xml: <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/NCT05992220</url>
    </required_header>
    <id_info>
      <org_study_id>KCT0007365</org_study_id>
      <secondary_id>KCT0007365</secondary_id>
      <nct_id>NCT05992220</nct_id>
    </id_info>
    <brief_title>Atezolizumab Plus Bevacizumab Alone or Combined With External Beam Radiotherapy for HCC With Macrovascular Invasion</brief_title>
    <acronym>ALERT-HCC</acronym>
    <official_title>A Randomized, Multicenter, Open-Label, Phase II Trial of Atezolizumab Plus Bevacizumab Alone or Combined With External Beam RadioTherapy for HepatoCellular Carcinoma With Macrovascular Invasion (ALERT-HCC)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Asan Medical Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Seoul National University Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Hanyang University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Soon Chun Hyang University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Asan Medical Center</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>
        The recent global IMbrave150 study evaluated the combination of atezolizumab and bevacizumab&#xD;
        versus sorafenib in 501 patients with advanced or metastatic Hepatocellular Carcinoma (HCC).&#xD;
        The median overall survival (OS) was notably better in the atezolizumab/bevacizumab group.&#xD;
        However, for HCC patients with intrahepatic macrovascular invasion (MVI), the prognosis&#xD;
        remains poor, indicating a significant unmet need in this group.&#xD;
  &#xD;
        External Beam Radiotherapy (EBRT) has shown promising results in treating HCC with MVI,&#xD;
        especially when used in combination with trans-arterial chemoembolization (TACE). It has been&#xD;
        reported that radiotherapy may make tumor cells more susceptible to immune-mediated therapy,&#xD;
        potentially enhancing the effects of atezolizumab and bevacizumab.&#xD;
  &#xD;
        Thus, this study aims to investigate the efficacy and safety of atezolizumab/bevacizumab&#xD;
        alone versus atezolizumab/bevacizumab in combination with EBRT in HCC patients with&#xD;
        macrovascular invasion.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        A total of 138 subjects are randomly assigned to one of two treatment groups (69 patients in&#xD;
        the atezolizumab+bevacizumab group and 69 patients in the Atezolizumab plus Bevacizumab&#xD;
        combined EBRT group).&#xD;
  &#xD;
          -  Radiotherapy combination:&#xD;
  &#xD;
               -  Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.&#xD;
  &#xD;
               -  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.&#xD;
  &#xD;
               -  The external beam radiotherapy will commence after day 2 of the first cycle of&#xD;
                  Atezolizumab+Bevacizumab, and will be delivered in accordance with institutional&#xD;
                  protocol.&#xD;
  &#xD;
          -  Atezolizumab+Bevacizumab:&#xD;
  &#xD;
               -  Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.&#xD;
  &#xD;
               -  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.&#xD;
  &#xD;
        Additional study identifiers: This study was also registered on the WHO's International&#xD;
        Clinical Trials Registry Platform, CRIS, before the first participant was enrolled (ID:&#xD;
        KCT0007365, Date of registration: 2022-06-08).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">October 22, 2022</start_date>
    <completion_date type="Anticipated">March 2026</completion_date>
    <primary_completion_date type="Anticipated">March 2026</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>randomized, multicenter, open-label study</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>progression-free survival rate</measure>
      <time_frame>up to approximately 3 years</time_frame>
      <description>Randomization to the first occurrence of disease progression or death from any cause, whichever occurs first</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Overall survival rate</measure>
      <time_frame>up to approximately 3 years</time_frame>
      <description>Randomization to death from any cause, through the end of study</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Objective response</measure>
      <time_frame>up to approximately 3 years</time_frame>
      <description>complete response or partial response as determined by the Investigator according to RECIST V1.1</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Adverse reaction rate</measure>
      <time_frame>through study completion, up to approximately 3 years</time_frame>
      <description>Adverse reaction rate assessed by CTCAE version 5</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time to deterioration</measure>
      <time_frame>through study completion, up to approximately 3 years</time_frame>
      <description>The time from randomization to first deterioration (decrease from baseline of ≥10 points) in the patient-reported global health status (GHS) / Quality of life (QoL), physical function, or role function scales of the EORTC QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Duration of response</measure>
      <time_frame>up to approximately 3 years</time_frame>
      <description>the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression or death is documented, whichever occurs first. DOR will be assessed in patients who had an objective response.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Tumor marker response (AFP, PIVKA-II)</measure>
      <time_frame>through study completion, up to approximately 3 years</time_frame>
      <description>The decrease of &gt;20% in serum concentration of each marker from baseline across all time points during study period.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">138</enrollment>
    <condition>Hepatocellular Carcinoma</condition>
    <condition>Hepatocellular Cancer</condition>
    <condition>Hepatocellular Carcinoma Non-resectable</condition>
    <condition>Hepatocellular Carcinoma Stage IV</condition>
    <condition>Liver Cancer</condition>
    <arm_group>
      <arm_group_label>Radiotherapy combination</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Atezolizumab+Bevacizumab, combined EBRT to vascular invasion&#xD;
  Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.&#xD;
  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.&#xD;
  The external beam radiotherapy will commence after day 2 of the first cycle of A+B, and will be delivered in accordance with institutional protocol.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Atezolizumab+Bevacizumab</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.&#xD;
  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.</description>
    </arm_group>
    <intervention>
      <intervention_type>Radiation</intervention_type>
      <intervention_name>Atezolizumab plus bevacizumab, combined EBRT to vascular invasion</intervention_name>
      <description>The external beam radiotherapy will commence after day 2 of the first cycle of atezolizumab+bevacizumab, and will be delivered in accordance with institutional protocol.&#xD;
  3D-conformal radiotherapy technique is used to determine target volumes, radiation ports, and dose prescriptions by using a 3D radiotherapy planning system.&#xD;
  The gross tumor volume (GTV) includes vascular invasion and a 2-cm margin into the contiguous HCC. The GTV can consist of the entire HCC and vascular invasion at the discretion of the investigator.&#xD;
  The target dose is 45 Gy, however, the total dose can be reduced as low as 30 Gy according to the liver function, liver volumes, or the maximum dose to the stomach/duodenum during the planning process according to the judgment of the radiation oncologist of each participating sites.</description>
      <arm_group_label>Radiotherapy combination</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Atezolizumab plus bevacizumab</intervention_name>
      <description>Atezolizumab plus bevacizumab q3w</description>
      <arm_group_label>Atezolizumab+Bevacizumab</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Older than 19 years of age, lower than 80 years of age&#xD;
  &#xD;
            -  Child-Pugh class A hepatic function&#xD;
  &#xD;
            -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1&#xD;
  &#xD;
            -  Patients with HCC [diagnosed according to AASLD guidelines] invading the intrahepatic&#xD;
               vascular system&#xD;
  &#xD;
            -  No prior systemic therapy for HCC&#xD;
  &#xD;
            -  At least one measurable HCC lesion with ≥ 1cm diameter&#xD;
  &#xD;
            -  Adequate hematologic and organ function&#xD;
  &#xD;
                 -  Hemoglobin ≥ 9.0 g/dL&#xD;
  &#xD;
                 -  Absolute neutrophil count ≥ 1,000 /mm3&#xD;
  &#xD;
                 -  Platelet ≥ 50,000/ mm3 without transfusion&#xD;
  &#xD;
            -  Total bilirubin ≤ 2.5 mg/dL&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Treatment history of prior systemic treatment of HCC&#xD;
  &#xD;
            -  Liver transplant recipients&#xD;
  &#xD;
            -  Patients with peptic ulcer, untreated or incompletely treated varices with bleeding or&#xD;
               high-risk for bleeding&#xD;
  &#xD;
            -  Any serious illness (e.g., active infection or inflammatory condition) or uncontrolled&#xD;
               severe medical comorbidity&#xD;
  &#xD;
            -  A history of treated malignancy (other than HCC) is allowable if the patient's&#xD;
               malignancy has been in complete remission, off chemotherapy and without additional&#xD;
               surgical intervention, during the preceding two years&#xD;
  &#xD;
            -  Abdominal/pelvic radiotherapy within 28 days prior to initiation of study treatment,&#xD;
               except palliative radiotherapy to bone lesions within 7 days prior to initiation of&#xD;
               study treatment&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>20 Years</minimum_age>
      <maximum_age>79 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Ju Hyun Shim</last_name>
      <role>Principal Investigator</role>
      <affiliation>Asan Medical Center</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Jihyun An</last_name>
      <phone>82-31-560-2209</phone>
      <email>starlit1@naver.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Ju Hyun Shim</last_name>
      <email>s5854@amc.seoul.kr</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Asan Medical Center</name>
        <address>
          <city>Seoul</city>
          <country>Korea, Republic of</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Ju Hyun Shim</last_name>
      </contact>
    </location>
    <location_countries>
      <country>Korea, Republic of</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 27, 2023</study_first_submitted>
    <study_first_submitted_qc>August 7, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 15, 2023</study_first_posted>
    <last_update_submitted>August 7, 2023</last_update_submitted>
    <last_update_submitted_qc>August 7, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 15, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Asan Medical Center</investigator_affiliation>
      <investigator_full_name>Ju Hyun Shim</investigator_full_name>
      <investigator_title>Principal Investigator</investigator_title>
    </responsible_party>
    <keyword>HCC; vascular invasion; portal vein tumor thrombosis; BCLC stage C</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carcinoma</mesh_term>
      <mesh_term>Carcinoma, Hepatocellular</mesh_term>
      <mesh_term>Liver Neoplasms</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Bevacizumab</mesh_term>
      <mesh_term>Atezolizumab</mesh_term>
      <mesh_term>Antibodies, Monoclonal</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05992220
  org study id: KCT0007365
  secondary id: KCT0007365
  nct id: NCT05992220
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  The recent global IMbrave150 study evaluated the combination of atezolizumab and bevacizumab
        versus sorafenib in 501 patients with advanced or metastatic Hepatocellular Carcinoma (HCC).
        The median overall survival (OS) was notably better in the atezolizumab/bevacizumab group.
        However, for HCC patients with intrahepatic macrovascular invasion (MVI), the prognosis
        remains poor, indicating a significant unmet need in this group.
  
        External Beam Radiotherapy (EBRT) has shown promising results in treating HCC with MVI,
        especially when used in combination with trans-arterial chemoembolization (TACE). It has been
        reported that radiotherapy may make tumor cells more susceptible to immune-mediated therapy,
        potentially enhancing the effects of atezolizumab and bevacizumab.
  
        Thus, this study aims to investigate the efficacy and safety of atezolizumab/bevacizumab
        alone versus atezolizumab/bevacizumab in combination with EBRT in HCC patients with
        macrovascular invasion.
  A total of 138 subjects are randomly assigned to one of two treatment groups (69 patients in
        the atezolizumab+bevacizumab group and 69 patients in the Atezolizumab plus Bevacizumab
        combined EBRT group).
  
          -  Radiotherapy combination:
  
               -  Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.
  
               -  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.
  
               -  The external beam radiotherapy will commence after day 2 of the first cycle of
                  Atezolizumab+Bevacizumab, and will be delivered in accordance with institutional
                  protocol.
  
          -  Atezolizumab+Bevacizumab:
  
               -  Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.
  
               -  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.
  
        Additional study identifiers: This study was also registered on the WHO's International
        Clinical Trials Registry Platform, CRIS, before the first participant was enrolled (ID:
        KCT0007365, Date of registration: 2022-06-08).
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: randomized, multicenter, open-label study
  primary purpose: Treatment
  masking: None (Open Label)
  measure: progression-free survival rate
  time frame: up to approximately 3 years
  description: Randomization to the first occurrence of disease progression or death from any cause, whichever occurs first
  measure: Overall survival rate
  time frame: up to approximately 3 years
  description: Randomization to death from any cause, through the end of study
  measure: Objective response
  time frame: up to approximately 3 years
  description: complete response or partial response as determined by the Investigator according to RECIST V1.1
  measure: Adverse reaction rate
  time frame: through study completion, up to approximately 3 years
  description: Adverse reaction rate assessed by CTCAE version 5
  measure: Time to deterioration
  time frame: through study completion, up to approximately 3 years
  description: The time from randomization to first deterioration (decrease from baseline of ≥10 points) in the patient-reported global health status (GHS) / Quality of life (QoL), physical function, or role function scales of the EORTC QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks
  measure: Duration of response
  time frame: up to approximately 3 years
  description: the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression or death is documented, whichever occurs first. DOR will be assessed in patients who had an objective response.
  measure: Tumor marker response (AFP, PIVKA-II)
  time frame: through study completion, up to approximately 3 years
  description: The decrease of >20% in serum concentration of each marker from baseline across all time points during study period.
  arm group label: Radiotherapy combination
  arm group type: Experimental
  description: Atezolizumab+Bevacizumab, combined EBRT to vascular invasion
  Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.
  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.
  The external beam radiotherapy will commence after day 2 of the first cycle of A+B, and will be delivered in accordance with institutional protocol.
  arm group label: Atezolizumab+Bevacizumab
  arm group type: Active Comparator
  description: Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle.
  Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.
  intervention type: Radiation
  intervention name: Atezolizumab plus bevacizumab, combined EBRT to vascular invasion
  description: The external beam radiotherapy will commence after day 2 of the first cycle of atezolizumab+bevacizumab, and will be delivered in accordance with institutional protocol.
  3D-conformal radiotherapy technique is used to determine target volumes, radiation ports, and dose prescriptions by using a 3D radiotherapy planning system.
  The gross tumor volume (GTV) includes vascular invasion and a 2-cm margin into the contiguous HCC. The GTV can consist of the entire HCC and vascular invasion at the discretion of the investigator.
  The target dose is 45 Gy, however, the total dose can be reduced as low as 30 Gy according to the liver function, liver volumes, or the maximum dose to the stomach/duodenum during the planning process according to the judgment of the radiation oncologist of each participating sites.
  arm group label: Radiotherapy combination
  intervention type: Drug
  intervention name: Atezolizumab plus bevacizumab
  description: Atezolizumab plus bevacizumab q3w
  arm group label: Atezolizumab+Bevacizumab
  criteria: 
  gender: All
  minimum age: 20 Years
  maximum age: 79 Years
  healthy volunteers: No
  last name: Ju Hyun Shim
  role: Principal Investigator
  affiliation: Asan Medical Center
  last name: Jihyun An
  phone: 82-31-560-2209
  email: starlit1@naver.com
  last name: Ju Hyun Shim
  email: s5854@amc.seoul.kr
  facility: 
  status: Recruiting
  contact: 
  country: Korea, Republic of
  responsible party type: Principal Investigator
  investigator affiliation: Asan Medical Center
  investigator full name: Ju Hyun Shim
  investigator title: Principal Investigator
  mesh term: Carcinoma
  mesh term: Carcinoma, Hepatocellular
  mesh term: Liver Neoplasms
  mesh term: Bevacizumab
  mesh term: Atezolizumab
  mesh term: Antibodies, Monoclonal