<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/NCT02997995</url>
  </required_header>
  <id_info>
    <org_study_id>UC-0140/1606</org_study_id>
    <secondary_id>UCBG-105</secondary_id>
    <secondary_id>BIG 16-01</secondary_id>
    <secondary_id>2016-000764-42</secondary_id>
    <nct_id>NCT02997995</nct_id>
  </id_info>
  <brief_title>Durvalumab and Endocrine Therapy in ER+/Her2- Breast Cancer After CD8+ Infiltration Effective Immune-Attractant Exposure</brief_title>
  <acronym>ULTIMATE</acronym>
  <official_title>A Phase II Trial Testing Durvalumab Combined With Endocrine Therapy in Patients With ER+/Her2- Breast Cancer Eligible for Neoadjuvant Endocrine Therapy And Who Present CD8+ T Cell Infiltration After 4-6 Weeks Exposure to Immune-Attractant</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UNICANCER</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Breast International Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>UNICANCER</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>
      This is an open-label, multicentric, international, phase II trial testing aromatase&#xD;
      inhibitors in combination with durvalumab in patients with CD8+ T cell infiltration (&gt;10%&#xD;
      CD8+ T cells in the tumor). The trial includes two sequences: The first part of the treatment&#xD;
      will consist in 4-6 weeks treatment with immune-attractants; in the second part, CD8+&#xD;
      patients will receive 6 months of durvalumab combined with exemestane.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is conducted in 2 parts:&#xD;
&#xD;
      Part 1: lymphocyte attraction. After the screening phase, the patient will receive&#xD;
      immune-attractant combined with exemestane for six weeks.&#xD;
&#xD;
      As immune-attractants are added over the course of the study, they will appear as subsequent&#xD;
      appendices in the full protocol.&#xD;
&#xD;
      Up to 4 cohorts may be tested sequentially in this design until up to 240 evaluable patients&#xD;
      have been treated.&#xD;
&#xD;
      The first cohort of patients will receive tremelimumab (3 mg/kg, single infusion) combined&#xD;
      with exemestane (25 mg daily). In each cohort, an interim analysis will be performed after 30&#xD;
      patients in order to potentially stop the cohort (if less than 25% of patients present &gt;10%&#xD;
      CD8+ cells in the tumor after 3 weeks). If all 4 cohorts are closed and the target number of&#xD;
      56 patients for part 2 has not been reached, additional patients will be recruited and&#xD;
      treated with the best performing immune-attractant treatment based on the part I results.&#xD;
      From the moment 56 patients are included in part 2, no more patients will be entered in part&#xD;
      1.&#xD;
&#xD;
      After three weeks (+/- 3 days), a tumor biopsy will be done. Patients who present &gt;10% CD8+&#xD;
      cells in the tumor after 3 weeks and remain eligible will be included in the second part of&#xD;
      the trial (patients who do not present CD8+ T cells on the 3-week biopsy will be treated at&#xD;
      the investigator's choice).&#xD;
&#xD;
      Part 2: lymphocyte activation (anti-PD1 treatment) Four to six weeks after immune-attractant&#xD;
      start, patients having &gt;10% CD8+ cells in the tumor will receive durvalumab 1500 mg Q4W&#xD;
      (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months.&#xD;
&#xD;
      Part 2 will include two steps. In the first step, we will include 23 patients. If 2 or more&#xD;
      pathological complete responses are observed in these 23 patients, the part 2 will move to&#xD;
      step 2. 33 additional patients will be included in the step 2.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 15, 2017</start_date>
  <completion_date type="Actual">August 28, 2020</completion_date>
  <primary_completion_date type="Actual">July 15, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>pathological Complete Response</measure>
    <time_frame>at time of surgery</time_frame>
    <description>Response at surgery</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of CD8+ T cell</measure>
    <time_frame>at biopsy (3 weeks)</time_frame>
    <description>exam at biopsy and comparison between biopsy and Baseline biopsy rates</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical response</measure>
    <time_frame>after 6 months of Durvalumab</time_frame>
    <description>Clinical exam</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Ki67</measure>
    <time_frame>at surgery</time_frame>
    <description>measure of Ki67</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicities</measure>
    <time_frame>1 year and 8 months</time_frame>
    <description>Common terminology criteria for adverse events (CTC-AE) v4.03</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Predictive value of Mutational load for efficacy of Durvalumab</measure>
    <time_frame>on baseline biopsy and blood samples</time_frame>
    <description>exome sequencing on baseline samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Predictive value of PDL1 expression for the efficacy of Durvalumab</measure>
    <time_frame>on baseline biopsy and biopsy at 3 weeks</time_frame>
    <description>correlate Immune infiltrate intensity with the proportion of tumor cells expressing PD-L1 by Ventana SP263 assay</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">61</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Estrogen Receptor Positive Tumor</condition>
  <condition>Menopause</condition>
  <condition>Hormone Antagonist</condition>
  <arm_group>
    <arm_group_label>Immune-attractant/lymphocyte activation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After the screening phase, the patient will receive immune-attractant combined with exemestane for six weeks. After three weeks (+/- 3 days), a tumor biopsy will be done. Patients who present &gt;10% CD8+ cells in the tumor after 3 weeks and remain eligible will be included in the second part of the trial i.e. lymphocyte activation. In this second part, patients will receive durvalumab 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months. The pathological response will be checked by surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Immune-attractant</intervention_name>
    <description>The first cohort patients will receive tremelimumab (3 mg/kg, single infusion) as immune-attractants combined with exemestane (25 mg daily).</description>
    <arm_group_label>Immune-attractant/lymphocyte activation</arm_group_label>
    <other_name>Tremelimumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Durvalumab (lymphocyte activation) will be administrated at a dose of 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months</description>
    <arm_group_label>Immune-attractant/lymphocyte activation</arm_group_label>
    <other_name>MEDI4736</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biopsy</intervention_name>
    <description>After three weeks (+/- 3 days) of immune-attractants, a tumor biopsy will be done. Patients who present &gt;10% CD8+ cells in the tumor after 3 weeks will receive the Durvalumab</description>
    <arm_group_label>Immune-attractant/lymphocyte activation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥18 years post-menopausal according to one of the following criteria:&#xD;
&#xD;
               -  Age &gt;60 years&#xD;
&#xD;
               -  Or Bilateral ovariectomy&#xD;
&#xD;
               -  Or Age ≤60, with an uterus and presenting an amenorrhea of more than 12 months&#xD;
                  and FSH and estradiol in the postmenopausal range&#xD;
&#xD;
               -  Or Age ≤60, without an uterus and FSH and estradiol in the postmenopausal range&#xD;
&#xD;
          2. Histologically proven invasive breast cancer eligible to neoadjuvant endocrine therapy&#xD;
             according to multidisciplinary tumor board.&#xD;
&#xD;
             Note: Multicentric/multifocal tumors are allowed if all share the same characteristics&#xD;
&#xD;
          3. cT2-T4, any N; cT2 are eligible only if the clinical tumor size is &gt;3 cm&#xD;
&#xD;
          4. Non metastatic, M0 (according to clinical staging)&#xD;
&#xD;
          5. Luminal A patients ER-positive by immunohistochemistry (IHC) according to the&#xD;
             following criteria (local assessment): Grade I or II AND ER-positive (≥60%) AND Ki67&#xD;
             &lt;20%&#xD;
&#xD;
          6. Her2-negative by IHC (score 0 or 1+) and/or fluorescent in situ hybridization&#xD;
             (FISH)/chromogenic in situ hybridization (CISH) negative according to local assessment&#xD;
&#xD;
          7. CD8+ T Cell infiltration defined as &gt;10% cells stained with anti-CD8 monoclonal&#xD;
             antibody by IHC at the 3-week biopsy (applicable for inclusion in part 2 only)&#xD;
&#xD;
          8. Available tumor samples from baseline biopsy&#xD;
&#xD;
          9. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance&#xD;
             status of 0 or 1 at enrolment&#xD;
&#xD;
         10. Adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  Hemoglobin ≥9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count ≥1.5 × 10⁹/L&#xD;
&#xD;
               -  Platelet count ≥100 × 10⁹/L&#xD;
&#xD;
               -  Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to&#xD;
                  patients with confirmed Gilbert's syndrome, who will be allowed in consultation&#xD;
                  with their physician&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 × ULN&#xD;
&#xD;
               -  Adequate renal function as determined by CKD-EPI formula (using actual body&#xD;
                  weight)&#xD;
&#xD;
         11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory&#xD;
             tests, and other trial procedures&#xD;
&#xD;
         12. Written informed consent obtained prior to performing any protocol-related procedures,&#xD;
             including screening evaluations&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Inflammatory breast cancer&#xD;
&#xD;
          2. No prior exposure to immune-mediated therapy including, but not limited to, other&#xD;
             anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2&#xD;
             (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines&#xD;
&#xD;
          3. Any concurrent chemotherapy, investigational product (IP), biologic therapy for cancer&#xD;
             treatment&#xD;
&#xD;
          4. Previous Radiotherapy treatment to more than 30% of the bone marrow;&#xD;
&#xD;
          5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the&#xD;
             first dose&#xD;
&#xD;
          6. History of allogenic organ transplantation&#xD;
&#xD;
          7. Active or prior documented autoimmune or inflammatory disorders (including&#xD;
             inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis with the&#xD;
             exception of diverticulosis, celiac disease or other serious gastrointestinal chronic&#xD;
             conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis&#xD;
             syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease,&#xD;
             rheumatoid arthritis, hypophysitis, uveitis, etc within the past 3 years prior to the&#xD;
             start of treatment. The following are exceptions to this criterion:&#xD;
&#xD;
               -  Patients with vitiligo or alopecia&#xD;
&#xD;
               -  Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone&#xD;
                  replacement or psoriasis not requiring systemic treatment&#xD;
&#xD;
          8. Any condition that, in the opinion of the Investigator, would interfere with the&#xD;
             evaluation of investigational product or interpretation of patient safety or study&#xD;
             results, including ongoing or active infection, symptomatic congestive heart failure,&#xD;
             uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial&#xD;
             lung disease, or psychiatric illness/social situations that would limit compliance&#xD;
             with study requirement, substantially increase risk of incurring adverse events from&#xD;
             investigational products, or compromise the ability of the patient to give written&#xD;
             informed consent&#xD;
&#xD;
          9. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms&#xD;
&#xD;
         10. History of active primary immunodeficiency&#xD;
&#xD;
         11. Known history of active tuberculosis&#xD;
&#xD;
         12. Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus&#xD;
             (HIV)&#xD;
&#xD;
         13. Current or prior use of immunosuppressive medication within 14 days before the first&#xD;
             dose. The following are exceptions to this criterion:&#xD;
&#xD;
               -  Intranasal, inhaled, topical steroids, or local steroid injections (eg,&#xD;
                  intra-articular injection)&#xD;
&#xD;
               -  Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of&#xD;
                  prednisone or its equivalent&#xD;
&#xD;
               -  Steroids as premedication for hypersensitivity reactions (eg, CT scan&#xD;
                  premedication)&#xD;
&#xD;
         14. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.&#xD;
&#xD;
             Note: Patients, if enrolled, should not receive live vaccine during the study and up&#xD;
             to 30 days after the last dose of IP&#xD;
&#xD;
         15. Known allergy or hypersensitivity to any medicinal product used in the trial or any&#xD;
             excipient&#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>Fabrice Andre, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gustave Roussy, Cancer Campus, Grand Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centre Hospitalier cote Basque</name>
      <address>
        <city>Bayonne</city>
        <zip>64109</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Bergonié</name>
      <address>
        <city>Bordeaux</city>
        <zip>33000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre François Baclesse</name>
      <address>
        <city>Caen</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier de Cahors</name>
      <address>
        <city>Cahors</city>
        <zip>46000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hôspitalier de Cholet</name>
      <address>
        <city>Cholet</city>
        <zip>49300</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre George François Leclerc</name>
      <address>
        <city>Dijon</city>
        <zip>21000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Daniel Hollard Groupe Hôspitalier</name>
      <address>
        <city>Grenoble</city>
        <zip>38028</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Oscar Lambret</name>
      <address>
        <city>Lille</city>
        <zip>59020</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Limoges</name>
      <address>
        <city>Limoges</city>
        <zip>87042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Bretagne Sud</name>
      <address>
        <city>Lorient</city>
        <zip>56100</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Léon Bérard</name>
      <address>
        <city>Lyon</city>
        <zip>69008</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Paoli Calmettes</name>
      <address>
        <city>Marseille</city>
        <zip>13009</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Curie Site Paris</name>
      <address>
        <city>Paris</city>
        <zip>75005</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Saint Louis APHP</name>
      <address>
        <city>Paris</city>
        <zip>75010</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Perpignan</name>
      <address>
        <city>Perpignan</city>
        <zip>66000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Jean Godinot</name>
      <address>
        <city>Reims</city>
        <zip>51726</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Curie Hôpital René Huguenin</name>
      <address>
        <city>Saint Cloud</city>
        <zip>92210</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Paul Strauss</name>
      <address>
        <city>Strasbourg</city>
        <zip>67065</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Claudius Regaud</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Bretonneau - Centre Henry Kaplan</name>
      <address>
        <city>Tours</city>
        <zip>37044</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <zip>94800</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ICO Badalona</name>
      <address>
        <city>Badalona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinic Barcelona</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HU Vall Hebron</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HU Arnau de Vilanova</name>
      <address>
        <city>Lleida</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CIO Clara Campal</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HU Ramon y Cajal</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario de Valencia</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sahlgrenska University Hospital</name>
      <address>
        <city>Gothenburg</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Spain</country>
    <country>Sweden</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>December 9, 2016</study_first_submitted>
  <study_first_submitted_qc>December 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>September 29, 2020</last_update_submitted>
  <last_update_submitted_qc>September 29, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>T2-T4 Breast cancer</keyword>
  <keyword>Estrogen Receptor Positive Tumor</keyword>
  <keyword>PD-1</keyword>
  <keyword>Neoadjuvant</keyword>
  <keyword>Immune-attractants</keyword>
  <keyword>lymphocytes activation</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>Durvalumab</mesh_term>
    <mesh_term>Tremelimumab</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/NCT02997995
org study id: UC-0140/1606
secondary id: UCBG-105
secondary id: BIG 16-01
secondary id: 2016-000764-42
nct id: NCT02997995
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is an open-label, multicentric, international, phase II trial testing aromatase
      inhibitors in combination with durvalumab in patients with CD8+ T cell infiltration (>10%
      CD8+ T cells in the tumor). The trial includes two sequences: The first part of the treatment
      will consist in 4-6 weeks treatment with immune-attractants; in the second part, CD8+
      patients will receive 6 months of durvalumab combined with exemestane.
The study is conducted in 2 parts:

      Part 1: lymphocyte attraction. After the screening phase, the patient will receive
      immune-attractant combined with exemestane for six weeks.

      As immune-attractants are added over the course of the study, they will appear as subsequent
      appendices in the full protocol.

      Up to 4 cohorts may be tested sequentially in this design until up to 240 evaluable patients
      have been treated.

      The first cohort of patients will receive tremelimumab (3 mg/kg, single infusion) combined
      with exemestane (25 mg daily). In each cohort, an interim analysis will be performed after 30
      patients in order to potentially stop the cohort (if less than 25% of patients present >10%
      CD8+ cells in the tumor after 3 weeks). If all 4 cohorts are closed and the target number of
      56 patients for part 2 has not been reached, additional patients will be recruited and
      treated with the best performing immune-attractant treatment based on the part I results.
      From the moment 56 patients are included in part 2, no more patients will be entered in part
      1.

      After three weeks (+/- 3 days), a tumor biopsy will be done. Patients who present >10% CD8+
      cells in the tumor after 3 weeks and remain eligible will be included in the second part of
      the trial (patients who do not present CD8+ T cells on the 3-week biopsy will be treated at
      the investigator's choice).

      Part 2: lymphocyte activation (anti-PD1 treatment) Four to six weeks after immune-attractant
      start, patients having >10% CD8+ cells in the tumor will receive durvalumab 1500 mg Q4W
      (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months.

      Part 2 will include two steps. In the first step, we will include 23 patients. If 2 or more
      pathological complete responses are observed in these 23 patients, the part 2 will move to
      step 2. 33 additional patients will be included in the step 2.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: pathological Complete Response
time frame: at time of surgery
description: Response at surgery
measure: Number of CD8+ T cell
time frame: at biopsy (3 weeks)
description: exam at biopsy and comparison between biopsy and Baseline biopsy rates
measure: Clinical response
time frame: after 6 months of Durvalumab
description: Clinical exam
measure: Assessment of Ki67
time frame: at surgery
description: measure of Ki67
measure: Toxicities
time frame: 1 year and 8 months
description: Common terminology criteria for adverse events (CTC-AE) v4.03
measure: Predictive value of Mutational load for efficacy of Durvalumab
time frame: on baseline biopsy and blood samples
description: exome sequencing on baseline samples
measure: Predictive value of PDL1 expression for the efficacy of Durvalumab
time frame: on baseline biopsy and biopsy at 3 weeks
description: correlate Immune infiltrate intensity with the proportion of tumor cells expressing PD-L1 by Ventana SP263 assay
arm group label: Immune-attractant/lymphocyte activation
arm group type: Experimental
description: After the screening phase, the patient will receive immune-attractant combined with exemestane for six weeks. After three weeks (+/- 3 days), a tumor biopsy will be done. Patients who present >10% CD8+ cells in the tumor after 3 weeks and remain eligible will be included in the second part of the trial i.e. lymphocyte activation. In this second part, patients will receive durvalumab 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months. The pathological response will be checked by surgery.
intervention type: Drug
intervention name: Immune-attractant
description: The first cohort patients will receive tremelimumab (3 mg/kg, single infusion) as immune-attractants combined with exemestane (25 mg daily).
arm group label: Immune-attractant/lymphocyte activation
other name: Tremelimumab
intervention type: Drug
intervention name: Durvalumab
description: Durvalumab (lymphocyte activation) will be administrated at a dose of 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months
arm group label: Immune-attractant/lymphocyte activation
other name: MEDI4736
intervention type: Procedure
intervention name: Biopsy
description: After three weeks (+/- 3 days) of immune-attractants, a tumor biopsy will be done. Patients who present >10% CD8+ cells in the tumor after 3 weeks will receive the Durvalumab
arm group label: Immune-attractant/lymphocyte activation
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Fabrice Andre, Prof
role: Principal Investigator
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
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country: France
country: Spain
country: Sweden
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Durvalumab
mesh term: Tremelimumab
sharing ipd: Undecided