<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/NCT03818685</url>
  </required_header>
  <id_info>
    <org_study_id>ET17-093 BreastImmune03</org_study_id>
    <nct_id>NCT03818685</nct_id>
  </id_info>
  <brief_title>Evaluate the Clinical Benefit of a Post-operative Treatment Associating Radiotherapy + Nivolumab + Ipilimumab Versus Radiotherapy + Capecitabine for Triple Negative Breast Cancer Patients With Residual Disease</brief_title>
  <acronym>BreastImmune03</acronym>
  <official_title>A Multicenter, Randomised, Open-label Phase II Study to Evaluate the Clinical Benefit of a Post-operative Treatment Associating Radiotherapy + Nivolumab + Ipilimumab Versus Radiotherapy + Capecitabine for Triple Negative Breast Cancer Patients With Residual Disease After Neoadjuvant Chemotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Leon Berard</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre Leon Berard</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>
      To evaluate the clinical benefit of a post-operative adjuvant therapy combining radiotherapy&#xD;
      + Nivolumab + Ipilimumab versus radiotherapy + Capecitabine in Triple Negative Breast Cancer&#xD;
      (TNBC) patients with residual disease after neoadjuvant chemotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This trial is an open-label, randomised, multicentric, comparative, Phase II study aiming to&#xD;
      evaluate the clinical benefit of a combined treatment associating radiotherapy + Nivolumab +&#xD;
      Ipilimumab versus radiotherapy + Capecitabine (standard treatment) in early TNBC patients who&#xD;
      have Residual cancer burden (RCB) II or III residual disease after neoadjuvant chemotherapy.&#xD;
&#xD;
      Following validation of eligibility criteria, patients will be randomised (1:1) to receive:&#xD;
&#xD;
        -  Arm A: Nivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV,&#xD;
           every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.&#xD;
&#xD;
        -  Arm B: Capecitabine (1000 mg/m2 twice a day, Bis In Die [BID]), 14 days on / 7 days off&#xD;
           for 8 cycles.&#xD;
&#xD;
      In both arms, radiotherapy will be administered as per standard practice and has to be&#xD;
      initiated one week before C1D1.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 2, 2019</start_date>
  <completion_date type="Anticipated">March 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">November 1, 2023</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>
    <intervention_model_description>This trial is an open-label, randomised, multicentric, comparative, Phase II study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease free survival (DFS)</measure>
    <time_frame>At 2 years</time_frame>
    <description>DFS is defined as the time from randomization until the date of the first relapse (local/regional recurrence or distant metastasis) or death (from any cause) whichever comes firsts and regardless of whether the patient withdraws from randomised study treatment or receives another anti-cancer therapy prior to disease relapse.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Overall survival will be measured from the date of randomization to the date of death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Local-regional recurrence</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Local-regional recurrence (LRR) refers to relapse of the primary tumor site</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Distant metastasis</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Distant metastasis is defined as presence of any non-local metastatic sites.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease recurrence/relapse (local or distant)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Rate of patients with recurrence at 1 year and 2 year post-randomisation as well as time to recurrence will be analysed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Event</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The assessment of safety will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTCAE-V5.0) grade.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EORTC QLQ C30</measure>
    <time_frame>At Baseline, every 12 weeks and 30 days after the last dose</time_frame>
    <description>Patient reported outcomes and quality of life will be assessed using the validated following questionnaire: The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30). The QLQ-C30 incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures are also included. See scoring manual at :https://www.eortc.be/qol/files/SCManualQLQ-C30.pdf.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Questionnaire EORTC QLQ BR-23</measure>
    <time_frame>At Baseline, every 12 weeks and 30 days after the last dose</time_frame>
    <description>Patient reported outcomes and quality of life will be assessed using the validated following questionnaire :The European Organization for Research and Treatment of Cancer Breast-Cancer-Specific Quality of Life Questionnaire. See details at :https://www.eortc.be.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Questionnaire EORTC QLQ FA-12 Fatigue</measure>
    <time_frame>At Baseline, every 12 weeks and 30 days after the last dose</time_frame>
    <description>Patient reported outcomes and quality of life will be assessed using the validated following questionnaire : EORTC QLQ FA-12 Fatigue.&#xD;
The European Organisation for Research and Treatment of Cancer (EORTC) Group has developed a multidimensional instrument measuring cancer-related fatigue to be used in conjunction with the quality of life core questionnaire (EORTC QLQ-C30). The module EORTC QLQ-FA12 assesses physical, cognitive, and emotional aspects of cancer-related fatigue. See details at :https://www.eortc.be.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Questionnaire patient self-rating mood scale.</measure>
    <time_frame>At Baseline, every 12 weeks and 30 days after the last dose</time_frame>
    <description>Patient reported outcomes and quality of life will be assessed using the following questionnaire : patient self-rating mood scale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mutational profiles</measure>
    <time_frame>At Baseline and in case of disease relapse up to 2 years</time_frame>
    <description>To define the molecular characteristics of the tumor' patients: Mutational profiles of tumors (Whole Exome seq,)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Copy Number alterations.</measure>
    <time_frame>At Baseline and in case of disease relapse up to 2 years</time_frame>
    <description>To define the molecular characteristics of the tumor' patients: Copy Number alterations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Loss of heterozygosity.</measure>
    <time_frame>At Baseline and in case of disease relapse up to 2 years</time_frame>
    <description>To define the molecular characteristics of the tumor' patients: loss of heterozygosity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Circulating tumor DNA</measure>
    <time_frame>At Baseline and in case of disease relapse up to 2 years</time_frame>
    <description>Circulating tumor DNA detection and analysis will be performed on tumor' patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Molecular Subtyping</measure>
    <time_frame>At Baseline and in case of disease relapse up to 2 years</time_frame>
    <description>To define Molecular Subtyping of TNBC (RNAseq) on tumor' patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune monitoring</measure>
    <time_frame>At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse</time_frame>
    <description>To perform Immune monitoring of circulating immune cells and circulating tumor cells on blood sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Circulating growth factors</measure>
    <time_frame>At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse</time_frame>
    <description>To assess levels of circulating growth factors and cytokines on blood sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokines</measure>
    <time_frame>At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse</time_frame>
    <description>To assess levels of cytokines on blood sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PDL1</measure>
    <time_frame>At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse</time_frame>
    <description>To assess the presence in plasma of soluble PDL1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PDL2</measure>
    <time_frame>At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse</time_frame>
    <description>To assess the presence in plasma of soluble PDL2.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">95</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Triple Negative Breast Neoplasms</condition>
  <arm_group>
    <arm_group_label>Nivolumab + Ipilimumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV, every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Capecitabine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Capecitabine (1000 mg/m2 twice a day, Bis In Die), 14 days on / 7 days off for 8 cycles.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Radiotherapy will be maintained in each Arm.</description>
    <arm_group_label>Nivolumab + Ipilimumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Radiotherapy will be maintained in each Arm.</description>
    <arm_group_label>Nivolumab + Ipilimumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine</intervention_name>
    <description>Radiotherapy will be maintained in each Arm.</description>
    <arm_group_label>Capecitabine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female patient 18 years of age on day of signing informed consent form.&#xD;
&#xD;
          -  Histologically proven TNBC defined as follows : HER2 negativity must be confirmed (by&#xD;
             one of the following: Fluorescence in situ hybridization (FISH) negative (FISH ratio&#xD;
             &lt;2.2), or Immunohistochemistry (IHC): 0-1+, or IHC 2-3+ and FISH-negative (FISH ratio&#xD;
             &lt;2.2)) and less than 1% of cells stained by immunohistochemistry (IHC) for ER and PR&#xD;
             as per ASCO guidelines.&#xD;
&#xD;
          -  TNBC previously treated by : Standard neoadjuvant chemotherapy containing&#xD;
             anthracycline and taxanes and Surgery.&#xD;
&#xD;
          -  TNBC patients currently treated by post-operative radiotherapy as per standard and/or&#xD;
             institutional guidelines.&#xD;
&#xD;
          -  No radiological evidence of metastatic disease documented by a CT-Scan of Chest&#xD;
             abdomen and pelvis.&#xD;
&#xD;
          -  Residual disease with RCB of Class II or III documented before randomisation using the&#xD;
             surgery specimen.&#xD;
&#xD;
          -  Availability of a representative formalin-fixed paraffin-embedded (FFPE) tumor block&#xD;
             from surgery specimen with its histological report.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.&#xD;
&#xD;
          -  Adequate end organ and bone marrow function as defined in protocol. All screening lab&#xD;
             tests should be performed within 7 days before C1D1.&#xD;
&#xD;
          -  Absence of significant treatment-related toxicity i.e. &gt; Grade 1 as per CTCAE v5.0,&#xD;
             except alopecia (all grades are acceptable), neuropathy (Grade 2 is acceptable) or&#xD;
             biological values as defined in protocol.&#xD;
&#xD;
          -  Minimal wash-out period for prior treatments (i.e. minimal delay from last dose of&#xD;
             prior treatment to C1D1): any investigational agent &gt; 4 weeks (or 5 half-lives&#xD;
             whichever is longer with a minimum of 2 weeks), any monoclonal antibody &gt; 4 weeks, any&#xD;
             targeted therapies &gt; 4 weeks, - live vaccine &gt; 4 weeks, systemic steroids at doses&#xD;
             higher than 10 mg/day prednisone equivalent or other immunosuppressive agents &gt; 3&#xD;
             weeks, sorivudine or its chemically related analogues such as brivudine &gt; 4 weeks.&#xD;
&#xD;
          -  Women of child-bearing potential must have a negative serum pregnancy test within 7&#xD;
             days before C1D1.&#xD;
&#xD;
          -  Women of child-bearing potential must agree to use 1 effective form of contraception&#xD;
             from the time of the negative pregnancy test up to 5 months after the last dose of&#xD;
             study drugs.&#xD;
&#xD;
          -  Patient should understand, sign, and date the written voluntary informed consent form&#xD;
             at the screening visit prior to any protocol-specific procedures performed.&#xD;
&#xD;
          -  Patient should be able and willing to comply with study visits and procedures as per&#xD;
             protocol.&#xD;
&#xD;
          -  Patients must be covered by a medical insurance.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patient has a metastatic TN breast cancer.&#xD;
&#xD;
          -  Patient has previously received therapy with an anti- PD-1, anti- PD-L1, or anti-CTLA4&#xD;
             or any other immunotherapies.&#xD;
&#xD;
          -  Patient has a known additional malignancy that is progressing or requires active&#xD;
             treatment. Exceptions include basal cell carcinoma of the skin, squamous cell&#xD;
             carcinoma of the skin, or in situ cervical cancer that has undergone curative therapy&#xD;
             and other completely treated prior malignancy if no evidence of disease for ≥ 2 years.&#xD;
&#xD;
          -  Patient presents a contraindication to Nivolumab or Ipilimumab treatment as per&#xD;
             respective SPC including known hypersensitivity to one of these study drugs or severe&#xD;
             hypersensitivity reaction to any monoclonal antibody.&#xD;
&#xD;
          -  Patient presents a contraindication to Capecitabine treatment as per SPC including :&#xD;
             1) History of severe and unexpected reactions to fluoropyrimidine therapy, 2)&#xD;
             Hypersensitivity to Capecitabine or to any of the excipients listed in SPC or&#xD;
             fluorouracil, 3) Patients with known complete absence of dihydropyrimidine&#xD;
             dehydrogenase activity, 4) Treatment with sorivudine or its chemically related&#xD;
             analogues, such as brivudine, 5) any contraindication listed in respective SPC.&#xD;
&#xD;
          -  Patient has active autoimmune disease that has required systemic treatment in the past&#xD;
             3 months before C1D1 or a documented history of clinically severe autoimmune disease,&#xD;
             or a syndrome that requires systemic steroids at doses higher than 10 mg/d prednisone&#xD;
             equivalents or immunosuppressive agents.&#xD;
&#xD;
          -  Patient requires the use of one of the following forbidden treatment during the study&#xD;
             treatment period: any investigational anticancer therapy other than the protocol&#xD;
             specified thérapies, any concurrent chemotherapy, immunotherapy, biologic for cancer&#xD;
             treatment, other than the ones stated in the protocol. Concurrent use of hormones for&#xD;
             non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement&#xD;
             therapy) is acceptable, major surger, live vaccines, immunosuppressive agents and&#xD;
             immunosuppressive high doses of systemic corticosteroids i.e. doses &gt;10 mg/d&#xD;
             prednisone or equivalent, sorivudine or its chemically related analogues such as&#xD;
             brivudine and any treatment contra-indicated as per Capecitabine SPC.&#xD;
&#xD;
          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced&#xD;
             pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic&#xD;
             organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.&#xD;
&#xD;
          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease&#xD;
             (Class II or greater), myocardial infarction within 3 months prior to C1D1 unstable&#xD;
             arrhythmias or unstable angina, Known Left Ventricular Ejection Fraction (LVEF) &lt; 50%.&#xD;
&#xD;
          -  Patient has a known history of active Bacillus Tuberculosis.&#xD;
&#xD;
          -  Patient has an active infection requiring systemic therapy.&#xD;
&#xD;
          -  Patient has Active hepatitis B (chronic or acute; defined as having a positive&#xD;
             hepatitis B surface antigen [HBsAg] test at screening), Active hepatitis C (Patients&#xD;
             positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for&#xD;
             HCV RNA at screening) or Human Immunodeficiency Virus (HIV) infection (HIV 1/2&#xD;
             antibodies).&#xD;
&#xD;
          -  Prior allogeneic bone marrow transplantation or solid organ transplant in the past.&#xD;
&#xD;
          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating Investigator.&#xD;
&#xD;
          -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive children within the projected&#xD;
             duration of the trial, starting with the screening visit through 5 months after the&#xD;
             last dose of study drugs.&#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>Olivier Tredan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre Leon Berard</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut de Cancérologie de l'Ouest</name>
      <address>
        <city>Angers</city>
        <zip>49055</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Sainte Catherine</name>
      <address>
        <city>Avignon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU Besançon</name>
      <address>
        <city>Besançon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Francois Baclesse</name>
      <address>
        <city>Caen</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre d'Oncologie Radiothérapie 37</name>
      <address>
        <city>Chambray-lès-Tours</city>
        <zip>37170</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Prive Jean Mermoz</name>
      <address>
        <city>Lyon</city>
        <zip>69008</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Léon Bérard</name>
      <address>
        <city>Lyon</city>
        <zip>69373</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinique de la Sauvegarde</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Paoli Calmettes</name>
      <address>
        <city>Marseille</city>
        <zip>13273</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Antoine Lacassagne</name>
      <address>
        <city>Nice</city>
        <zip>06189</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Curie</name>
      <address>
        <city>Paris</city>
        <zip>75005</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GH Pitié-Salpêtrière-Charles Foix</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Jean Godinot</name>
      <address>
        <city>Reims</city>
        <zip>51056</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Curie</name>
      <address>
        <city>Saint Cloud</city>
        <zip>92201</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut de Cancérologie de l'Ouest</name>
      <address>
        <city>Saint-Herblain</city>
        <zip>44805</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>Hôpital Drôme Ardèche</name>
      <address>
        <city>Valence</city>
        <zip>26000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 18, 2019</study_first_submitted>
  <study_first_submitted_qc>January 24, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 28, 2019</study_first_posted>
  <last_update_submitted>May 4, 2023</last_update_submitted>
  <last_update_submitted_qc>May 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Residual disease with RCB of Class II or III</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Triple Negative Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03818685
org study id: ET17-093 BreastImmune03
nct id: NCT03818685
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To evaluate the clinical benefit of a post-operative adjuvant therapy combining radiotherapy
      + Nivolumab + Ipilimumab versus radiotherapy + Capecitabine in Triple Negative Breast Cancer
      (TNBC) patients with residual disease after neoadjuvant chemotherapy.
This trial is an open-label, randomised, multicentric, comparative, Phase II study aiming to
      evaluate the clinical benefit of a combined treatment associating radiotherapy + Nivolumab +
      Ipilimumab versus radiotherapy + Capecitabine (standard treatment) in early TNBC patients who
      have Residual cancer burden (RCB) II or III residual disease after neoadjuvant chemotherapy.

      Following validation of eligibility criteria, patients will be randomised (1:1) to receive:

        -  Arm A: Nivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV,
           every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.

        -  Arm B: Capecitabine (1000 mg/m2 twice a day, Bis In Die [BID]), 14 days on / 7 days off
           for 8 cycles.

      In both arms, radiotherapy will be administered as per standard practice and has to be
      initiated one week before C1D1.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This trial is an open-label, randomised, multicentric, comparative, Phase II study
primary purpose: Treatment
masking: None (Open Label)
measure: Disease free survival (DFS)
time frame: At 2 years
description: DFS is defined as the time from randomization until the date of the first relapse (local/regional recurrence or distant metastasis) or death (from any cause) whichever comes firsts and regardless of whether the patient withdraws from randomised study treatment or receives another anti-cancer therapy prior to disease relapse.
measure: Overall survival
time frame: Up to 2 years
description: Overall survival will be measured from the date of randomization to the date of death from any cause.
measure: Local-regional recurrence
time frame: Up to 2 years
description: Local-regional recurrence (LRR) refers to relapse of the primary tumor site
measure: Distant metastasis
time frame: Up to 2 years
description: Distant metastasis is defined as presence of any non-local metastatic sites.
measure: Disease recurrence/relapse (local or distant)
time frame: Up to 2 years
description: Rate of patients with recurrence at 1 year and 2 year post-randomisation as well as time to recurrence will be analysed.
measure: Adverse Event
time frame: Up to 2 years
description: The assessment of safety will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTCAE-V5.0) grade.
measure: EORTC QLQ C30
time frame: At Baseline, every 12 weeks and 30 days after the last dose
description: Patient reported outcomes and quality of life will be assessed using the validated following questionnaire: The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30). The QLQ-C30 incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures are also included. See scoring manual at :https://www.eortc.be/qol/files/SCManualQLQ-C30.pdf.
measure: Questionnaire EORTC QLQ BR-23
time frame: At Baseline, every 12 weeks and 30 days after the last dose
description: Patient reported outcomes and quality of life will be assessed using the validated following questionnaire :The European Organization for Research and Treatment of Cancer Breast-Cancer-Specific Quality of Life Questionnaire. See details at :https://www.eortc.be.
measure: Questionnaire EORTC QLQ FA-12 Fatigue
time frame: At Baseline, every 12 weeks and 30 days after the last dose
description: Patient reported outcomes and quality of life will be assessed using the validated following questionnaire : EORTC QLQ FA-12 Fatigue.
The European Organisation for Research and Treatment of Cancer (EORTC) Group has developed a multidimensional instrument measuring cancer-related fatigue to be used in conjunction with the quality of life core questionnaire (EORTC QLQ-C30). The module EORTC QLQ-FA12 assesses physical, cognitive, and emotional aspects of cancer-related fatigue. See details at :https://www.eortc.be.
measure: Questionnaire patient self-rating mood scale.
time frame: At Baseline, every 12 weeks and 30 days after the last dose
description: Patient reported outcomes and quality of life will be assessed using the following questionnaire : patient self-rating mood scale.
measure: Mutational profiles
time frame: At Baseline and in case of disease relapse up to 2 years
description: To define the molecular characteristics of the tumor' patients: Mutational profiles of tumors (Whole Exome seq,)
measure: Copy Number alterations.
time frame: At Baseline and in case of disease relapse up to 2 years
description: To define the molecular characteristics of the tumor' patients: Copy Number alterations.
measure: Loss of heterozygosity.
time frame: At Baseline and in case of disease relapse up to 2 years
description: To define the molecular characteristics of the tumor' patients: loss of heterozygosity.
measure: Circulating tumor DNA
time frame: At Baseline and in case of disease relapse up to 2 years
description: Circulating tumor DNA detection and analysis will be performed on tumor' patients.
measure: Molecular Subtyping
time frame: At Baseline and in case of disease relapse up to 2 years
description: To define Molecular Subtyping of TNBC (RNAseq) on tumor' patients.
measure: Immune monitoring
time frame: At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
description: To perform Immune monitoring of circulating immune cells and circulating tumor cells on blood sample.
measure: Circulating growth factors
time frame: At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
description: To assess levels of circulating growth factors and cytokines on blood sample.
measure: Cytokines
time frame: At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
description: To assess levels of cytokines on blood sample.
measure: PDL1
time frame: At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
description: To assess the presence in plasma of soluble PDL1.
measure: PDL2
time frame: At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
description: To assess the presence in plasma of soluble PDL2.
arm group label: Nivolumab + Ipilimumab
arm group type: Experimental
description: Nivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV, every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.
arm group label: Capecitabine
arm group type: Active Comparator
description: Capecitabine (1000 mg/m2 twice a day, Bis In Die), 14 days on / 7 days off for 8 cycles.
intervention type: Drug
intervention name: Nivolumab
description: Radiotherapy will be maintained in each Arm.
arm group label: Nivolumab + Ipilimumab
intervention type: Drug
intervention name: Ipilimumab
description: Radiotherapy will be maintained in each Arm.
arm group label: Nivolumab + Ipilimumab
intervention type: Drug
intervention name: Capecitabine
description: Radiotherapy will be maintained in each Arm.
arm group label: Capecitabine
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Olivier Tredan, MD
role: Principal Investigator
affiliation: Centre Leon Berard
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country: France
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Triple Negative Breast Neoplasms
mesh term: Capecitabine
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: No