<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/NCT02978404</url>
  </required_header>
  <id_info>
    <org_study_id>16.206</org_study_id>
    <secondary_id>OZM-080</secondary_id>
    <nct_id>NCT02978404</nct_id>
  </id_info>
  <brief_title>Combining Radiosurgery and Nivolumab in the Treatment of Brain Metastases</brief_title>
  <official_title>A Phase II, Multi-centre Study, of Combining Radiosurgery and Nivolumab in the Treatment of Brain Metastases From Non-small Cell Lung Cancer and Renal Cell Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre hospitalier de l'Université de Montréal (CHUM)</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Centre hospitalier de l'Université de Montréal (CHUM)</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>
      Stereotactic radiosurgery (SRS) is increasingly administered as the sole treatment of brain&#xD;
      metastases, in order to spare acute and long term side effects associated with whole brain&#xD;
      radiotherapy. Local control of SRS treated lesions is good, but patients tend to develop&#xD;
      additional brain metastases subsequently.&#xD;
&#xD;
      Nivolumab is a modulator of the immune system. Treatment with Nivolumab is associated with an&#xD;
      increase in local control and survival in patients with non-small cell lung cancer and clear&#xD;
      cell renal cell carcinoma. In the presence of Nivolumab, treatment of brain metastases with&#xD;
      SRS may trigger an immune reaction against cancer. Therefore, the combination of SRS with&#xD;
      Nivolumab may reduce the development of new brain metastases and improve patient survival.&#xD;
&#xD;
      The purpose of this study is to assess the effect of combining Nivolumab and SRS in&#xD;
      controlling cancer progression. SRS will be administered to patients while they are receiving&#xD;
      Nivolumab.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 2, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Actual">January 31, 2021</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>Intracranial progression-free survival</measure>
    <time_frame>1 year</time_frame>
    <description>To evaluate whether the combination SRS with Nivolumab will improve the intracranial progression-free survival of patients.&#xD;
Response will be assessed as per RECIST version 1.1.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treated brain lesions control rate</measure>
    <time_frame>1 year</time_frame>
    <description>Treated brain lesions control will be assessed as per RECIST version 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival after receiving Nivolumab.</measure>
    <time_frame>2 years</time_frame>
    <description>Overall Survival is assessed at the end of the study at 2 years. A subject will be classified as either alive or dead due to any cause.&#xD;
The time to event will be calculated as the time from Day 1 until date of death.&#xD;
Day 1 is the date of 1st treatment consisting of an infusion of Nivolumab.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum response rate of distant non-irradiated disease</measure>
    <time_frame>1 year</time_frame>
    <description>Response will be assessed as per RECIST version 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>1 year</time_frame>
    <description>Response will be assessed as per RECIST version 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between tumor PD-L1 expression and clinical outcomes</measure>
    <time_frame>1 year</time_frame>
    <description>Tumor PD-L1 expression level will be correlated with patient overall response rate, loco-regional recurrence free survival and overall survival.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient quality of life</measure>
    <time_frame>1 year</time_frame>
    <description>Quality of life will be assessed using the the Functional Assessment of Cancer Therapy - General (FACT-G) and the Brain Subscale (FACT-BR) questionnaires. A composite score will be obtained from the score of each subscale. Quality of life decline is the time to the first minimal important difference in the composite score from baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function, as measured by the HVLT-R</measure>
    <time_frame>1 Year</time_frame>
    <description>Neurocognitive function will be assessed using the Hopkins Verbal Learning Test - Revised (HVLT-R). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function, as measured by TMT</measure>
    <time_frame>1 year</time_frame>
    <description>Neurocognitive function will be assessed using the Trail Making Test (TMT). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function, as measured by COWA</measure>
    <time_frame>1 Year</time_frame>
    <description>Neurocognitive function will be assessed using the Controlled Oral Word Association (COWA). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute and late toxicity of SRS + Nivolumab</measure>
    <time_frame>1 year</time_frame>
    <description>Adverse events will be coded according to MedDRA. The results will be tabulated to examine their frequency, organ systems affected, severity, and relationship to study treatment.&#xD;
Terminology Criteria for Adverse Events (CTCAE) V4.03 will be used for grading of AEs. Investigators will provide their assessment of causality as 1) unrelated, 2) unlikely, 3) possibly related, 4) probably, or 5) definitely related.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Imaging indicators of response</measure>
    <time_frame>1 year</time_frame>
    <description>Patient response to the treatment will be analysed using the Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Clear-Cell Metastatic Renal Cell Carcinoma</condition>
  <condition>Non Small Cell Lung Cancer Metastatic</condition>
  <condition>Brain Metastases, Adult</condition>
  <condition>Small Cell Lung Cancer</condition>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>Radiosurgery and Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Interventions: Nivolumab (240mg IV q2week or 480mg IV q4week) and Radiosurgery (15-20 Gray (Gy) in 1 fraction)&#xD;
Upon entering this trial, patients with metastatic brain disease(s) will receive Nivolumab. One to 2 week after receiving the first dose of Nivolumab, radiosurgery will be delivered at doses ranging from 15 to 20 Gy in 1 fraction to the brain metastases to a maximum volume of 10 cubic centimeter.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab is administered to patients to a maximum of 2 year.</description>
    <arm_group_label>Radiosurgery and Nivolumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiosurgery</intervention_name>
    <description>Up to 10 cubic centimeter of brain metastases will be treated with radiosurgery. The dose of radiosurgery depends on the size of individual metastases.</description>
    <arm_group_label>Radiosurgery and Nivolumab</arm_group_label>
    <other_name>SRS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men and women, ≥ 18 years of age&#xD;
&#xD;
          2. Willing and able to give written informed consent&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 28 days&#xD;
             prior to registration&#xD;
&#xD;
          4. Radiation Therapy Oncology Group (RTOG) neurological function score of 0-1 within 28&#xD;
             days prior to registration&#xD;
&#xD;
          5. Histologic diagnosis of NSCLC, SCLC, Melanoma OR ccRCC&#xD;
&#xD;
          6. Stage IV cancer with brain metastases (Patients may have untreated primary disease)&#xD;
&#xD;
          7. Presenting with previously un-irradiated brain metastasis (10 cc maximum volume of&#xD;
             brain disease based on the diagnostic screening MRI done within 28 days of&#xD;
             registration))&#xD;
&#xD;
          8. Measurable/evaluable brain disease&#xD;
&#xD;
          9. Having received less than 4 lines of prior systemic treatments&#xD;
&#xD;
         10. Ability to be treated with either gamma knife or a linear accelerator based&#xD;
             radiosurgery system&#xD;
&#xD;
         11. Ability to complete neurocognitive exams without assistance&#xD;
&#xD;
         12. Ability to complete QOL questionnaires with or without assistance&#xD;
&#xD;
         13. Screening laboratory values must meet the following criteria and should be obtained&#xD;
             within 28 days prior to registration:&#xD;
&#xD;
               -  White Blood Cell (WBC) ≥ 2000/uL&#xD;
&#xD;
               -  Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L&#xD;
&#xD;
               -  Platelets≥ 100 x 109/L&#xD;
&#xD;
               -  Hemoglobin ≥ 90 g/L (may be transfused)&#xD;
&#xD;
               -  Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or Creatinine Clearance ≥ 50&#xD;
                  ml/min (calculated -cockcroft-Gault)&#xD;
&#xD;
               -  Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤3 x ULN without&#xD;
                  liver metastasis,≤ 5 x ULN with liver metastases&#xD;
&#xD;
               -  Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have&#xD;
                  total bilirubin &lt; 3.0 mg/dL)&#xD;
&#xD;
         14. Women of childbearing potential (WOCBP) must use appropriate method(s) of&#xD;
             contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (28&#xD;
             days plus the time required for Nivolumab to undergo five half-lives) after the last&#xD;
             dose of investigational drug&#xD;
&#xD;
         15. Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the&#xD;
             start of Nivolumab&#xD;
&#xD;
         16. Women must not be breastfeeding&#xD;
&#xD;
         17. Men who are sexually active with WOCBP must use any contraceptive method with a&#xD;
             failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually&#xD;
             active with WOCBP will be instructed to adhere to contraception for a period of 31&#xD;
             weeks after the last dose of Nivolumab product. Women who are not of childbearing&#xD;
             potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men&#xD;
             do not require contraception).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Brain metastasis in the brainstem&#xD;
&#xD;
          2. Patients who experienced prior seizures are eligible, however patients should not have&#xD;
             had a seizure within 7 days of registration without the use of corticosteroids.&#xD;
&#xD;
          3. All other cancer histology other than NSCLC or ccRCC&#xD;
&#xD;
          4. Patients who cannot undergo MRI&#xD;
&#xD;
          5. Active, known or suspected autoimmune disease. Subjects are permitted to enroll if&#xD;
             they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to&#xD;
             autoimmune condition only requiring hormone replacement, psoriasis not requiring&#xD;
             systemic treatment, or conditions not expected to recur in the absence of an external&#xD;
             trigger&#xD;
&#xD;
          6. Patients with a condition requiring systemic treatment with either corticosteroids&#xD;
             including steroids used for treating peritumoral edema (&gt; 50 mg daily prednisone&#xD;
             equivalents) or other immunosuppressive medications within 14 days of study drug&#xD;
             administration. Inhaled or topical steroids and adrenal replacement doses &gt; 10 mg&#xD;
             daily prednisone equivalents are permitted in the absence of active autoimmune&#xD;
             disease.&#xD;
&#xD;
          7. Drugs with a predisposition to hepatoxicity should be used with caution in patients&#xD;
             treated with Nivolumab-containing regimen&#xD;
&#xD;
          8. Any underlying medical or psychiatric condition, which in the opinion of the&#xD;
             investigator will make the administration of Nivolumab hazardous or obscure the&#xD;
             interpretation of AEs, such as a condition associated with frequent diarrhea.&#xD;
&#xD;
          9. History of prior treatment with a CTLA-4, PD-1 or PD-L1 inhibitor, CD137 agonist, or&#xD;
             anti-PD-L2.&#xD;
&#xD;
         10. Concomitant therapy with any of the following: IL-2, interferon, or other non-study&#xD;
             immunotherapy regimens; immunosuppressive agents; other investigation therapies&#xD;
&#xD;
         11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for&#xD;
             treatment of either a psychiatric or physical (eg, infectious) illness.&#xD;
&#xD;
         12. Known history of hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus&#xD;
             ribonucleic acid (HCV antibody) indicating acute or chronic infection&#xD;
&#xD;
         13. History of allergy to study drug components.&#xD;
&#xD;
         14. Known history of testing positive for human immunodeficiency virus (HIV) or known&#xD;
             acquired immunodeficiency syndrome (AIDS).&#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>Philip Wong, MD, FRCPC</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre hospitalier de l'Université de Montréal (CHUM)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centre Hospitalier de l'Université de Montréal</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H2L 4M1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McGill University Health Centre</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H4A 3J1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jewish General Hospital</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H3T 1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Sherbrooke</name>
      <address>
        <city>Sherbrooke</city>
        <state>Quebec</state>
        <zip>J1H 5N4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>November 21, 2016</study_first_submitted>
  <study_first_submitted_qc>November 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 1, 2016</study_first_posted>
  <last_update_submitted>February 13, 2023</last_update_submitted>
  <last_update_submitted_qc>February 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>radiosurgery</keyword>
  <keyword>PD-1</keyword>
  <keyword>Nivolumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Carcinoma, Renal Cell</mesh_term>
    <mesh_term>Small Cell Lung Carcinoma</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>
  <!-- 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/NCT02978404
org study id: 16.206
secondary id: OZM-080
nct id: NCT02978404
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Stereotactic radiosurgery (SRS) is increasingly administered as the sole treatment of brain
      metastases, in order to spare acute and long term side effects associated with whole brain
      radiotherapy. Local control of SRS treated lesions is good, but patients tend to develop
      additional brain metastases subsequently.

      Nivolumab is a modulator of the immune system. Treatment with Nivolumab is associated with an
      increase in local control and survival in patients with non-small cell lung cancer and clear
      cell renal cell carcinoma. In the presence of Nivolumab, treatment of brain metastases with
      SRS may trigger an immune reaction against cancer. Therefore, the combination of SRS with
      Nivolumab may reduce the development of new brain metastases and improve patient survival.

      The purpose of this study is to assess the effect of combining Nivolumab and SRS in
      controlling cancer progression. SRS will be administered to patients while they are receiving
      Nivolumab.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Intracranial progression-free survival
time frame: 1 year
description: To evaluate whether the combination SRS with Nivolumab will improve the intracranial progression-free survival of patients.
Response will be assessed as per RECIST version 1.1.
measure: Treated brain lesions control rate
time frame: 1 year
description: Treated brain lesions control will be assessed as per RECIST version 1.1.
measure: Overall survival after receiving Nivolumab.
time frame: 2 years
description: Overall Survival is assessed at the end of the study at 2 years. A subject will be classified as either alive or dead due to any cause.
The time to event will be calculated as the time from Day 1 until date of death.
Day 1 is the date of 1st treatment consisting of an infusion of Nivolumab.
measure: Maximum response rate of distant non-irradiated disease
time frame: 1 year
description: Response will be assessed as per RECIST version 1.1.
measure: Progression-free survival
time frame: 1 year
description: Response will be assessed as per RECIST version 1.1.
measure: Correlation between tumor PD-L1 expression and clinical outcomes
time frame: 1 year
description: Tumor PD-L1 expression level will be correlated with patient overall response rate, loco-regional recurrence free survival and overall survival.
measure: Patient quality of life
time frame: 1 year
description: Quality of life will be assessed using the the Functional Assessment of Cancer Therapy - General (FACT-G) and the Brain Subscale (FACT-BR) questionnaires. A composite score will be obtained from the score of each subscale. Quality of life decline is the time to the first minimal important difference in the composite score from baseline.
measure: Neurocognitive function, as measured by the HVLT-R
time frame: 1 Year
description: Neurocognitive function will be assessed using the Hopkins Verbal Learning Test - Revised (HVLT-R). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
measure: Neurocognitive function, as measured by TMT
time frame: 1 year
description: Neurocognitive function will be assessed using the Trail Making Test (TMT). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
measure: Neurocognitive function, as measured by COWA
time frame: 1 Year
description: Neurocognitive function will be assessed using the Controlled Oral Word Association (COWA). Neurocognitive failure is the time to the first failure on the assessments using the Reliable Change Index. Baseline neurocognitive function will be compared to the test results at 1 year using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
measure: Acute and late toxicity of SRS + Nivolumab
time frame: 1 year
description: Adverse events will be coded according to MedDRA. The results will be tabulated to examine their frequency, organ systems affected, severity, and relationship to study treatment.
Terminology Criteria for Adverse Events (CTCAE) V4.03 will be used for grading of AEs. Investigators will provide their assessment of causality as 1) unrelated, 2) unlikely, 3) possibly related, 4) probably, or 5) definitely related.
measure: Imaging indicators of response
time frame: 1 year
description: Patient response to the treatment will be analysed using the Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria.
arm group label: Radiosurgery and Nivolumab
arm group type: Experimental
description: Interventions: Nivolumab (240mg IV q2week or 480mg IV q4week) and Radiosurgery (15-20 Gray (Gy) in 1 fraction)
Upon entering this trial, patients with metastatic brain disease(s) will receive Nivolumab. One to 2 week after receiving the first dose of Nivolumab, radiosurgery will be delivered at doses ranging from 15 to 20 Gy in 1 fraction to the brain metastases to a maximum volume of 10 cubic centimeter.
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab is administered to patients to a maximum of 2 year.
arm group label: Radiosurgery and Nivolumab
intervention type: Radiation
intervention name: Radiosurgery
description: Up to 10 cubic centimeter of brain metastases will be treated with radiosurgery. The dose of radiosurgery depends on the size of individual metastases.
arm group label: Radiosurgery and Nivolumab
other name: SRS
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Philip Wong, MD, FRCPC
role: Principal Investigator
affiliation: Centre hospitalier de l'Université de Montréal (CHUM)
facility: 
facility: 
facility: 
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Neoplasm Metastasis
mesh term: Carcinoma, Renal Cell
mesh term: Small Cell Lung Carcinoma
mesh term: Brain Neoplasms
mesh term: Nivolumab