<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/NCT03815890</url>
  </required_header>
  <id_info>
    <org_study_id>M18BEL</org_study_id>
    <nct_id>NCT03815890</nct_id>
  </id_info>
  <brief_title>Pre-operative Trial for Breast Cancer With Nivolumab in Combination With Novel IO</brief_title>
  <acronym>BELLINI</acronym>
  <official_title>Pre-operative Phase II Trial for Breast Cancer With Nivolumab in Combination With Novel IO (BELLINI Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Netherlands Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>The Netherlands Cancer Institute</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine whether short-term pre-operative nivolumab either as monotherapy or in&#xD;
      combination with low dose doxorubicin or novel IO combinations can induce immune activation&#xD;
      in early BC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators aim to test the activity of nivolumab monotherapy in primary breast tumors&#xD;
      in a pre-operative window of opportunity trial. As the data of the investigators generated in&#xD;
      the TONIC trial (metastatic TNBC) indicate that low dose doxorubicin may 'prime' the tumor&#xD;
      microenvironment (TME) resulting in higher response rates on nivolumab, in addition, cohorts&#xD;
      for treatment with nivolumab plus low dose doxorubicin will be opened. Given the emerging&#xD;
      data on other immunomodulatory strategies, this platform study allows opening additional&#xD;
      cohorts for promising novel immune-oncology (IO) drugs for which a strong efficacy signal has&#xD;
      been seen without drug safety issues. The investigators will study the TME and systemic host&#xD;
      factors with specific emphasis on immunosuppressive processes that can potentially be&#xD;
      targeted by novel IO agents to further optimize BC immunotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 4, 2019</start_date>
  <completion_date type="Anticipated">January 7, 2027</completion_date>
  <primary_completion_date type="Anticipated">January 7, 2025</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>Sequential Assignment</intervention_model>
    <intervention_model_description>Separate cohorts will be opened in this trial. LumB and TNBC tumors will be divided in separate cohorts.More cohorts, e.g. combining nivolumab and novel IO, can open after the start of this trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Immune activation after pre-operative nivolumab</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>measuring the tumor-associated CD8 and expression of genes induced by IFNy after pre-operative immunotherapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events according to NCI Common Toxicity Criteria version 5.0</measure>
    <time_frame>up to 3 weeks after surgery, an average of 6 months</time_frame>
    <description>Adverse events in all regimens will be graded according to NCI Common Toxicity Criteria version 5.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiological response rate</measure>
    <time_frame>At 4 weeks</time_frame>
    <description>The percentage of patients having a complete response, partial response or stable disease per cohort assessed by MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathological response rate</measure>
    <time_frame>up to 3 weeks after surgery, an average of 6 months</time_frame>
    <description>The percentage of patients having a complete response or residual cancer burden per cohort</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>1A; LumB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>1B; TNBC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2A; LUMB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab and ipilimumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2B; TNBC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab and ipilimumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3B; TNBC, High TIL</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab and ipilimumab</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>2 courses 240 mg flat dose</description>
    <arm_group_label>1A; LumB</arm_group_label>
    <arm_group_label>1B; TNBC</arm_group_label>
    <arm_group_label>2A; LUMB</arm_group_label>
    <arm_group_label>2B; TNBC</arm_group_label>
    <arm_group_label>3B; TNBC, High TIL</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>single dose ipilimumab (1mg/kg) at day 1</description>
    <arm_group_label>2A; LUMB</arm_group_label>
    <arm_group_label>2B; TNBC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>two courses ipilimumab (1mg/kg) at day 1 and 21</description>
    <arm_group_label>3B; TNBC, High TIL</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
          -  18 years or older at moment of inclusion;&#xD;
&#xD;
          -  Female gender;&#xD;
&#xD;
          -  WHO performance status 0 or 1;&#xD;
&#xD;
          -  Resectable primary breast cancer stage I-III. Nodal status must be examined by&#xD;
             ultrasound, fine needle aspiration, sentinel node biopsy, or FDG-PET scan.&#xD;
&#xD;
          -  The tumors must be:&#xD;
&#xD;
               -  at least 10 mm (minimum cT1c) as determined by MRI&#xD;
&#xD;
               -  TNBC defined as ER&lt;10%, HER2-negative OR luminal B defined as ER≥10%,&#xD;
                  HER2-negative with either Ki67≥20% or PR =&lt;20% OR grade 3. HER2 negative is&#xD;
                  defined as an IHC score of &lt;2 or 2+ with a negative ISH.&#xD;
&#xD;
               -  For TNBC patients: TIL≥5%&#xD;
&#xD;
               -  For LumB breast cancer patients: TIL≥1%&#xD;
&#xD;
               -  For cohort 3B: N0 status, TN and TIL ≥50%&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  evidence or suspicion of metastatic disease. Evaluation of the presence of distant&#xD;
             metastases may include chest X-ray, liver ultrasound, isotope bone-scan, CT-scan of&#xD;
             chest and abdomen and/or FDG-PET scan, according to local procedures;&#xD;
&#xD;
          -  evidence of a concurrent contralateral or ipsilateral second primary infiltrating&#xD;
             breast cancer. Evaluation of the presence of a concurrent second primary breast cancer&#xD;
             may include mammography, breast ultrasound and/or MRI breast;&#xD;
&#xD;
          -  other malignancy except carcinoma in situ and basal-cell and squamous carcinoma of the&#xD;
             skin, unless the other malignancy was treated ≥5 years ago with curative intent&#xD;
             without the use of chemotherapy or radiotherapy&#xD;
&#xD;
          -  previous radiation therapy or chemotherapy;&#xD;
&#xD;
          -  prior treatment with checkpoint inhibitors (including anti- PD1, -PD-L1, -CTLA-4);&#xD;
&#xD;
          -  concurrent anti-cancer treatment, neoadjuvant therapy or another investigational drug;&#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>M Kok, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NKI-AvL</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>M Kok, MD</last_name>
    <phone>3120512</phone>
    <phone_ext>9111</phone_ext>
    <email>m.kok@nki.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>I Nederlof</last_name>
    <phone>3120512</phone>
    <phone_ext>9111</phone_ext>
    <email>i.nederlof@nki.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>NKI-AVL</name>
      <address>
        <city>Amsterdam</city>
        <zip>1066CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>M Kok, MD</last_name>
      <email>m.kok@nki.nl</email>
    </contact>
    <contact_backup>
      <last_name>I Nederlof</last_name>
      <email>i.nederlof@nki.nl</email>
    </contact_backup>
    <investigator>
      <last_name>M Kok, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>December 13, 2018</study_first_submitted>
  <study_first_submitted_qc>January 22, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>March 21, 2023</last_update_submitted>
  <last_update_submitted_qc>March 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>pre-operative</keyword>
  <keyword>triple negative and Luminal B</keyword>
  <keyword>resectable, stage I-III</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>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>to be determined</ipd_description>
  </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/NCT03815890
org study id: M18BEL
nct id: NCT03815890
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To determine whether short-term pre-operative nivolumab either as monotherapy or in
      combination with low dose doxorubicin or novel IO combinations can induce immune activation
      in early BC.
The investigators aim to test the activity of nivolumab monotherapy in primary breast tumors
      in a pre-operative window of opportunity trial. As the data of the investigators generated in
      the TONIC trial (metastatic TNBC) indicate that low dose doxorubicin may 'prime' the tumor
      microenvironment (TME) resulting in higher response rates on nivolumab, in addition, cohorts
      for treatment with nivolumab plus low dose doxorubicin will be opened. Given the emerging
      data on other immunomodulatory strategies, this platform study allows opening additional
      cohorts for promising novel immune-oncology (IO) drugs for which a strong efficacy signal has
      been seen without drug safety issues. The investigators will study the TME and systemic host
      factors with specific emphasis on immunosuppressive processes that can potentially be
      targeted by novel IO agents to further optimize BC immunotherapy.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: Separate cohorts will be opened in this trial. LumB and TNBC tumors will be divided in separate cohorts.More cohorts, e.g. combining nivolumab and novel IO, can open after the start of this trial.
primary purpose: Treatment
masking: None (Open Label)
measure: Immune activation after pre-operative nivolumab
time frame: through study completion, an average of 1 year
description: measuring the tumor-associated CD8 and expression of genes induced by IFNy after pre-operative immunotherapy
measure: Incidence of Treatment-Emergent Adverse Events according to NCI Common Toxicity Criteria version 5.0
time frame: up to 3 weeks after surgery, an average of 6 months
description: Adverse events in all regimens will be graded according to NCI Common Toxicity Criteria version 5.0.
measure: Radiological response rate
time frame: At 4 weeks
description: The percentage of patients having a complete response, partial response or stable disease per cohort assessed by MRI
measure: Pathological response rate
time frame: up to 3 weeks after surgery, an average of 6 months
description: The percentage of patients having a complete response or residual cancer burden per cohort
arm group label: 1A; LumB
arm group type: Experimental
description: Nivolumab
arm group label: 1B; TNBC
arm group type: Experimental
description: Nivolumab
arm group label: 2A; LUMB
arm group type: Experimental
description: Nivolumab and ipilimumab
arm group label: 2B; TNBC
arm group type: Experimental
description: Nivolumab and ipilimumab
arm group label: 3B; TNBC, High TIL
arm group type: Experimental
description: Nivolumab and ipilimumab
intervention type: Drug
intervention name: Nivolumab
description: 2 courses 240 mg flat dose
arm group label: 1A; LumB
arm group label: 1B; TNBC
arm group label: 2A; LUMB
arm group label: 2B; TNBC
arm group label: 3B; TNBC, High TIL
intervention type: Drug
intervention name: Ipilimumab
description: single dose ipilimumab (1mg/kg) at day 1
arm group label: 2A; LUMB
arm group label: 2B; TNBC
intervention type: Drug
intervention name: Ipilimumab
description: two courses ipilimumab (1mg/kg) at day 1 and 21
arm group label: 3B; TNBC, High TIL
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: M Kok, MD
role: Principal Investigator
affiliation: NKI-AvL
last name: M Kok, MD
phone: 3120512
phone ext: 9111
email: m.kok@nki.nl
last name: I Nederlof
phone: 3120512
phone ext: 9111
email: i.nederlof@nki.nl
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Netherlands
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: Undecided
ipd description: to be determined