<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/NCT03307603</url>
  </required_header>
  <id_info>
    <org_study_id>CASE3216</org_study_id>
    <nct_id>NCT03307603</nct_id>
  </id_info>
  <brief_title>Yttrium-90 Radioembolization + Nivolumab for Liver + Extra-hepatic Metastases From Colorectal Cancer</brief_title>
  <official_title>A Phase Ib/II Study of Yttrium-90 Radioembolization With Nivolumab for Treatment of Liver and Extra-hepatic Metastases From Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Case Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Case Comprehensive Cancer Center</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study has two portions. The main goal of the Phase Ib portion of this research study is&#xD;
      to see at what time Yttrium-90 (Y-90) radioembolization therapy and nivolumab can safely be&#xD;
      given to patients without having too many side effects. Other purposes of this research study&#xD;
      will be to study any tumor responses.&#xD;
&#xD;
      The Phase II portion of the study will test how many patients show shrinkage in their tumor&#xD;
      with this combination of medicines and what changes occur inside the cancer cells and blood&#xD;
      cells after treatment. The study team will pick the part of the study each subject&#xD;
      participates in.&#xD;
&#xD;
      Y-90 radioembolization therapy is minimally invasive procedure that combines two types of&#xD;
      therapy (embolization which blocks certain blood vessels, and radiation therapy, which kills&#xD;
      cancer cells) to treat cancer tumors in the liver. This works with tiny glass or resin beads&#xD;
      filled with the radioactive isotope yttrium-90 (Y-90). They are placed inside the blood&#xD;
      vessels that feed the tumor in the liver. This blocks the supply of blood to the cancer cells&#xD;
      and delivers a high dose of radiation to the tumor while sparing normal tissue.&#xD;
&#xD;
      Nivolumab is an FDA approved medicine that is used for the treatment of different types of&#xD;
      cancers and metastases (second growths from cancer).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objective&#xD;
&#xD;
      Phase Ib: To determine the safety and tolerability of Y-90 radioembolization therapy when&#xD;
      given in conjunction with neoadjuvant/adjuvant nivolumab as assessed by CTCAE version 4, in&#xD;
      patients with metastatic colorectal cancer who undergo Y-90 radioembolization to hepatic&#xD;
      metastases and have additional disease located outside of the radioembolization field.&#xD;
&#xD;
      Phase II: To determine the objective response rate (RR) as assessed by RECIST criteria of&#xD;
      metastases located outside of the Y-90 radioembolization treatment field in patients with&#xD;
      metastatic colorectal cancer who undergo Y-90 radioembolization to hepatic metastases and&#xD;
      receive neoadjuvant/adjuvant nivolumab.&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
      Phase Ib:&#xD;
&#xD;
      To assess the response rate (RR) of patients with metastatic colorectal cancer who undergo&#xD;
      standard Y-90 radioembolization therapy to hepatic metastases as well as neoadjuvant/adjuvant&#xD;
      nivolumab as assessed by measurement of foci located outside of the Y-90 radioembolization&#xD;
      field.&#xD;
&#xD;
      Phase II:&#xD;
&#xD;
      To assess the progression free survival (PFS) of patients with metastatic colorectal cancer&#xD;
      who undergo standard Y-90 radioembolization therapy to hepatic metastases as well as&#xD;
      neoadjuvant/adjuvant nivolumab as assessed by measurement of metastatic foci located outside&#xD;
      of the Y-90 radioembolization field.&#xD;
&#xD;
      To assess the 1-year and 2-year overall survival (OS) rate of patients with metastatic&#xD;
      colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases&#xD;
      as well as neoadjuvant/adjuvant nivolumab.&#xD;
&#xD;
      Correlative Objectives&#xD;
&#xD;
      To characterize the baseline expression and localization of immune markers including&#xD;
      Programmed cell death protein 1 (PD-1), Programmed cell death protein ligand 1 (PD-L1),&#xD;
      Programmed cell death protein ligand 2 (PD-L2), T-cell immunoglobulin and mucin-domain&#xD;
      containing-3 (TIM-3), Lymphocyte activation gene 3 (LAG-3), Tumor necrosis factor receptor&#xD;
      superfamily, member 4 (OX40) and Cluster of Differentiation 137 (CD137) within the tumor&#xD;
      microenvironment and correlate this with treatment response.&#xD;
&#xD;
      To examine the change in density of Cluster of Differentiation (CD8)+/Kiel-67 (Ki-67) high&#xD;
      tumor infiltrating lymphocytes and expression levels of PD-L1 in the tumor parenchyma prior&#xD;
      to and following treatment with Y-90 and nivolumab as assessed in a lesion outside of the&#xD;
      radioembolization field. Changes in biomarkers will be correlated with treatment response.&#xD;
&#xD;
      To assess baseline and changes in the immune signature of Y-90 naïve colorectal cancer in&#xD;
      patients with liver metastases who receive Y-90 radioembolization and nivolumab therapy.&#xD;
      Human transcriptome gene expression arrays will be performed and expression data will be used&#xD;
      to identify immune cell subsets using CIBERSORT and immune signatures will be assessed using&#xD;
      ImmuneSigDB.&#xD;
&#xD;
      To assess baseline and changes in non-targeted tumor antigens using Proto Array Human Protein&#xD;
      MicroArray Profiling and Immunoglobulin G (IgG) quantification in patients with liver&#xD;
      metastases who receive Y-90 radioembolization and nivolumab therapy. Changes in profile will&#xD;
      be correlated with treatment response.&#xD;
&#xD;
      Study Design&#xD;
&#xD;
      This is a single arm phase Ib/II trial assessing the safety and toxicity (phase Ib) followed&#xD;
      by the antitumor activity (response rate) (phase II) of nivolumab when administered in&#xD;
      combination with Y-90 radioembolization therapy.&#xD;
&#xD;
      Study design&#xD;
&#xD;
      Eligible patients will undergo Y-90 radioembolization to one side of the liver according to&#xD;
      standard practice as directed by an interventional radiologist. Yttrium-90 will be given as&#xD;
      biocompatible resin-based microspheres and will be introduced to the tumor(s) on one side of&#xD;
      the liver through a catheter placed in the right or left hepatic artery (depending on the&#xD;
      lobe treated). The dose of radiation will be determined by a radiologist and will be based on&#xD;
      body surface area and tumor burden. During the phase Ib portion of the study, nivolumab will&#xD;
      be administered per the scheduling algorithm at a flat dose of 240 mg intravenously over 30&#xD;
      +/- 5 minutes. Depending on the schedule being assessed, this may include a neoadjuvant dose&#xD;
      to be given prior to Y-90, and will contain an adjuvant dose following Y-90 therapy. During&#xD;
      the phase II portion of the study, nivolumab will be administered as determined during the&#xD;
      phase Ib portion of the study. Nivolumab will continue to be administered on an every 2 week&#xD;
      basis for a total of 48 weeks or until disease progression, unacceptable toxicity or&#xD;
      discontinuation due to patient/physician preference. Patients will be evaluated with a&#xD;
      history and physical exam as well as laboratory parameters once every 2 weeks throughout the&#xD;
      duration of the study. Patients will undergo CT scans of the chest and pelvis as well as MRI&#xD;
      of the liver to assess disease status 2 months following the Y-90 radioembolization&#xD;
      procedure, then every 3 months for a total of 2 years. Upon completing treatment, patients&#xD;
      will be followed monthly for another 100 days for toxicity monitoring. Archived tissue&#xD;
      specimens will be obtained at baseline and a post-treatment biopsy of a metastatic lesion&#xD;
      located outside of the Y-90 radioembolization field will be obtained 60 +/- 5 days following&#xD;
      treatment with Y-90 radioembolization for assessment of intratumoral immunogenicity.&#xD;
      Carcinoembryonic antigen (CEA) levels will be assessed at baseline, then once monthly for 6&#xD;
      months, then every 3 months for a total of 2 years. Patients will have a pre-treatment serum&#xD;
      sample collected as well as post-treatment samples collected approximately 6 weeks, 12 weeks&#xD;
      and 20 weeks after treatment with Y-90 radioembolization for banking, to be used in the&#xD;
      future assessment of putative biomarkers.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Sponsor chose not to continue&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 2018</start_date>
  <completion_date type="Anticipated">March 2021</completion_date>
  <primary_completion_date type="Anticipated">March 2019</primary_completion_date>
  <phase>Phase 1/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>Phase I: Average number of serious adverse events experience by patients</measure>
    <time_frame>Up to 2 years after starting study</time_frame>
    <description>assessed by CTCAE version 4 of nivolumab in combination with Y-90 radioembolization when administered to patients with metastatic colorectal cancer who have hepatic metastases appropriate for treatment with Y-90 radioembolization therapy.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II: Response rate</measure>
    <time_frame>Up to 2 years after starting study</time_frame>
    <description>assessed by RECIST 1.1 criteria of metastases outside of the Y-90 radioembolization treatment field in patients with metastatic colorectal cancer who undergo Y-90 radioembolization therapy to hepatic metastases followed by nivolumab.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Phase I: Progression free survival (PFS)</measure>
    <time_frame>Up to 2 years after starting study</time_frame>
    <description>Progression free survival (PFS) of patients with metastatic colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases followed by nivolumab as assessed by metastatic foci located outside of the Y-90 radioembolization field.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase I: Overall survival</measure>
    <time_frame>Up to 2 years after starting study</time_frame>
    <description>Overall survival of patients with metastatic colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases followed by nivolumab.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II: Progression free survival (PFS)</measure>
    <time_frame>Up to 2 years after starting study</time_frame>
    <description>Progression free survival (PFS) of patients with metastatic colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases followed by nivolumab as assessed by metastatic foci located outside of the Y-90 radioembolization field.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II: Overall survival</measure>
    <time_frame>Up to 2 years after starting study</time_frame>
    <description>Overall survival of patients with metastatic colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases followed by nivolumab.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Yttrium-90 + Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>240 mg Nivolumab intravenously, beginning at 2 weeks after Yttrium-90 treatment and given every 2 weeks until progression or toxicity. Additional dose at 2 weeks prior to Y-90 will be given if the first 3 patients do not have toxicity. If any of the first 3 patients have toxicity, the schedule can be relaxed to begin 3 weeks after Y-90 treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>yttrium-90 radioembolization</intervention_name>
    <description>Yttrium-90 will be given as biocompatible resin-based microspheres and will be introduced to the tumor(s) on one side of the liver through a catheter placed in the right or left hepatic artery. The dose of radiation will be determined by a radiologist and will be based on body surface area and tumor burden.</description>
    <arm_group_label>Yttrium-90 + Nivolumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase Ib - nivolumab</intervention_name>
    <description>240 mg intravenously</description>
    <arm_group_label>Yttrium-90 + Nivolumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase II - nivolumab</intervention_name>
    <description>nivolumab will be administered as determined during the phase Ib portion of the study. Nivolumab will be administered on an every 2 week basis for a total of 48 weeks or until disease progression, unacceptable toxicity or discontinuation due to patient/physician preference.</description>
    <arm_group_label>Yttrium-90 + Nivolumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed metastatic colorectal&#xD;
             cancer.&#xD;
&#xD;
          -  Patients must have liver metastases and be appropriate for treatment with Y-90&#xD;
             radioembolization therapy as determined by the treating medical oncologist and&#xD;
             interventional radiologist. Prior Y-90 therapy is not permitted.&#xD;
&#xD;
          -  Patients must have measurable disease that is located outside of the Y-90&#xD;
             radioembolization field.&#xD;
&#xD;
          -  Patients must have a metastatic focus amenable to biopsy that is located outside of&#xD;
             the Y-90 radioembolization field. It is permissible to use the same lesion for biopsy&#xD;
             as for assessment to tumor response.&#xD;
&#xD;
          -  Patients must have received at least one line of prior chemotherapy and must have had&#xD;
             resolution of all side effects to at least at Grade 1 prior to trial entry.&#xD;
&#xD;
          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of&#xD;
             0-1.&#xD;
&#xD;
          -  Patients must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  Hemoglobin ≥ 9.0 g/dl&#xD;
&#xD;
               -  Leukocytes ≥ 2,000/mcL&#xD;
&#xD;
               -  Absolute neutrophil count ≥ 1,500/mcL&#xD;
&#xD;
               -  Platelet count ≥ 100,000/mcL&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except in patients with&#xD;
                  Gilbert Syndrome, who can have a total bilirubin &lt; 3.0 mg/dL)&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) (SGOT) ≤ 3 X institutional upper limit of normal&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) (SGPT) ≤ 3 X institutional upper limit of normal&#xD;
&#xD;
               -  Serum creatinine ≤ 1.5 X ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using&#xD;
                  the Cockcroft-Gault formula below):&#xD;
&#xD;
        Female CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL&#xD;
&#xD;
        Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL&#xD;
&#xD;
        -Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception.&#xD;
        WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time&#xD;
        required for nivolumab to undergo five half-lives) after the last dose of investigational&#xD;
        drug. Women of childbearing potential&quot; is defined as any female who has experienced&#xD;
        menarche and who has not undergone surgical sterilization (hysterectomy or bilateral&#xD;
        oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of&#xD;
        amenorrhea in a woman over 45 in the absence of other biological or physiological causes.&#xD;
        In addition, women under the age of 62 must have a documented serum follicle stimulating&#xD;
        hormone (FSH) level less than 40 mili-international units/milliliter (mIU/mL).&#xD;
&#xD;
        Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on&#xD;
        the importance of pregnancy prevention and the implications of an unexpected pregnancy.&#xD;
        Investigators shall advise on the use of highly effective methods of contraception, with&#xD;
        have a failure rate of &lt; 1% when used consistently and correctly.&#xD;
&#xD;
          -  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;
          -  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 investigational product. Women who are not of&#xD;
             childbearing potential (i.e., who are postmenopausal or surgically sterile as well as&#xD;
             azoospermic men do not require contraception).&#xD;
&#xD;
          -  Patients must have the ability to understand and the willingness to sign a written&#xD;
             informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with ongoing toxicities &gt; grade 1 according to NCI CTCAE Version 4.0&#xD;
             (excluding alopecia and neuropathy) due to prior anti-cancer therapy.&#xD;
&#xD;
          -  Patients receiving any other investigational agent or active chemotherapy.&#xD;
&#xD;
          -  Patients who have previously been treated an anti-PD-1, anti-PD-L1, anti-PD-L2,&#xD;
             anti-Cytotoxic T-lymphocyte associated protein (CTLA)-4 antibody, or any other&#xD;
             antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint&#xD;
             pathways.&#xD;
&#xD;
          -  Patients with a known autoimmune disease. Patients are permitted to enroll if they&#xD;
             have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune&#xD;
             condition only requiring hormone replacement, psoriasis not requiring systemic&#xD;
             treatment, or conditions not expected to recur in the absence of an external trigger.&#xD;
&#xD;
          -  Patients having a condition requiring systemic treatment with either corticosteroids&#xD;
             (&gt; 10 mg/day prednisone equivalents) or other immunosuppressive medications within 14&#xD;
             days of study drug administration. Inhaled or topical steroids and adrenal replacement&#xD;
             doses &gt; 10 mg/day prednisone equivalents are permitted in the absence of active&#xD;
             autoimmune disease.&#xD;
&#xD;
          -  Patients who are positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis&#xD;
             C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection.&#xD;
&#xD;
          -  Patients with a known history of testing positive for human immunodeficiency virus&#xD;
             (HIV) or known acquired immunodeficiency syndrome (AIDS).&#xD;
&#xD;
          -  Patients who have received prior external beam radiation therapy to the liver.&#xD;
&#xD;
          -  Patients who have clinical evidence of ascites or are in clinical liver failure.&#xD;
&#xD;
          -  Patients who are known to have greater than 20% lung shunting of the hepatic artery&#xD;
             blood flow determined by Technetium microaggregated albumin (MAA) scan (if conducted&#xD;
             prior to study enrollment).&#xD;
&#xD;
          -  Patients who have had a standard of care pre-assessment angiogram that demonstrates&#xD;
             abnormal vascular anatomy that would result in significant reflux of hepatic arterial&#xD;
             blood to the stomach, pancreas or bowel.&#xD;
&#xD;
          -  Patients with known portal vein thrombosis.&#xD;
&#xD;
          -  Patients with untreated brain metastases or leptomeningeal metastases will be&#xD;
             excluded. Patients with brain metastases are eligible if metastases have been treated&#xD;
             and there is no magnetic resonance imaging (MRI) evidence of progression for at least&#xD;
             4 weeks after treatment is complete and within 28 days prior to the first dose of&#xD;
             nivolumab administration. There must also be no requirement for immunosuppressive&#xD;
             doses of systemic corticosteroids (&gt; 10 mg/day prednisone equivalents) for at least 2&#xD;
             weeks prior to study drug administration.&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illness including, but not limited to ongoing&#xD;
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,&#xD;
             cardiac arrhythmia, or psychiatric illness/social situations that would limit&#xD;
             compliance with study requirements.&#xD;
&#xD;
          -  Patients who are pregnant or breastfeeding will be excluded from the study due to the&#xD;
             potential teratogenic or abortifacient effects that may result from nivolumab or Y-90&#xD;
             Theraspheres. Because there is an unknown, but potential risk for adverse events in&#xD;
             nursing infants secondary to treatment of the mother with nivolumab and Y-90,&#xD;
             breastfeeding should be discontinued if the mother is treated with nivolumab and Y-90.&#xD;
             These potential risks may also apply to other agents used in this study.&#xD;
&#xD;
          -  HIV-positive patients on combination antiretroviral therapy are ineligible because of&#xD;
             the potential for pharmacokinetic interactions with nivolumab. In addition, these&#xD;
             subjects are at increased risk of lethal infections when treated with&#xD;
             immunosuppressive agents. Screening HIV testing is not required.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jennifer Eads, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center</affiliation>
  </overall_official>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>September 7, 2017</study_first_submitted>
  <study_first_submitted_qc>October 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 11, 2017</study_first_posted>
  <last_update_submitted>February 24, 2018</last_update_submitted>
  <last_update_submitted_qc>February 24, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Yttrium-90 radioembolization</keyword>
  <keyword>Nivolumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal 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/NCT03307603
org study id: CASE3216
nct id: NCT03307603
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study has two portions. The main goal of the Phase Ib portion of this research study is
      to see at what time Yttrium-90 (Y-90) radioembolization therapy and nivolumab can safely be
      given to patients without having too many side effects. Other purposes of this research study
      will be to study any tumor responses.

      The Phase II portion of the study will test how many patients show shrinkage in their tumor
      with this combination of medicines and what changes occur inside the cancer cells and blood
      cells after treatment. The study team will pick the part of the study each subject
      participates in.

      Y-90 radioembolization therapy is minimally invasive procedure that combines two types of
      therapy (embolization which blocks certain blood vessels, and radiation therapy, which kills
      cancer cells) to treat cancer tumors in the liver. This works with tiny glass or resin beads
      filled with the radioactive isotope yttrium-90 (Y-90). They are placed inside the blood
      vessels that feed the tumor in the liver. This blocks the supply of blood to the cancer cells
      and delivers a high dose of radiation to the tumor while sparing normal tissue.

      Nivolumab is an FDA approved medicine that is used for the treatment of different types of
      cancers and metastases (second growths from cancer).
Primary Objective

      Phase Ib: To determine the safety and tolerability of Y-90 radioembolization therapy when
      given in conjunction with neoadjuvant/adjuvant nivolumab as assessed by CTCAE version 4, in
      patients with metastatic colorectal cancer who undergo Y-90 radioembolization to hepatic
      metastases and have additional disease located outside of the radioembolization field.

      Phase II: To determine the objective response rate (RR) as assessed by RECIST criteria of
      metastases located outside of the Y-90 radioembolization treatment field in patients with
      metastatic colorectal cancer who undergo Y-90 radioembolization to hepatic metastases and
      receive neoadjuvant/adjuvant nivolumab.

      Secondary Objectives

      Phase Ib:

      To assess the response rate (RR) of patients with metastatic colorectal cancer who undergo
      standard Y-90 radioembolization therapy to hepatic metastases as well as neoadjuvant/adjuvant
      nivolumab as assessed by measurement of foci located outside of the Y-90 radioembolization
      field.

      Phase II:

      To assess the progression free survival (PFS) of patients with metastatic colorectal cancer
      who undergo standard Y-90 radioembolization therapy to hepatic metastases as well as
      neoadjuvant/adjuvant nivolumab as assessed by measurement of metastatic foci located outside
      of the Y-90 radioembolization field.

      To assess the 1-year and 2-year overall survival (OS) rate of patients with metastatic
      colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases
      as well as neoadjuvant/adjuvant nivolumab.

      Correlative Objectives

      To characterize the baseline expression and localization of immune markers including
      Programmed cell death protein 1 (PD-1), Programmed cell death protein ligand 1 (PD-L1),
      Programmed cell death protein ligand 2 (PD-L2), T-cell immunoglobulin and mucin-domain
      containing-3 (TIM-3), Lymphocyte activation gene 3 (LAG-3), Tumor necrosis factor receptor
      superfamily, member 4 (OX40) and Cluster of Differentiation 137 (CD137) within the tumor
      microenvironment and correlate this with treatment response.

      To examine the change in density of Cluster of Differentiation (CD8)+/Kiel-67 (Ki-67) high
      tumor infiltrating lymphocytes and expression levels of PD-L1 in the tumor parenchyma prior
      to and following treatment with Y-90 and nivolumab as assessed in a lesion outside of the
      radioembolization field. Changes in biomarkers will be correlated with treatment response.

      To assess baseline and changes in the immune signature of Y-90 naïve colorectal cancer in
      patients with liver metastases who receive Y-90 radioembolization and nivolumab therapy.
      Human transcriptome gene expression arrays will be performed and expression data will be used
      to identify immune cell subsets using CIBERSORT and immune signatures will be assessed using
      ImmuneSigDB.

      To assess baseline and changes in non-targeted tumor antigens using Proto Array Human Protein
      MicroArray Profiling and Immunoglobulin G (IgG) quantification in patients with liver
      metastases who receive Y-90 radioembolization and nivolumab therapy. Changes in profile will
      be correlated with treatment response.

      Study Design

      This is a single arm phase Ib/II trial assessing the safety and toxicity (phase Ib) followed
      by the antitumor activity (response rate) (phase II) of nivolumab when administered in
      combination with Y-90 radioembolization therapy.

      Study design

      Eligible patients will undergo Y-90 radioembolization to one side of the liver according to
      standard practice as directed by an interventional radiologist. Yttrium-90 will be given as
      biocompatible resin-based microspheres and will be introduced to the tumor(s) on one side of
      the liver through a catheter placed in the right or left hepatic artery (depending on the
      lobe treated). The dose of radiation will be determined by a radiologist and will be based on
      body surface area and tumor burden. During the phase Ib portion of the study, nivolumab will
      be administered per the scheduling algorithm at a flat dose of 240 mg intravenously over 30
      +/- 5 minutes. Depending on the schedule being assessed, this may include a neoadjuvant dose
      to be given prior to Y-90, and will contain an adjuvant dose following Y-90 therapy. During
      the phase II portion of the study, nivolumab will be administered as determined during the
      phase Ib portion of the study. Nivolumab will continue to be administered on an every 2 week
      basis for a total of 48 weeks or until disease progression, unacceptable toxicity or
      discontinuation due to patient/physician preference. Patients will be evaluated with a
      history and physical exam as well as laboratory parameters once every 2 weeks throughout the
      duration of the study. Patients will undergo CT scans of the chest and pelvis as well as MRI
      of the liver to assess disease status 2 months following the Y-90 radioembolization
      procedure, then every 3 months for a total of 2 years. Upon completing treatment, patients
      will be followed monthly for another 100 days for toxicity monitoring. Archived tissue
      specimens will be obtained at baseline and a post-treatment biopsy of a metastatic lesion
      located outside of the Y-90 radioembolization field will be obtained 60 +/- 5 days following
      treatment with Y-90 radioembolization for assessment of intratumoral immunogenicity.
      Carcinoembryonic antigen (CEA) levels will be assessed at baseline, then once monthly for 6
      months, then every 3 months for a total of 2 years. Patients will have a pre-treatment serum
      sample collected as well as post-treatment samples collected approximately 6 weeks, 12 weeks
      and 20 weeks after treatment with Y-90 radioembolization for banking, to be used in the
      future assessment of putative biomarkers.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase I: Average number of serious adverse events experience by patients
time frame: Up to 2 years after starting study
description: assessed by CTCAE version 4 of nivolumab in combination with Y-90 radioembolization when administered to patients with metastatic colorectal cancer who have hepatic metastases appropriate for treatment with Y-90 radioembolization therapy.
measure: Phase II: Response rate
time frame: Up to 2 years after starting study
description: assessed by RECIST 1.1 criteria of metastases outside of the Y-90 radioembolization treatment field in patients with metastatic colorectal cancer who undergo Y-90 radioembolization therapy to hepatic metastases followed by nivolumab.
measure: Phase I: Progression free survival (PFS)
time frame: Up to 2 years after starting study
description: Progression free survival (PFS) of patients with metastatic colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases followed by nivolumab as assessed by metastatic foci located outside of the Y-90 radioembolization field.
measure: Phase I: Overall survival
time frame: Up to 2 years after starting study
description: Overall survival of patients with metastatic colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases followed by nivolumab.
measure: Phase II: Progression free survival (PFS)
time frame: Up to 2 years after starting study
description: Progression free survival (PFS) of patients with metastatic colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases followed by nivolumab as assessed by metastatic foci located outside of the Y-90 radioembolization field.
measure: Phase II: Overall survival
time frame: Up to 2 years after starting study
description: Overall survival of patients with metastatic colorectal cancer who undergo standard Y-90 radioembolization therapy to hepatic metastases followed by nivolumab.
arm group label: Yttrium-90 + Nivolumab
arm group type: Experimental
description: 240 mg Nivolumab intravenously, beginning at 2 weeks after Yttrium-90 treatment and given every 2 weeks until progression or toxicity. Additional dose at 2 weeks prior to Y-90 will be given if the first 3 patients do not have toxicity. If any of the first 3 patients have toxicity, the schedule can be relaxed to begin 3 weeks after Y-90 treatment.
intervention type: Radiation
intervention name: yttrium-90 radioembolization
description: Yttrium-90 will be given as biocompatible resin-based microspheres and will be introduced to the tumor(s) on one side of the liver through a catheter placed in the right or left hepatic artery. The dose of radiation will be determined by a radiologist and will be based on body surface area and tumor burden.
arm group label: Yttrium-90 + Nivolumab
intervention type: Drug
intervention name: Phase Ib - nivolumab
description: 240 mg intravenously
arm group label: Yttrium-90 + Nivolumab
intervention type: Drug
intervention name: Phase II - nivolumab
description: nivolumab will be administered as determined during the phase Ib portion of the study. Nivolumab will be administered on an every 2 week basis for a total of 48 weeks or until disease progression, unacceptable toxicity or discontinuation due to patient/physician preference.
arm group label: Yttrium-90 + Nivolumab
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: Jennifer Eads, MD
role: Principal Investigator
affiliation: University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
country: United States
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Nivolumab