<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/NCT02989636</url>
  </required_header>
  <id_info>
    <org_study_id>J16138</org_study_id>
    <secondary_id>IRB00117650</secondary_id>
    <secondary_id>NCI-2016-01638</secondary_id>
    <secondary_id>P30CA006973</secondary_id>
    <secondary_id>18-020</secondary_id>
    <secondary_id>CA209-594</secondary_id>
    <nct_id>NCT02989636</nct_id>
  </id_info>
  <brief_title>Nivolumab With or Without Stereotactic Radiosurgery in Treating Patients With Recurrent, Advanced, or Metastatic Chordoma</brief_title>
  <official_title>Phase I Safety Study of Stereotactic Radiosurgery With Concurrent and Adjuvant PD-1 Antibody Nivolumab in Subjects With Recurrent or Advanced Chordoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chordoma Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects of nivolumab with or without stereotactic&#xD;
      radiosurgery (SRS) in treating patients with chordoma that has come back or spread from where&#xD;
      it started to other places in the body. Monoclonal antibodies, such as nivolumab, may&#xD;
      interfere with the ability of tumor cells to grow and spread. Stereotactic radiosurgery is a&#xD;
      specialized radiation therapy that delivers a single, high dose of radiation directly to the&#xD;
      tumor and may cause less damage to normal tissue. It is not yet known whether giving&#xD;
      nivolumab with or without stereotactic radiosurgery may work better in treating patients with&#xD;
      chordoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the safety profile of nivolumab alone and nivolumab in combination with&#xD;
      stereotactic radiosurgery to treat patients with recurrent or advanced chordoma.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate toxicity and tolerability of nivolumab alone and nivolumab in combination with&#xD;
      stereotactic radiosurgery.&#xD;
&#xD;
      II. To estimate growth modulation index on target lesion. III. To estimate a clinical&#xD;
      response (partial response [PR] + complete response [CR] within 6 month + stable disease [SD]&#xD;
      beyond 6 months).&#xD;
&#xD;
      IV. To assess progression-free survival and progression-free survival (PFS) rate at 6 months.&#xD;
&#xD;
      V. To assess overall survival rate at 1 year, 3 years and 5 years.&#xD;
&#xD;
      TERTIARY OBJECTIVES:&#xD;
&#xD;
      I. To explore peripheral blood immune response during and after treatment.&#xD;
&#xD;
      OUTLINE: Patients are assigned to 1 of 2 arms.&#xD;
&#xD;
      ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat&#xD;
      every 14 days for 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      ARM II: Patients receive nivolumab as in Arm I. Patients undergo stereotactic radiosurgery&#xD;
      (SRS) as per standard of care on day 8 of course 1.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 100 days and every 10 weeks&#xD;
      thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 10, 2017</start_date>
  <completion_date type="Anticipated">November 2023</completion_date>
  <primary_completion_date type="Anticipated">November 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of dose limiting toxicities evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</measure>
    <time_frame>Up to 12 weeks after initial dose of nivolumab</time_frame>
    <description>Proportion of serious adverse events will be estimated using the binomial distribution along with 95% confidence interval (exact method).</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Chordoma</condition>
  <arm_group>
    <arm_group_label>Arm I (nivolumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 14 days for 8 doses, then every 28 days for a total of 2 years in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (nivolumab, SRS)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive nivolumab as in Arm I. Patients undergo stereotactic radiosurgery (SRS) as per standard of care on day 8 of course 1.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Arm I (nivolumab)</arm_group_label>
    <arm_group_label>Arm II (nivolumab, SRS)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm I (nivolumab)</arm_group_label>
    <arm_group_label>Arm II (nivolumab, SRS)</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>MDX-1106</other_name>
    <other_name>NIVO</other_name>
    <other_name>ONO-4538</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic Radiosurgery</intervention_name>
    <description>Undergo SRS</description>
    <arm_group_label>Arm II (nivolumab, SRS)</arm_group_label>
    <other_name>Stereotactic External Beam Irradiation</other_name>
    <other_name>stereotactic external-beam radiation therapy</other_name>
    <other_name>Stereotactic Radiation Therapy</other_name>
    <other_name>Stereotactic Radiotherapy</other_name>
    <other_name>stereotaxic radiation therapy</other_name>
    <other_name>stereotaxic radiosurgery</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically confirmed diagnosis of chordoma; the pathologic&#xD;
             confirmation may be from another metastatic site&#xD;
&#xD;
          -  Patients may have metastases, with newly identified peripheral metastases&#xD;
&#xD;
          -  Cross-sectional imaging evidence of progression of recurrent or metastatic disease&#xD;
&#xD;
          -  Previous treatment information (name of agent, treatment starting date, and date of&#xD;
             progression) must be available for review&#xD;
&#xD;
          -  Measurable disease in one or more site. (Per RECIST criteria: Measurable lesions are&#xD;
             defined as those that can be accurately measured in at least one dimension (longest&#xD;
             diameter to be recorded) as &gt;= 10 mm with CT scan, MRI, or calipers by clinical exam.&#xD;
             All tumor measurements must be recorded in millimeters (or decimal fractions of&#xD;
             centimeters)).&#xD;
&#xD;
          -  Karnofsky performance scale &gt;= 70%&#xD;
&#xD;
          -  White blood cells (WBC) &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Total bilirubin =&lt; 2 x institutional upper limit of normal&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =&lt;&#xD;
             2.5 x institutional upper limit of normal&#xD;
&#xD;
          -  Creatinine within normal institutional limits OR according to Johns Hopkins magnetic&#xD;
             resonance imaging (MRI) policy&#xD;
&#xD;
          -  Women of child bearing potential (WOCBP) should use an adequate method to avoid&#xD;
             pregnancy for 5 months plus the time required for nivolumab to undergo approximately&#xD;
             five half-lives) after the last dose of investigational drug; in order for a woman to&#xD;
             be determined not of child-bearing potential, she must have &gt;= 12 months of&#xD;
             non-therapy induced amenorrhea or be surgically sterile&#xD;
&#xD;
          -  Men receiving nivolumab and who are sexually active with WOCBP will be instructed to&#xD;
             adhere to contraception for a period of 7 months after the last dose of&#xD;
             investigational product&#xD;
&#xD;
          -  Ability to understand and the willingness to sign written informed consent document(s)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior chemotherapy within 21 days or 5 half-lives (whichever is shorter) days of&#xD;
             starting treatment&#xD;
&#xD;
          -  Prior therapy with investigational drugs within 21 days or at least 5 half-lives&#xD;
             (whichever is shorter) before study administration&#xD;
&#xD;
          -  Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL-2 antibody&#xD;
&#xD;
          -  Neurologic dysfunction that would confound the evaluation of neurologic and other&#xD;
             adverse events&#xD;
&#xD;
          -  Known allergy to compounds of similar chemical or biologic composition to nivolumab&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
&#xD;
          -  Known history of human immunodeficiency virus&#xD;
&#xD;
          -  Active infection requiring therapy, including positive tests for hepatitis B surface&#xD;
             antigen or hepatitis C ribonucleic acid (RNA)&#xD;
&#xD;
          -  Active autoimmune disease, history of autoimmune disease or history of syndrome that&#xD;
             required systemic steroids or immunosuppressive medications, e.g. organ, tissue, or&#xD;
             allogenic hematopoietic stem cell transplant (HSCT) recipients. Exceptions include&#xD;
             those with resolved childhood asthma/atopy. Subjects with asthma who require&#xD;
             intermittent use of bronchodilators (such as albuterol) will not be excluded from this&#xD;
             study. Subjects are also permitted to enroll if they have vitiligo, type I diabetes&#xD;
             mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone&#xD;
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to&#xD;
             recur in the absence of an external trigger&#xD;
&#xD;
          -  Patients should be excluded if they have a condition requiring systemic treatment with&#xD;
             either corticosteroids (&gt; 10 mg daily prednisone equivalents) or other&#xD;
             immunosuppressive medications within 14 days of study drug administration; inhaled or&#xD;
             topical steroids and adrenal replacement doses &gt; 10 mg daily prednisone equivalents&#xD;
             are permitted in the absence of active autoimmune disease&#xD;
&#xD;
          -  Use of any vaccines against infectious diseases (e.g. varicella, influenza, etc.) up&#xD;
             to 4 weeks (28 days) before receiving nivolumab&#xD;
&#xD;
          -  Prisoners or subjects who are compulsorily detained for treatment of either a&#xD;
             psychiatric or physical (e.g. infectious disease) illness&#xD;
&#xD;
          -  Prior radiation doses equivalent to, or greater than, 8000 cGy in 200 cGy fractions&#xD;
&#xD;
          -  Any radiation to the target lesions within 6 months of enrollment&#xD;
&#xD;
          -  Unable to meet radiation treatment plan parameters&#xD;
&#xD;
          -  Unavailable for follow up visits after treatment&#xD;
&#xD;
          -  Prior malignancy unless disease free for ≥ 2 years. Curatively treated basal or&#xD;
             squamous cell carcinoma of the skin, totally excised melanoma of stage IIA or lower,&#xD;
             low- or intermediate-grade localized prostate cancer (Gleason sum ≤7), and&#xD;
             curatively-treated carcinoma in situ of the cervix, breast, or bladder are allowed&#xD;
             regardless.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lawrence Kleinberg, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University/Sidney Kimmel Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins University/Sidney Kimmel Cancer Center</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan-Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>December 8, 2016</study_first_submitted>
  <study_first_submitted_qc>December 8, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 12, 2016</study_first_posted>
  <last_update_submitted>August 10, 2023</last_update_submitted>
  <last_update_submitted_qc>August 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chordoma</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>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/NCT02989636
org study id: J16138
secondary id: IRB00117650
secondary id: NCI-2016-01638
secondary id: P30CA006973
secondary id: 18-020
secondary id: CA209-594
nct id: NCT02989636
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the side effects of nivolumab with or without stereotactic
      radiosurgery (SRS) in treating patients with chordoma that has come back or spread from where
      it started to other places in the body. Monoclonal antibodies, such as nivolumab, may
      interfere with the ability of tumor cells to grow and spread. Stereotactic radiosurgery is a
      specialized radiation therapy that delivers a single, high dose of radiation directly to the
      tumor and may cause less damage to normal tissue. It is not yet known whether giving
      nivolumab with or without stereotactic radiosurgery may work better in treating patients with
      chordoma.
PRIMARY OBJECTIVES:

      I. To assess the safety profile of nivolumab alone and nivolumab in combination with
      stereotactic radiosurgery to treat patients with recurrent or advanced chordoma.

      SECONDARY OBJECTIVES:

      I. To evaluate toxicity and tolerability of nivolumab alone and nivolumab in combination with
      stereotactic radiosurgery.

      II. To estimate growth modulation index on target lesion. III. To estimate a clinical
      response (partial response [PR] + complete response [CR] within 6 month + stable disease [SD]
      beyond 6 months).

      IV. To assess progression-free survival and progression-free survival (PFS) rate at 6 months.

      V. To assess overall survival rate at 1 year, 3 years and 5 years.

      TERTIARY OBJECTIVES:

      I. To explore peripheral blood immune response during and after treatment.

      OUTLINE: Patients are assigned to 1 of 2 arms.

      ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat
      every 14 days for 2 years in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive nivolumab as in Arm I. Patients undergo stereotactic radiosurgery
      (SRS) as per standard of care on day 8 of course 1.

      After completion of study treatment, patients are followed up at 100 days and every 10 weeks
      thereafter.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of dose limiting toxicities evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
time frame: Up to 12 weeks after initial dose of nivolumab
description: Proportion of serious adverse events will be estimated using the binomial distribution along with 95% confidence interval (exact method).
arm group label: Arm I (nivolumab)
arm group type: Experimental
description: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 14 days for 8 doses, then every 28 days for a total of 2 years in the absence of disease progression or unacceptable toxicity.
arm group label: Arm II (nivolumab, SRS)
arm group type: Experimental
description: Patients receive nivolumab as in Arm I. Patients undergo stereotactic radiosurgery (SRS) as per standard of care on day 8 of course 1.
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Arm I (nivolumab)
arm group label: Arm II (nivolumab, SRS)
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Arm I (nivolumab)
arm group label: Arm II (nivolumab, SRS)
other name: BMS-936558
other name: MDX-1106
other name: NIVO
other name: ONO-4538
other name: Opdivo
intervention type: Radiation
intervention name: Stereotactic Radiosurgery
description: Undergo SRS
arm group label: Arm II (nivolumab, SRS)
other name: Stereotactic External Beam Irradiation
other name: stereotactic external-beam radiation therapy
other name: Stereotactic Radiation Therapy
other name: Stereotactic Radiotherapy
other name: stereotaxic radiation therapy
other name: stereotaxic radiosurgery
criteria: 
gender: All
minimum age: 15 Years
maximum age: N/A
healthy volunteers: No
last name: Lawrence Kleinberg, MD
role: Principal Investigator
affiliation: Johns Hopkins University/Sidney Kimmel Cancer Center
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Chordoma
mesh term: Nivolumab
sharing ipd: No