.&#xD;
&#xD;
      Study treatment management&#xD;
&#xD;
      After signing the informed consent form (ICF) and confirmed pre- eligibility, patients will&#xD;
      be pre-registered in the study. A tissue biopsy from the primary breast cancer has to be&#xD;
      provided at screening and will be used to perform central confirmation of Ki67 levels and HR&#xD;
      status, as well as central assessment of RS. Pre-registered patients can receive up to 4&#xD;
      weeks of letrozole before inclusion; pre-menopausal patients will require to combine it with&#xD;
      a Luteinizing Hormone-Releasing Hormone (LHRH) analogue. Patients are eligible to enter one&#xD;
      of the two cohorts according to RS assessment as follow:&#xD;
&#xD;
        -  Cohort A: patients with pre-treatment RS 18-25;&#xD;
&#xD;
        -  Cohort B: patients with pre-treatment RS 26-100. Patients with pre-treatment RS 0-17&#xD;
           will be considered not eligible. Patients allocated to the cohort A or B will receive 24&#xD;
           weeks of palbociclib (for 21 days every 4 weeks) in combination with letrozole (once&#xD;
           daily, beginning on day 1 and continuing through day 28 of every 28-day cycle).&#xD;
           Premenopausal women must also be treated with an LHRH analogue during the treatment&#xD;
           phase.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 7, 2019</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">July 30, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is an international, multicenter, open-label, non-comparative, Simon´s two-stage design, phase II clinical trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Two arms of patients (according to Recurrence Score results), but both arms will be treated with the same treatment</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Difference on Recurrence Score between pre and post-treatment (molecular results)</measure>
    <time_frame>6 months</time_frame>
    <description>To explore after 6 months of treatment the ability of palbociclib in combination with letro-zole to induce global molecular changes measured by either the Oncotype DX Breast Recurrence Score® (the &quot;Assay&quot;) test result at surgery (post-treatment Recurrence Score® (RS) result), or pathological Complete Response (pCR) in patients with aggres-sive luminal tumors (pre-treatment RS result 18-25 or 26-100, and Ki67&gt;20).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Molecular changes</measure>
    <time_frame>6 months</time_frame>
    <description>Concordance rate among post-treatment RS result and residual cancer burden (RCB), Ki67, and preoperative endocrine prognostic index (PEPI) score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Molecular induction</measure>
    <time_frame>6 months of treatment</time_frame>
    <description>To explore the ability of palbociclib in combination with letrozole to induce global mo-lecular reduction measured by either the post-treatment RS result, and/or Residual Cancer Burden (RCB), and/or Ki67 in patients with aggressive luminal tumors (pre-treatment RS result 18-25 or 26-100 and Ki67&gt;20) after 6 months of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Global molecular reduction</measure>
    <time_frame>6 months of treatment</time_frame>
    <description>To verify the ability of palbociclib in combination with letrozole to induce global mo-lecular changes (measured as either post-treatment RS≤25 or RCB score of 0-I) in &gt;35% of patients in cohort B with pre-treatment RS 26-100;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>increase RS result</measure>
    <time_frame>6 months of treatment</time_frame>
    <description>To verify the ability of palbociclib in combination with letrozole to induce changes in RS result (measured as post-treatment RS 26-100) in &lt;3% of patients in cohort A with pre-treatment RS 18-25;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the concordance rate between the RCB score (0- I vs. II-III) and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in com-bination with letrozole;</measure>
    <time_frame>6 months of treatment</time_frame>
    <description>To evaluate the concordance rate between the RCB score (0- I vs. II-III) and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in com-bination with letrozole;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the concordance rate between the pCR and the post-treatment RS re-sult in both cohorts of patients after treatment with palbociclib in combination with letro-zole;</measure>
    <time_frame>6 month of treatment</time_frame>
    <description>To evaluate the concordance rate between the pCR and the post-treatment RS re-sult in both cohorts of patients after treatment with palbociclib in combination with letro-zole;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in RS</measure>
    <time_frame>6 month of treatment</time_frame>
    <description>To determine the change in RS result as measured by median absolute value or median percentage after 6 months of treatment: from pre-treatment RS 18-25 to post-treatment RS 0-17 for patients in cohort A and from pre-treatment RS 26-100 to post-treatment RS≤25 for patients in cohort B.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>overall repsonse</measure>
    <time_frame>6 month of treatment</time_frame>
    <description>To determine the Overall Response Rate (ORR) of patients treated with palbociclib in combination with letrozole.</description>
  </other_outcome>
  <other_outcome>
    <measure>duration of response</measure>
    <time_frame>6 month of treatment</time_frame>
    <description>To evaluate the Duration of Response (DoR) of palbociclib in combination with letrozole.</description>
  </other_outcome>
  <other_outcome>
    <measure>Time to response</measure>
    <time_frame>6 month of treatment</time_frame>
    <description>To evaluate the Time to Response (TTR) of palbociclib in combination with letrozole.</description>
  </other_outcome>
  <other_outcome>
    <measure>Clinical benefit</measure>
    <time_frame>6 month of treatment</time_frame>
    <description>To assess the Clinical Benefit Rate (CBR) of palbociclib in combination with letrozole.</description>
  </other_outcome>
  <other_outcome>
    <measure>Evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole</measure>
    <time_frame>6 month of treatment</time_frame>
    <description>To evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole</description>
  </other_outcome>
  <other_outcome>
    <measure>Safety and tolerability of the combination Letrozole plus Palbociclib</measure>
    <time_frame>6 month of treatment</time_frame>
    <description>To assess the safety and tolerability of palbociclib in combination with letrozole. &quot;Number of participants with treatment-related adverse events as assessed by CTCAE v4.0&quot;.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">66</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Letrozole (2,5 mg/day during 28 days of each Cycle) + Palbociclib (125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer interventions: Letrozol (2,5 mg/day during 28 days of each Cycle)+ Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Letrozole (2,5 mg/day during 28 days of each Cycle) + Palbociclib (125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer interventions: Letrozol (2,5 mg/day during 28 days of each Cycle)+ Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib</intervention_name>
    <description>Letrozole(2,5 mg/day during 28 days of each Cycle) + Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer for patients with pre-treatment recurrence Score of 18-25</description>
    <arm_group_label>Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib</arm_group_label>
    <other_name>None othe intervention name</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib</intervention_name>
    <description>Letrozole(2,5 mg/day during 28 days of each Cycle) + Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer for patients with pre-treatment recurrence Score of 26-100</description>
    <arm_group_label>Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib</arm_group_label>
    <other_name>None othe intervention name</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        IInclusion criteria&#xD;
&#xD;
        Patients must meet ALL of the following inclusion criteria to be eligible for enrolment&#xD;
        into the study:&#xD;
&#xD;
          1. Female patients over 18 years of age.&#xD;
&#xD;
          2. Patients have been informed about the nature of study, have agreed to participate in&#xD;
             the study, and have signed the informed consent form prior to participation in any&#xD;
             study-related activities.&#xD;
&#xD;
          3. Premenopausal and postmenopausal women. Premenopausal women must be treated with LHRH&#xD;
             analogue since patient pre- registration. Premenopausal or postmenopausal status&#xD;
             should have been established before starting study treatment with letrozole plus&#xD;
             palbociclib based on the following classification:&#xD;
&#xD;
               1. Postmenopausal status is defined as either:&#xD;
&#xD;
                    -  Prior bilateral oophorectomy; Or&#xD;
&#xD;
                    -  Age&gt;60 years; Or&#xD;
&#xD;
                    -  Age&lt;60 years and amenorrhoeic for 12 months in the absence of chemotherapy,&#xD;
                       tamoxifen, toremifene or ovarian suppression, and follicle-stimulating&#xD;
                       hormone (FSH) and estradiol in postmenopausal range.&#xD;
&#xD;
               2. Premenopausal status is defined as all those women who do not meet any of above&#xD;
                  criteria.&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.&#xD;
&#xD;
          5. Histologically confirmed infiltrating breast cancer.&#xD;
&#xD;
          6. HR-positive (estrogen receptor [ER]-positive and/or progesterone receptor&#xD;
             [PgR]-positive) EBCs (breast cancers that have at least 10% of cells staging positive&#xD;
             for ER and/or PgR). ER and/or PgR status will be centrally confirmed by using&#xD;
             immunohistochemistry (IHC) testing for an Allred score of 6-8 in at least one of them.&#xD;
&#xD;
          7. Patients with HER2-negative breast cancer through in situ hybridization test&#xD;
             (fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH],&#xD;
             or silver enhanced in situ hybridization [SISH]) or negative immunohistochemical&#xD;
             status of 0, 1+, or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or&#xD;
             SISH) test is required.&#xD;
&#xD;
          8. Ki67 levels ≥ 20% confirmed by IHC testing in a central laboratory.&#xD;
&#xD;
          9. Tumor size &gt; 2,0 cm (T2-4 according to TNM staging system, but always &gt; 2,0 cm) by&#xD;
             mammogram, breast ultrasound, or breast magnetic resonance imaging (MRI).&#xD;
&#xD;
         10. Patients must have a measurable disease by mammogram and/or breast ultrasound.&#xD;
&#xD;
         11. Patients with two significant lesions (both larger than 1 cm and with more than 1 cm&#xD;
             distance between them) will require tumor sample from both lesions and proper&#xD;
             preoperative marking of both. To be registered, both lesions should fulfil inclusion&#xD;
             criteria 5 and 6 and both tumor samples will be submitted. Patient with more than 2&#xD;
             significant lesions will not be eligible.&#xD;
&#xD;
         12. Limited node involvement (N0-2, according to TNM staging system), assessed by&#xD;
             ultrasound. Sentinel lymph node biopsy or axillary dissection, are allowed.&#xD;
&#xD;
         13. No metastatic disease (M0, according to TNM staging system).&#xD;
&#xD;
         14. Available pre-treatment tissue sample (biopsy) material (formalin- fixed&#xD;
             paraffin-embedded (FFPE) for central confirmation and RS evaluation by the Assay.&#xD;
&#xD;
         15. Patients agree to collection of tissue biopsy from the primary breast cancer at the&#xD;
             time of study inclusion (screening), at Cycle 1 Day 14 of treatment, and after 24&#xD;
             weeks (surgery), or if experience intolerable side effects, disease progression, or&#xD;
             withdraw during 24 weeks of study treatment.&#xD;
&#xD;
         16. No prior chemotherapy, endocrine, or radiation therapy for current disease.&#xD;
&#xD;
         17. Adequate organ function:&#xD;
&#xD;
               1. Hematological: White blood cell (WBC) count ≥ 3.0 x 109/L, absolute neutrophil&#xD;
                  count (ANC) ≥ 1.5x 109/L, platelet count ≥ 75.0 x109/L, and hemoglobin ≥ 10.0&#xD;
                  g/dL (≥ 6.2 mmol/L).&#xD;
&#xD;
               2. Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (x ULN) (or total&#xD;
                  bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN in patients with&#xD;
                  well-documented Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN;&#xD;
                  aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN.&#xD;
&#xD;
               3. Renal: Serum creatinine ≤ 1.5 x ULN.&#xD;
&#xD;
         18. Resolution of all acute toxic effects of prior surgical procedures to grade ≤1 as&#xD;
             determined by the NCI CTCAE v.5.0.&#xD;
&#xD;
        Exclusion criteria&#xD;
&#xD;
        Patients will be excluded from the study if they meet ANY of the following criteria:&#xD;
&#xD;
          1. Metastatic progression (M1, according to TNM staging system).&#xD;
&#xD;
          2. Substantial nodal involvement (N&gt;2, according to TNM staging system).&#xD;
&#xD;
          3. Non-large tumor (T0-1, according to TNM staging system).&#xD;
&#xD;
          4. Bilateral breast carcinoma.&#xD;
&#xD;
          5. Inflammatory carcinoma (T4d, according to TNM staging system).&#xD;
&#xD;
          6. Patient with multicentric or multifocal (more than 2 lesions) breast cancer.&#xD;
&#xD;
          7. Excisional biopsy of the primary tumor.&#xD;
&#xD;
          8. Known hypersensitivity to any palbociclib excipients.&#xD;
&#xD;
          9. Known hypersensitivity to any letrozole excipients.&#xD;
&#xD;
         10. Patients unable to swallow tablets.&#xD;
&#xD;
         11. Patients have a concurrent malignancy or malignancy within five years of study&#xD;
             enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin&#xD;
             carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk&#xD;
             of recurrence, discussion with the Medical Monitor is required.&#xD;
&#xD;
         12. Previous radiotherapy on the ipsilateral chest wall for the treatment of any other&#xD;
             malignancy.&#xD;
&#xD;
         13. Major surgery (defined as requiring general anesthesia) or significant traumatic&#xD;
             injury within four weeks of start of study treatment, or patients who have not&#xD;
             recovered from the side effects of any major surgery, or patients that may require&#xD;
             major surgery during the course of the study.&#xD;
&#xD;
         14. Have a serious concomitant systemic disorder (i.e., active infection including HIV, or&#xD;
             cardiac disease) incompatible with the study (at the discretion of investigator).&#xD;
&#xD;
         15. Patients with an active bleeding diathesis, previous history of bleeding diathesis, or&#xD;
             anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon&#xD;
             as it is used as prophylaxis intention).&#xD;
&#xD;
         16. History of malabsorption syndrome or other condition that would interfere with enteral&#xD;
             absorption.&#xD;
&#xD;
         17. Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day&#xD;
             methylprednisolone equivalent (excluding inhaled steroids).&#xD;
&#xD;
         18. QTc interval &gt; 480 msec on basal assessments, personal history of long or short QT&#xD;
             syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes&#xD;
             (TdP).&#xD;
&#xD;
         19. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging&#xD;
             drug (i.e., hypocalcemia, hypokalemia, or hypomagnesemia).&#xD;
&#xD;
         20. Participation in the treatment phase of an interventional trial within 30 days prior&#xD;
             to study treatment start.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pre and post menopausal females</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Antonio Llombart, PdH</last_name>
    <role>Principal Investigator</role>
    <affiliation>MedSIR</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital da Luz</name>
      <address>
        <city>Lisboa</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Fernando Fonseca</name>
      <address>
        <city>Lisboa</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Portuguese Institute of Oncology of Oporto</name>
      <address>
        <city>Oporto</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ICO Badalona</name>
      <address>
        <city>Badalona</city>
        <state>Barcelona</state>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ICO l'Hospitalet</name>
      <address>
        <city>L'Hospitalet de Llobregat</city>
        <state>Barcelona</state>
        <zip>08007</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de Jaén</name>
      <address>
        <city>Jaen</city>
        <state>Jaén</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complejo Hospitalario Universitario A Coruña (CHUAC)</name>
      <address>
        <city>A Coruña</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>H. Vall Hebrón</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital del Mar</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Reina Sofia</name>
      <address>
        <city>Cordoba</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Onkologikoa</name>
      <address>
        <city>Donostia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Arnau de Vilanova</name>
      <address>
        <city>Lleida</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Ramón y Cajal</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen del Rocío</name>
      <address>
        <city>Sevilla</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Valenciano de Oncologia</name>
      <address>
        <city>Valencia</city>
        <zip>46009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Arnau de Vilanova de Valencia</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinico Universitario de Valencia</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Miguel Servet</name>
      <address>
        <city>Zaragoza</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Portugal</country>
    <country>Spain</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 4, 2019</study_first_submitted>
  <study_first_submitted_qc>January 25, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 28, 2019</study_first_posted>
  <last_update_submitted>November 25, 2020</last_update_submitted>
  <last_update_submitted_qc>November 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>
    <mesh_term>Palbociclib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>20 hospital will participate at this trial: 17 sites at Spain and 3 at Portugal</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>The trial separate 2 stage: Stage I it will be radomized 26 patients (20 Sites) from January 2019 to June2019 and Stage II: 40 patients (25 sites) from February 2020 to July 2020.</ipd_time_frame>
    <ipd_access_criteria>patient should be randomized od Data base of hospitals</ipd_access_criteria>
  </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/NCT03819010
org study id: MedOPP199
secondary id: 2018-001702-28
nct id: NCT03819010
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
This is an international, multicenter, open-label, non-comparative, Simon´s two-stage design,
      phase II clinical trial.
Primary objective:

      To explore after 6 months of treatment the ability of palbociclib in combination with
      letrozole to induce global molecular changes measured by either the Oncotype DX Breast
      Recurrence Score® (the "Assay") test result at surgery (post-treatment Recurrence Score® (RS)
      result), or pathological Complete Response (pCR) in patients with aggressive luminal tumors
      (pre-treatment RS result 18-25 or 26-100, and Ki67≥ 20).

      Secondary objectives:

      BIOLOGY

        -  To explore the ability of palbociclib in combination with letrozole to induce global
           molecular changes measured by post-treatment RS result, in patients with aggressive
           luminal tumors (pre-treatment RS result 18-25 and Ki67≥ 20) after 6 months of treatment.

        -  To explore the ability of palbociclib in combination with letrozole to induce global
           molecular reduction measured by either the post-treatment RS result, and/or Residual
           Cancer Burden (RCB), and/or Ki67 in patients with aggressive luminal tumors
           (pre-treatment RS result 18-25 or 26-100 and Ki67 ≥ 20) after 6 months of treatment.

        -  To verify the ability of palbociclib in combination with letrozole to induce global
           molecular reduction (measured as either post-treatment RS≤25 or RCB score of 0-I) in
           >35% of patients in cohort B with pre-treatment RS 26-100;

        -  To verify the ability of palbociclib in combination with letrozole to induce increase in
           RS result (measured as post-treatment RS 26-100) in <3% of patients in cohort A with
           pre-treatment RS 18-25;

        -  To evaluate the concordance rate between the RCB score (0- I vs. II-III) and the
           post-treatment RS result in both cohorts of patients after treatment with palbociclib in
           combination with letrozole;

        -  To evaluate the concordance rate between the preoperative endocrine prognostic index
           (PEPI) score and post-treatment RS result in both cohorts of patients after treatment
           with palbociclib in combination with letrozole;

        -  To evaluate the concordance rate between the pCR and the post-treatment RS result in
           both cohorts of patients after treatment with palbociclib in combination with letrozole;

        -  To determine the change in RS result as measured by median absolute value or median
           percentage after 6 months of treatment: from pre-treatment RS 18-25 to post-treatment RS
           0-17 for patients in cohort A and from pre-treatment RS 26-100 to post-treatment RS≤25
           for patients in cohort B.

      EFFICACY

        -  To determine the Overall Response Rate (ORR) of patients treated with palbociclib in
           combination with letrozole.

        -  To evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole.

        -  To determine the rate of breast conserving surgery.

      SAFETY

      • To assess the safety and tolerability of palbociclib in combination with letrozole.

      A two-stage Simon's statistical design will be used for both cohorts (minimax design in
      co-hort B and optimal design in cohort A). A total of 66 patients will be enrolled into this
      trial, N=33 patients in cohort with high-risk tumors (Cohort B: pre-treatment RS>25) and N=33
      patients in cohort with intermediate-risk tumors (Cohort A: pre-treatment RS18-25).

      The accrual goal will be of 26 patients (N=13 patients in each cohort) during the first
      stage. The interim analysis has been planned after 15 patients (cohort B) and 9 patients
      (cohort A) will be available for biological response evaluation, and in case of positive
      findings, the trial will recruit additional 40 patients (N=20 patients in each cohort).

        -  The study would be defined as positive at final analysis in the cohort B (pre-treatment
           RS>25), if 8 or more than 8 patients with biological signal (post-treatment RS≤25) are
           observed (≥28.6%) among 28 evaluable patients.

        -  The study would be defined as positive at final analysis in the cohort A (pre-treatment
           RS18-25), if 25 or more than 25 patients with biological stabilization (post-treatment
           RS≤25) are observed (≥89.3%) among 28 evaluable patients.

      Study treatment management

      After signing the informed consent form (ICF) and confirmed pre- eligibility, patients will
      be pre-registered in the study. A tissue biopsy from the primary breast cancer has to be
      provided at screening and will be used to perform central confirmation of Ki67 levels and HR
      status, as well as central assessment of RS. Pre-registered patients can receive up to 4
      weeks of letrozole before inclusion; pre-menopausal patients will require to combine it with
      a Luteinizing Hormone-Releasing Hormone (LHRH) analogue. Patients are eligible to enter one
      of the two cohorts according to RS assessment as follow:

        -  Cohort A: patients with pre-treatment RS 18-25;

        -  Cohort B: patients with pre-treatment RS 26-100. Patients with pre-treatment RS 0-17
           will be considered not eligible. Patients allocated to the cohort A or B will receive 24
           weeks of palbociclib (for 21 days every 4 weeks) in combination with letrozole (once
           daily, beginning on day 1 and continuing through day 28 of every 28-day cycle).
           Premenopausal women must also be treated with an LHRH analogue during the treatment
           phase.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: This is an international, multicenter, open-label, non-comparative, Simon´s two-stage design, phase II clinical trial.
primary purpose: Treatment
masking: None (Open Label)
masking description: Two arms of patients (according to Recurrence Score results), but both arms will be treated with the same treatment
measure: Difference on Recurrence Score between pre and post-treatment (molecular results)
time frame: 6 months
description: To explore after 6 months of treatment the ability of palbociclib in combination with letro-zole to induce global molecular changes measured by either the Oncotype DX Breast Recurrence Score® (the "Assay") test result at surgery (post-treatment Recurrence Score® (RS) result), or pathological Complete Response (pCR) in patients with aggres-sive luminal tumors (pre-treatment RS result 18-25 or 26-100, and Ki67>20).
measure: Molecular changes
time frame: 6 months
description: Concordance rate among post-treatment RS result and residual cancer burden (RCB), Ki67, and preoperative endocrine prognostic index (PEPI) score
measure: Molecular induction
time frame: 6 months of treatment
description: To explore the ability of palbociclib in combination with letrozole to induce global mo-lecular reduction measured by either the post-treatment RS result, and/or Residual Cancer Burden (RCB), and/or Ki67 in patients with aggressive luminal tumors (pre-treatment RS result 18-25 or 26-100 and Ki67>20) after 6 months of treatment.
measure: Global molecular reduction
time frame: 6 months of treatment
description: To verify the ability of palbociclib in combination with letrozole to induce global mo-lecular changes (measured as either post-treatment RS≤25 or RCB score of 0-I) in >35% of patients in cohort B with pre-treatment RS 26-100;
measure: increase RS result
time frame: 6 months of treatment
description: To verify the ability of palbociclib in combination with letrozole to induce changes in RS result (measured as post-treatment RS 26-100) in <3% of patients in cohort A with pre-treatment RS 18-25;
measure: Evaluate the concordance rate between the RCB score (0- I vs. II-III) and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in com-bination with letrozole;
time frame: 6 months of treatment
description: To evaluate the concordance rate between the RCB score (0- I vs. II-III) and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in com-bination with letrozole;
measure: Evaluate the concordance rate between the pCR and the post-treatment RS re-sult in both cohorts of patients after treatment with palbociclib in combination with letro-zole;
time frame: 6 month of treatment
description: To evaluate the concordance rate between the pCR and the post-treatment RS re-sult in both cohorts of patients after treatment with palbociclib in combination with letro-zole;
measure: Changes in RS
time frame: 6 month of treatment
description: To determine the change in RS result as measured by median absolute value or median percentage after 6 months of treatment: from pre-treatment RS 18-25 to post-treatment RS 0-17 for patients in cohort A and from pre-treatment RS 26-100 to post-treatment RS≤25 for patients in cohort B.
measure: overall repsonse
time frame: 6 month of treatment
description: To determine the Overall Response Rate (ORR) of patients treated with palbociclib in combination with letrozole.
measure: duration of response
time frame: 6 month of treatment
description: To evaluate the Duration of Response (DoR) of palbociclib in combination with letrozole.
measure: Time to response
time frame: 6 month of treatment
description: To evaluate the Time to Response (TTR) of palbociclib in combination with letrozole.
measure: Clinical benefit
time frame: 6 month of treatment
description: To assess the Clinical Benefit Rate (CBR) of palbociclib in combination with letrozole.
measure: Evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole
time frame: 6 month of treatment
description: To evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole
measure: Safety and tolerability of the combination Letrozole plus Palbociclib
time frame: 6 month of treatment
description: To assess the safety and tolerability of palbociclib in combination with letrozole. "Number of participants with treatment-related adverse events as assessed by CTCAE v4.0".
arm group label: Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib
arm group type: Active Comparator
description: Letrozole (2,5 mg/day during 28 days of each Cycle) + Palbociclib (125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer interventions: Letrozol (2,5 mg/day during 28 days of each Cycle)+ Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer
arm group label: Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib
arm group type: Active Comparator
description: Letrozole (2,5 mg/day during 28 days of each Cycle) + Palbociclib (125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer interventions: Letrozol (2,5 mg/day during 28 days of each Cycle)+ Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer
intervention type: Drug
intervention name: Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib
description: Letrozole(2,5 mg/day during 28 days of each Cycle) + Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer for patients with pre-treatment recurrence Score of 18-25
arm group label: Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib
other name: None othe intervention name
intervention type: Drug
intervention name: Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib
description: Letrozole(2,5 mg/day during 28 days of each Cycle) + Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer for patients with pre-treatment recurrence Score of 26-100
arm group label: Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib
other name: None othe intervention name
criteria: 
gender: Female
gender based: Yes
gender description: Pre and post menopausal females
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Antonio Llombart, PdH
role: Principal Investigator
affiliation: MedSIR
facility: 
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country: Portugal
country: Spain
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Letrozole
mesh term: Palbociclib
sharing ipd: Yes
ipd description: 20 hospital will participate at this trial: 17 sites at Spain and 3 at Portugal
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: The trial separate 2 stage: Stage I it will be radomized 26 patients (20 Sites) from January 2019 to June2019 and Stage II: 40 patients (25 sites) from February 2020 to July 2020.
ipd access criteria: patient should be randomized od Data base of hospitals