<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/NCT03033446</url>
  </required_header>
  <id_info>
    <org_study_id>CA209-678</org_study_id>
    <nct_id>NCT03033446</nct_id>
  </id_info>
  <brief_title>Study of Y90-Radioembolization With Nivolumab in Asians With Hepatocellular Carcinoma</brief_title>
  <official_title>A Phase II Open-Label, Single Centre, Non-Randomised Trial Of Y90-Radioembolization In Combination With Nivolumab In Asian Patients With Advanced Hepatocellular Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Centre, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Centre, Singapore</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the effect of liver-localised radioembolization and&#xD;
      nivolumab on liver cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The hypothesis is that liver-localized radioembolization will stimulate tumour and/or HBV&#xD;
      specific T cell responses that are associated with favourable patient outcomes and that can&#xD;
      be boosted using nivolumab anti-PD1 checkpoint blockade immunotherapy.&#xD;
&#xD;
      Primary objective&#xD;
&#xD;
      To evaluate the response rates of Y90 radioembolization in combination with nivolumab in HCC&#xD;
&#xD;
      Secondary objectives&#xD;
&#xD;
        1. To evaluate time to response, response duration, time to treatment progression and sites&#xD;
           of progression when RE is combined with nivolumab&#xD;
&#xD;
        2. To assess progression free survival and overall survival when RE is combined with&#xD;
           nivolumab&#xD;
&#xD;
        3. To assess the quality of life using the FACT-HEP score and EORTC QLQ-C30&#xD;
&#xD;
        4. To assess the safety and tolerability of the combination of RE and nivolumab&#xD;
&#xD;
      Exploratory objectives&#xD;
&#xD;
        1. To evaluate the relationship between tumor biopsy PD-L1 expression and response to&#xD;
           treatment with Y90 radioembolization in combination with nivolumab&#xD;
&#xD;
        2. To assess relationship between blood lymphocyte (e.g., T cell) activation and phenotypic&#xD;
           profiles with response to treatment with Y90 radioembolization in combination with&#xD;
           nivolumab, using mass cytometry and fluorescence flow cytometry.&#xD;
&#xD;
        3. To assess relationship between HCC tumour mutational burden and response to treatment&#xD;
           with Y90 radioembolization in combination with nivolumab using whole-exome sequencing of&#xD;
           tumour biopsy samples&#xD;
&#xD;
        4. Where possible, to evaluate antigen-specific T cell responses to known HBV, HCC tumour&#xD;
           (including candidate mutation-derived tumour neo-antigens) and other unrelated antigens&#xD;
           (e.g. CMV, EBV, Influenza) in the blood and to assess kinetic changes in these responses&#xD;
           associated with response to treatment with Y90 radioembolization in combination with&#xD;
           nivolumab using mass cytometry and fluorescence flow cytometry.&#xD;
&#xD;
      Administration of study drug The first dose of nivolumab will be administered 21 days (+/- 3&#xD;
      days) after completion of RE. [The dose of Yttrium-90 will be determined as per institution&#xD;
      norm by the Nuclear Medicine physician, based on factors such as the subject's Body Surface&#xD;
      Area (BSA), the size of the tumour within the liver, and any dose modifications required for&#xD;
      percent lung shunting between 10 - 20% on the Tc-99MMA scan].&#xD;
&#xD;
      The dose given will be intravenous 240mg absolute over 30 minutes. Subsequent doses of&#xD;
      nivolumab will be administered in the outpatient setting at NCCS. After the first dose,&#xD;
      intravenous nivolumab 240mg will be given every 2 weeks.&#xD;
&#xD;
      A US or CT guided liver biopsy will be conducted by an interventional radiologist on C1D8&#xD;
      Subjects will be assessed for the following at EVERY visit: physical examination, ECOG&#xD;
      status, vital signs, Child-Pugh score and ALBI score CT or MRI scans to assess response to&#xD;
      treatment will be done before cycle 4, 8, 12 and then after every 12 weeks thereafter (±7&#xD;
      days).&#xD;
&#xD;
      FACT-HEP and EORTC QLQ C30 version 3.0 questionnaire at cycle 4 and 8.&#xD;
&#xD;
      Follow-Up Visit will be done 2-3 months after last dose. Survival updates will be obtained by&#xD;
      phone every 3-4 months after the follow-up visit and any new anti-cancer treatment given to&#xD;
      the subject will be recorded.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 20, 2016</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</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>Response Rate</measure>
    <time_frame>Tumour assessment at 8 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Response</measure>
    <time_frame>From date of first dose with Y90 Radioemolization (RE) until best overall response of Complete Response (CR) or Partial Response (PR) is achieved, up to 12 weeks after last dose of Nivolumab</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>From date of first assessment of CR or PR until the first date that progressive disease or death is documented, up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Progression</measure>
    <time_frame>From date of first dose with Y90 RE until the first date that progressive disease is documented, up to 12 weeks after last dose of Nivolumab</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>From date of first dose with Y90 RE until tumour progression, or death from any cause, up to 12 weeks after last dose of Nivolumab</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>From date of first dose with Y90 RE until death from any cause, up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life using the FACT-HEP score</measure>
    <time_frame>From date of screening until 3 months after last dose of Nivolumab</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life using EORTC QLQ-C30</measure>
    <time_frame>From date of screening until 3 months after last dose of Nivolumab</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events from the combination of RE and nivolumab assessed by NCI CTCAE v4.0</measure>
    <time_frame>While receiving study agent and up to 100 days after last dose of Nivolumab</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>HepatoCellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Y90-Radioembolization and Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Y-90 Radioembolization</intervention_name>
    <description>Dose of Yttrium-90 is determined based on BSA, size of liver tumor, and dose modifications required for percent lung shunting between 10-20% on the Tc-99MMA scan</description>
    <arm_group_label>Y90-Radioembolization and Nivolumab</arm_group_label>
    <other_name>Selective Internal Radiation Therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>21 days after Radioembolization, 240mg of IV Nivolumab over 30 minutes will be administered every 2 weeks</description>
    <arm_group_label>Y90-Radioembolization and Nivolumab</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with hepatocellular carcinoma (HCC) that is not suitable for resection or&#xD;
             liver transplant, who are planned for Y90 radioembolization as per institutional&#xD;
             practice.&#xD;
&#xD;
          2. Patients must have measurable disease with target lesion in liver, defined as at least&#xD;
             one lesion that can be accurately measured in at least one dimension (longest diameter&#xD;
             to be recorded) as &gt;20 mm with conventional techniques or as &gt;10 mm with spiral CT&#xD;
             scan.&#xD;
&#xD;
          3. Diagnosis of HCC confirmed by histology/cytology or clinically by AASLD criteria in&#xD;
             cirrhotic subjects. Patients without cirrhosis require histological confirmation of&#xD;
             diagnosis&#xD;
&#xD;
          4. No prior Y90 radioembolization therapy. Prior local therapies, such as surgery,&#xD;
             hepatic artery embolization/chemoembolization, radiofrequency ablation, percutaneous&#xD;
             ethanol injection or cryoabalastion is allowed, if the index lesion(s) remains outside&#xD;
             of the treatment field or has progressed since prior treatment. Local therapy must&#xD;
             have been completed at least 4 weeks prior to the baseline scan&#xD;
&#xD;
          5. Age ≥ 21 years.&#xD;
&#xD;
          6. ECOG performance status ≤ 2&#xD;
&#xD;
          7. Life expectancy of greater than 3 months&#xD;
&#xD;
          8. Only patients with Child-Pugh score for liver cirrhosis of A (sum of scores for five&#xD;
             parameters: 5-6) will be allowed into this trial&#xD;
&#xD;
          9. Subjects with HBV infection must be on antiviral therapy per regional standard of care&#xD;
             guidelines prior to initiation of study therapy. Both HBeAg positive and negative&#xD;
             subjects will be included.&#xD;
&#xD;
         10. Patients must have lesions in the liver that are amenable to CT-guided liver biopsy&#xD;
&#xD;
         11. Patients must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  Haemoglobin ≥ 8.5g/dL&#xD;
&#xD;
               -  Absolute Neutrophil Count ≥ 1.5 x 10^9/L&#xD;
&#xD;
               -  Platelets ≥ 50 x 10^9/L&#xD;
&#xD;
               -  Total Bilirubin &lt; 3 mg/dL&#xD;
&#xD;
               -  AST(SGOT)/ALT (SGPT) ≤ 3 x ULN&#xD;
&#xD;
               -  Creatinine ≤ 1.5 x ULN or measured/calculated Creatinine Clearance (CrCl) ≥ 60&#xD;
                  ml/min&#xD;
&#xD;
         12. Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
         13. Any surgery must be more than 28 days before start of study drug and any surgical&#xD;
             wounds must be completely healed&#xD;
&#xD;
         14. Female subjects of childbearing potential must have a negative serum or urine&#xD;
             pregnancy test within 3 days prior to receiving the first dose of study medication,&#xD;
             and must agree to adequate contraception use from time of signing the informed consent&#xD;
             through to 120 days after the last dose of the study drug. Male subjects must agree to&#xD;
             adequate contraception use from time of signing the informed consent through 120 days&#xD;
             after the last dose of the study drug.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients are excluded if they are receiving any other investigational agents or using&#xD;
             an investigational device within 4 weeks of first dose of treatment. Patients are&#xD;
             excluded if they are receiving other systemic therapy within 2 weeks of first dose of&#xD;
             treatment.&#xD;
&#xD;
          2. Patients with known brain metastases should be excluded from this clinical trial&#xD;
             because of their poor prognosis and because they often develop progressive neurologic&#xD;
             dysfunction that would confound the evaluation of neurologic and other adverse events.&#xD;
&#xD;
          3. Prior use of anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or&#xD;
             any drug specifically targeted T-cell costimulatory checkpoint pathways&#xD;
&#xD;
          4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that&#xD;
             would limit compliance with study requirements.&#xD;
&#xD;
          5. Subjects with any active autoimmune disease or history of known or suspected&#xD;
             autoimmune disease requiring systemic therapy within the past 2 years, except for&#xD;
             subjects with vitiligo, resolved childhood asthma/atopy or euthyroid patients with a&#xD;
             history of Grave's disease (subjects with suspected autoimmune thyroid disorders must&#xD;
             be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid&#xD;
             stimulating immunoglobulin prior to randomization). Replacement therapy (e.g. with&#xD;
             thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or&#xD;
             pituitary insufficiency etc) is not considered a form of systemic treatment&#xD;
&#xD;
          6. Pregnant women or breastfeeding mothers are excluded from this study because of the&#xD;
             potential risks to the foetus or baby. Women of child-bearing potential and men must&#xD;
             agree to use adequate contraception (hormonal or barrier method of birth control;&#xD;
             abstinence) prior to study entry and for the duration of study participation. Should a&#xD;
             woman become pregnant or suspect she is pregnant while participating in this study,&#xD;
             she should inform her treating physician immediately.&#xD;
&#xD;
          7. Diagnosis of immunodeficiency, including HIV/AIDS&#xD;
&#xD;
          8. Prior organ allograft or allogeneic bone marrow transplantation&#xD;
&#xD;
          9. History of severe hypersensitivity reactions to other monoclonal antibodies.&#xD;
&#xD;
         10. Prisoners or subjects who are involuntarily incarcerated&#xD;
&#xD;
         11. Subjects who are compulsorily detained for treatment of either a psychiatric or&#xD;
             physical (eg, infectious disease) illness&#xD;
&#xD;
         12. Inability to comply with restrictions and prohibited activities/treatments in this&#xD;
             study&#xD;
&#xD;
         13. Chronic treatment with systemic steroids or other immunosuppressive agent.&#xD;
&#xD;
         14. Subjects with concomitant second malignancies (except adequately treated&#xD;
             non-melanomatous skin cancers, in situ cervical cancers, localized prostate cancer or&#xD;
             in situ breast cancer) are excluded unless a complete remission was achieved at least&#xD;
             3 years prior to study entry and no additional therapy is required or anticipated to&#xD;
             be required&#xD;
&#xD;
         15. Prior radiation therapy to the liver or upper abdomen&#xD;
&#xD;
         16. Inability to undergo Y-90 radioembolisation due to inability to cathterise the hepatic&#xD;
             artery, portal vein thrombosis/occlusion limiting the ability to perform selective&#xD;
             infusion, Tc-99M MAA scan showing unfavourable shunt fraction between the liver and&#xD;
             pulmonary parenchyma, any other contraindications to RE as determined by the&#xD;
             interventional radiologist (e.g. other anatomic variants precluding safe&#xD;
             administration of Y90, severe peripheral vascular disease, uncorrectable coagulopathy&#xD;
             etc)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Wai-Meng TAI, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Centre, Singapore</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Cancer Centre - Singapore</name>
      <address>
        <city>Singapore</city>
        <zip>169610</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>January 18, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 26, 2017</study_first_posted>
  <last_update_submitted>May 25, 2022</last_update_submitted>
  <last_update_submitted_qc>May 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 26, 2022</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>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</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/NCT03033446
org study id: CA209-678
nct id: NCT03033446
lead sponsor: 
has dmc: No
The purpose of this study is to evaluate the effect of liver-localised radioembolization and
      nivolumab on liver cancer.
The hypothesis is that liver-localized radioembolization will stimulate tumour and/or HBV
      specific T cell responses that are associated with favourable patient outcomes and that can
      be boosted using nivolumab anti-PD1 checkpoint blockade immunotherapy.

      Primary objective

      To evaluate the response rates of Y90 radioembolization in combination with nivolumab in HCC

      Secondary objectives

        1. To evaluate time to response, response duration, time to treatment progression and sites
           of progression when RE is combined with nivolumab

        2. To assess progression free survival and overall survival when RE is combined with
           nivolumab

        3. To assess the quality of life using the FACT-HEP score and EORTC QLQ-C30

        4. To assess the safety and tolerability of the combination of RE and nivolumab

      Exploratory objectives

        1. To evaluate the relationship between tumor biopsy PD-L1 expression and response to
           treatment with Y90 radioembolization in combination with nivolumab

        2. To assess relationship between blood lymphocyte (e.g., T cell) activation and phenotypic
           profiles with response to treatment with Y90 radioembolization in combination with
           nivolumab, using mass cytometry and fluorescence flow cytometry.

        3. To assess relationship between HCC tumour mutational burden and response to treatment
           with Y90 radioembolization in combination with nivolumab using whole-exome sequencing of
           tumour biopsy samples

        4. Where possible, to evaluate antigen-specific T cell responses to known HBV, HCC tumour
           (including candidate mutation-derived tumour neo-antigens) and other unrelated antigens
           (e.g. CMV, EBV, Influenza) in the blood and to assess kinetic changes in these responses
           associated with response to treatment with Y90 radioembolization in combination with
           nivolumab using mass cytometry and fluorescence flow cytometry.

      Administration of study drug The first dose of nivolumab will be administered 21 days (+/- 3
      days) after completion of RE. [The dose of Yttrium-90 will be determined as per institution
      norm by the Nuclear Medicine physician, based on factors such as the subject's Body Surface
      Area (BSA), the size of the tumour within the liver, and any dose modifications required for
      percent lung shunting between 10 - 20% on the Tc-99MMA scan].

      The dose given will be intravenous 240mg absolute over 30 minutes. Subsequent doses of
      nivolumab will be administered in the outpatient setting at NCCS. After the first dose,
      intravenous nivolumab 240mg will be given every 2 weeks.

      A US or CT guided liver biopsy will be conducted by an interventional radiologist on C1D8
      Subjects will be assessed for the following at EVERY visit: physical examination, ECOG
      status, vital signs, Child-Pugh score and ALBI score CT or MRI scans to assess response to
      treatment will be done before cycle 4, 8, 12 and then after every 12 weeks thereafter (±7
      days).

      FACT-HEP and EORTC QLQ C30 version 3.0 questionnaire at cycle 4 and 8.

      Follow-Up Visit will be done 2-3 months after last dose. Survival updates will be obtained by
      phone every 3-4 months after the follow-up visit and any new anti-cancer treatment given to
      the subject will be recorded.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Response Rate
time frame: Tumour assessment at 8 weeks
measure: Time to Response
time frame: From date of first dose with Y90 Radioemolization (RE) until best overall response of Complete Response (CR) or Partial Response (PR) is achieved, up to 12 weeks after last dose of Nivolumab
measure: Duration of Response
time frame: From date of first assessment of CR or PR until the first date that progressive disease or death is documented, up to 2 years
measure: Time to Progression
time frame: From date of first dose with Y90 RE until the first date that progressive disease is documented, up to 12 weeks after last dose of Nivolumab
measure: Progression Free Survival
time frame: From date of first dose with Y90 RE until tumour progression, or death from any cause, up to 12 weeks after last dose of Nivolumab
measure: Overall Survival
time frame: From date of first dose with Y90 RE until death from any cause, up to 2 years
measure: Quality of Life using the FACT-HEP score
time frame: From date of screening until 3 months after last dose of Nivolumab
measure: Quality of Life using EORTC QLQ-C30
time frame: From date of screening until 3 months after last dose of Nivolumab
measure: Adverse events from the combination of RE and nivolumab assessed by NCI CTCAE v4.0
time frame: While receiving study agent and up to 100 days after last dose of Nivolumab
arm group label: Y90-Radioembolization and Nivolumab
arm group type: Experimental
intervention type: Radiation
intervention name: Y-90 Radioembolization
description: Dose of Yttrium-90 is determined based on BSA, size of liver tumor, and dose modifications required for percent lung shunting between 10-20% on the Tc-99MMA scan
arm group label: Y90-Radioembolization and Nivolumab
other name: Selective Internal Radiation Therapy
intervention type: Drug
intervention name: Nivolumab
description: 21 days after Radioembolization, 240mg of IV Nivolumab over 30 minutes will be administered every 2 weeks
arm group label: Y90-Radioembolization and Nivolumab
other name: Opdivo
criteria: 
gender: All
minimum age: 21 Years
maximum age: 99 Years
healthy volunteers: No
last name: David Wai-Meng TAI, MD
role: Principal Investigator
affiliation: National Cancer Centre, Singapore
facility: 
country: Singapore
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Nivolumab
sharing ipd: Undecided