<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/NCT03807765</url>
  </required_header>
  <id_info>
    <org_study_id>MCC-19765</org_study_id>
    <secondary_id>CA209-8NK</secondary_id>
    <nct_id>NCT03807765</nct_id>
  </id_info>
  <brief_title>Stereotactic Radiation and Nivolumab in the Management of Metastatic Breast Cancer Brain Metastases</brief_title>
  <official_title>Phase Ib Study of Stereotactic Radiation and Nivolumab in the Management of Metastatic Breast Cancer Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>H. Lee Moffitt Cancer Center and Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>H. Lee Moffitt Cancer Center and Research Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is to find out if administration of stereotactic radiosurgery (SRS) given after&#xD;
      Nivolumab will improve overall response rate/anti-tumor activity in patients with metastatic&#xD;
      breast cancer with brain metastases.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 30, 2019</start_date>
  <completion_date type="Anticipated">January 14, 2024</completion_date>
  <primary_completion_date type="Actual">September 8, 2020</primary_completion_date>
  <phase>Phase 1</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>Number of Participants who experience Dose Limiting Toxicities</measure>
    <time_frame>Up to 8 weeks</time_frame>
    <description>Neurologic dose limiting toxicities will be defined as: Symptomatic radionecrosis, &gt;/= Grade 3 headache, &gt;/= Grade 3 memory impairment, New onset &gt;/= grade 3 seizures.&#xD;
3 participants will be enrolled with an 8 week safety observation period. If no patients develop unacceptable neurologic toxicity attributable to SRS, the study will proceed. If 1 patient develops unacceptable neurologic toxicity among the first 3, an additional 3 patients will be enrolled to determine the rate of unacceptable toxicity with 6 patients. If no more patients develop unacceptable neurologic toxicities among the first 6 patients, the study will proceed with a dose expansion of 6 patients.&#xD;
If 2 or more patients develop unacceptable neurologic toxicity among the first 3 or 6 patients, the dose of radiation therapy will be adjusted. If excessive toxicities are noted with radiation dose level -1, treatment will proceed with nivolumab alone.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluation of intracranial local brain tumor following treatment</measure>
    <time_frame>At 3, 6 and 12 months post treatment</time_frame>
    <description>Intracranial local brain tumor control following SRS and Nivolumab will be determined from irradiated lesions according to Response Assessment in Neuro-Oncology (RANO) criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of intracranial distant brain tumor following treatment</measure>
    <time_frame>At 3, 6 and 12 months post treatment</time_frame>
    <description>Intracranial distant brain tumor control following SRS and Nivolumab will be determined by the development of new lesions outside of the irradiated area.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intracranial Progression Free Survival (PFS)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Time from the date of start of treatment to the investigator-determined date of progression (determined by RANO) or death due to any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Extracranial Progression Free Survival (PFS)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Time from the date of start of treatment to the investigator determined date of progression (determined by Immune-Related Response Evaluation Criteria in Solid Tumors [irRECIST]) or death due to any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>Overall Survival defined as time from the date of start of treatment to death.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Metastatic Breast Cancer</condition>
  <condition>Brain Metastases</condition>
  <arm_group>
    <arm_group_label>Nivolumab followed by stereotactic radiosurgery (SRS)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>480 mg Nivolumab will be given intravenously every 4 weeks, followed by SRS the week after the initial dose of Nivolumab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>480 mg intravenous Nivolumab administered every 4 weeks.</description>
    <arm_group_label>Nivolumab followed by stereotactic radiosurgery (SRS)</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic Radiosurgery</intervention_name>
    <description>Patients will receive single session SRS to intact brain metastases and post-operative cavities.&#xD;
A linear accelerator (LINAC)-based frameless delivery system will be used to deliver the stereotactic radiation. The lesion will be defined using gadolinium enhanced MRI with 1 mm slices for treatment planning purposes prior to the delivery of radiation. The MRI image will be co-registered and fused with CT imaging. Doses will be prescribed to ensure coverage of at least 95% of the planning target volume (PTV) with the prescription dose. Treatments will be delivered using dynamic conformal arcs or intensity modulated radiotherapy.</description>
    <arm_group_label>Nivolumab followed by stereotactic radiosurgery (SRS)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provides signed and dated informed consent&#xD;
&#xD;
          -  Stated willingness to comply with all study procedures and availability for the&#xD;
             duration of the study&#xD;
&#xD;
          -  Age 18 or older&#xD;
&#xD;
          -  Breast cancer with brain metastases, as documented by extracranial tumor biopsy with&#xD;
             MRI brain imaging or intracranial surgical pathology revealing brain metastases&#xD;
&#xD;
          -  10 or less brain metastases eligible for SRS to brain metastases or to the&#xD;
             post-operative bed&#xD;
&#xD;
          -  Maximum diameter of the largest intact brain metastases ≤ 4 cm&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group performance status 0 to 2&#xD;
&#xD;
          -  Prior treatment with taxane based chemotherapy with anthracyclines (if appropriate)&#xD;
&#xD;
          -  A formalin-fixed, paraffin-embedded tumor tissue block or 10 unstained slides of&#xD;
             intracranial/extracranial tumor sample (archival or recent) for biomarker evaluation&#xD;
             should be made available and submitted to the central lab for correlative studies. If&#xD;
             attempts to obtain archival tissue are unsuccessful the patient may be enrolled.&#xD;
&#xD;
          -  Individuals with prior SRS/fractioned stereotactic radiotherapy (FSRT) treatment will&#xD;
             be allowed if active measurable disease has not previously been treated with radiation&#xD;
             therapy&#xD;
&#xD;
          -  Continuing concurrent use of hormonal therapy or HER2-targeted therapy is allowed if&#xD;
             the patient exhibits brain metastases progression during treatment&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy&#xD;
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin)&#xD;
             within 24 hours prior to the administration of each dose of study agent.&#xD;
&#xD;
          -  WOCBP must agree to follow instructions for method(s) of contraception for the&#xD;
             duration of treatment with study drug(s), plus 5 half-lives of study drug (half-life&#xD;
             up to 25 days), plus 30 days (duration of ovulatory cycle) for a total of 5 months&#xD;
             after treatment completion.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of leptomeningeal disease&#xD;
&#xD;
          -  Prior whole brain radiation therapy&#xD;
&#xD;
          -  All toxicities attributed to prior anticancer therapy must have been resolved to Grade&#xD;
             1 (NCI CTCAE Version 5) or baseline before administration of study drug(s) . Some&#xD;
             exceptions apply.&#xD;
&#xD;
          -  Women who are pregnant or breastfeeding&#xD;
&#xD;
          -  Active, known, or suspected autoimmune disease. Patients with an autoimmune&#xD;
             paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded.&#xD;
             Some exceptions apply.&#xD;
&#xD;
          -  Prior therapy with antiPD-1, antiPD-L1, antiPD-L2, antiCD137, or antiCTLA-4 antibody&#xD;
             (including ipilimumab or any other antibody or drug specifically targeting T-cell&#xD;
             co-stimulation or checkpoint pathways)&#xD;
&#xD;
          -  Interstitial lung disease that is symptomatic or may interfere with the detection or&#xD;
             management of suspected drug-related pulmonary toxicity&#xD;
&#xD;
          -  Any patient requiring supplemental oxygen therapy&#xD;
&#xD;
          -  Patients with prior history of non-breast cancer malignancies are excluded except in&#xD;
             the case of adequately treated basal cell cancer, squamous cell skin cancer, chronic&#xD;
             lymphocytic leukemia, or other indolent diseases not requiring therapy&#xD;
&#xD;
          -  Known medical condition that, in the investigator's opinion, would increase the risk&#xD;
             associated with study participation or study drug(s) administration or that would&#xD;
             interfere with the interpretation of safety results&#xD;
&#xD;
          -  Major surgery or significant traumatic injury that has not been recovered from by 14&#xD;
             days before the initiation of study drug&#xD;
&#xD;
          -  Current or prior participation in a study of an investigational agent or&#xD;
             investigational device within 2 weeks of first dose of study treatment&#xD;
&#xD;
          -  Positive test for: a. Hepatitis B virus using Hepatitis B virus surface antigen&#xD;
             (Hepatitis B virus surface antigen) test b. Hepatitis C virus (HCV) using HCV&#xD;
             ribonucleic acid or HCV antibody test that indicates acute or chronic infection c.&#xD;
             Exception: Individuals with a positive test for HCV antibody but no detection of HCV&#xD;
             ribonucleic acid indicating no current infection are eligible&#xD;
&#xD;
          -  Medical history of testing positive for HIV or AIDS. No HIV testing is required,&#xD;
             unless mandated by a local health authority.&#xD;
&#xD;
          -  Inadequate hematologic function&#xD;
&#xD;
          -  Inadequate hepatic function&#xD;
&#xD;
          -  Inadequate pancreatic function&#xD;
&#xD;
          -  History of allergy or hypersensitivity to any of the study drugs or study drug&#xD;
             components&#xD;
&#xD;
          -  Individuals who are compulsorily detained for treatment of either a psychiatric or&#xD;
             physical (eg, infectious disease) illness&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kamran Ahmed, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>H. Lee Moffitt Cancer Center and Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>H. Lee Moffitt Cancer Center and Research Institute</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://moffitt.org/clinical-trials-research/clinical-trials/</url>
    <description>Moffitt Cancer Center Clinical Trials Website</description>
  </link>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>January 15, 2019</study_first_submitted>
  <study_first_submitted_qc>January 15, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 17, 2019</study_first_posted>
  <last_update_submitted>April 17, 2023</last_update_submitted>
  <last_update_submitted_qc>April 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>breast cancer</keyword>
  <keyword>brain metastases</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</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/NCT03807765
org study id: MCC-19765
secondary id: CA209-8NK
nct id: NCT03807765
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This study is to find out if administration of stereotactic radiosurgery (SRS) given after
      Nivolumab will improve overall response rate/anti-tumor activity in patients with metastatic
      breast cancer with brain metastases.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants who experience Dose Limiting Toxicities
time frame: Up to 8 weeks
description: Neurologic dose limiting toxicities will be defined as: Symptomatic radionecrosis, >/= Grade 3 headache, >/= Grade 3 memory impairment, New onset >/= grade 3 seizures.
3 participants will be enrolled with an 8 week safety observation period. If no patients develop unacceptable neurologic toxicity attributable to SRS, the study will proceed. If 1 patient develops unacceptable neurologic toxicity among the first 3, an additional 3 patients will be enrolled to determine the rate of unacceptable toxicity with 6 patients. If no more patients develop unacceptable neurologic toxicities among the first 6 patients, the study will proceed with a dose expansion of 6 patients.
If 2 or more patients develop unacceptable neurologic toxicity among the first 3 or 6 patients, the dose of radiation therapy will be adjusted. If excessive toxicities are noted with radiation dose level -1, treatment will proceed with nivolumab alone.
measure: Evaluation of intracranial local brain tumor following treatment
time frame: At 3, 6 and 12 months post treatment
description: Intracranial local brain tumor control following SRS and Nivolumab will be determined from irradiated lesions according to Response Assessment in Neuro-Oncology (RANO) criteria.
measure: Evaluation of intracranial distant brain tumor following treatment
time frame: At 3, 6 and 12 months post treatment
description: Intracranial distant brain tumor control following SRS and Nivolumab will be determined by the development of new lesions outside of the irradiated area.
measure: Intracranial Progression Free Survival (PFS)
time frame: Up to 12 months
description: Time from the date of start of treatment to the investigator-determined date of progression (determined by RANO) or death due to any cause, whichever occurs first.
measure: Extracranial Progression Free Survival (PFS)
time frame: Up to 12 months
description: Time from the date of start of treatment to the investigator determined date of progression (determined by Immune-Related Response Evaluation Criteria in Solid Tumors [irRECIST]) or death due to any cause, whichever occurs first.
measure: Overall Survival
time frame: Up to 24 months
description: Overall Survival defined as time from the date of start of treatment to death.
arm group label: Nivolumab followed by stereotactic radiosurgery (SRS)
arm group type: Experimental
description: 480 mg Nivolumab will be given intravenously every 4 weeks, followed by SRS the week after the initial dose of Nivolumab.
intervention type: Drug
intervention name: Nivolumab
description: 480 mg intravenous Nivolumab administered every 4 weeks.
arm group label: Nivolumab followed by stereotactic radiosurgery (SRS)
other name: Opdivo
intervention type: Radiation
intervention name: Stereotactic Radiosurgery
description: Patients will receive single session SRS to intact brain metastases and post-operative cavities.
A linear accelerator (LINAC)-based frameless delivery system will be used to deliver the stereotactic radiation. The lesion will be defined using gadolinium enhanced MRI with 1 mm slices for treatment planning purposes prior to the delivery of radiation. The MRI image will be co-registered and fused with CT imaging. Doses will be prescribed to ensure coverage of at least 95% of the planning target volume (PTV) with the prescription dose. Treatments will be delivered using dynamic conformal arcs or intensity modulated radiotherapy.
arm group label: Nivolumab followed by stereotactic radiosurgery (SRS)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kamran Ahmed, MD
role: Principal Investigator
affiliation: H. Lee Moffitt Cancer Center and Research Institute
facility: 
country: United States
url: https://moffitt.org/clinical-trials-research/clinical-trials/
description: Moffitt Cancer Center Clinical Trials Website
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms
mesh term: Nivolumab
sharing ipd: Undecided