<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/NCT04463368</url>
  </required_header>
  <id_info>
    <org_study_id>CA184-587</org_study_id>
    <nct_id>NCT04463368</nct_id>
  </id_info>
  <brief_title>Isolated Hepatic Perfusion in Combination With Ipilimumab and Nivolumab in Patients With Uveal Melanoma Metastases</brief_title>
  <acronym>SCANDIUM II</acronym>
  <official_title>SCANDIUM II Trial - A Phase I Randomized Controlled Multicentre Trial of Isolated Hepatic Perfusion in Combination With Ipilimumab and Nivolumab in Patients With Uveal Melanoma Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sahlgrenska University Hospital, Sweden</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sahlgrenska University Hospital, Sweden</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Uveal melanoma is the most common primary intraocular malignancy in adults. Despite&#xD;
      successful control of the primary tumour, metastatic disease will develop in approximately&#xD;
      35%-50% of the patients within 10 years. The liver is the most common site for metastases,&#xD;
      and about 50% of the patients will have isolated liver metastases. Isolated hepatic perfusion&#xD;
      is a regional treatment where the liver is completely isolated from the systemic circulation,&#xD;
      allowing a high concentration of chemotherapy to be perfused through the liver with minimal&#xD;
      systemic exposure. The introduction of modern immunotherapy in the treatment arsenal for&#xD;
      cutaneous melanoma also creates hope for patients with uveal melanoma metastases. However,&#xD;
      the results of immunotherapy have so far been disappointing. The reason for the low efficacy&#xD;
      could be that uveal melanoma develops in the immune privileged eye.&#xD;
&#xD;
      The hypothesis in this trial is that isolated hepatic perfusion with melphalan causes an&#xD;
      immunogenic type of cell death by local tumour destruction while leaving the immune-system&#xD;
      intact. This will cause an activation of the immune-system and the addition of ipilimumab and&#xD;
      nivolumab will enhance this effect, ultimately increasing the treatment efficacy.&#xD;
&#xD;
      The primary objective of this trial is to evaluate the safety and tolerability of isolated&#xD;
      hepatic perfusion together with ipilimumab and nivolumab when given at the same time or as a&#xD;
      sequenced regimen. The study design is a phase I randomized controlled, multicentre,&#xD;
      open-label trial. Active follow-up will be performed for 2 years. Patients will be randomized&#xD;
      after diagnoses of metastatic disease to one of the following treatment arms:&#xD;
&#xD;
      Arm A. Patients will be treated with IHP followed by 4 courses of ipilimumab 3mg/kg and&#xD;
      nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.&#xD;
&#xD;
      Arm B. Patients will be treated with 1 course of ipilimumab 3mg/kg and nivolumab 1mg/kg&#xD;
      followed by IHP after 3 weeks and then another 3 courses of ipilimumab 3mg/kg and nivolumab&#xD;
      1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 8, 2021</start_date>
  <completion_date type="Anticipated">September 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">August 10, 2023</primary_completion_date>
  <phase>Phase 1</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)</measure>
    <time_frame>1 year</time_frame>
    <description>Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of objective response rate (ORR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical benefit rate (CBR)</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of clinical benefit rate (CBR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of progression-free survival (PFS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hepatic progression-free survival (hPFS)</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of hepatic progression-free survival (hPFS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of overall survival (OS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to response (TTR)</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of time to response (TTR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>2 years</time_frame>
    <description>Evaluation of duration of response (DOR)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Uveal Melanoma</condition>
  <condition>Liver Metastases</condition>
  <arm_group>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be treated with IHP followed by 4 courses of ipilimumab 3mg/kg and nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be treated with 1 course of ipilimumab 3mg/kg and nivolumab 1mg/kg followed by IHP after 3 weeks and then another 3 courses of ipilimumab 3mg/kg and nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Isolated hepatic perfusion</intervention_name>
    <description>The procedure is performed under general anaesthesia. The caval vein is isolated infrahepatically above the renal veins and suprahepatically between the diaphragm and the pericardium. A catheter is placed in the retrohepatic portion of the caval vein for perfusion outflow. The portal vein is clamped and the proper hepatic artery is cannulated via the gastroduodenal artery. The liver perfusion is performed at a rate of 8- 9 ml/kg/min with a target liver temperature of 40 degrees Celsius. The leakage from the system was continuously recorded using Technetium labelled albumin (Vasculosis) injected into the perfusion circuit. Melphalan (1 mg/kg bodyweight divided into two doses, given 30 minutes apart) is added to the perfusion system. The perfusion is then continued for 60 minutes, after which the perfusion was discontinued.</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>4 courses of ipilimumab 3mg/kg every third week</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>4 courses of nivolumab 1mg/kg every third week</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Patient is ≥18 years of age on the day of signing informed consent&#xD;
&#xD;
          2. Patient is willing and able to provide written informed consent and comply with study&#xD;
             procedures. Written informed consent must be signed and dated before the start of&#xD;
             specific protocol procedures&#xD;
&#xD;
          3. Patient must have a histologically confirmed diagnosis of stage IV uveal melanoma. If&#xD;
             tissue biopsy is judged not feasible by the investigator, cytological diagnosis from&#xD;
             fine needle aspiration (FNA) will be accepted&#xD;
&#xD;
          4. Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per&#xD;
             RECIST 1.1 criteria with at least one target lesion identified in the liver.&#xD;
&#xD;
          5. ECOG performance status of 0 or 1&#xD;
&#xD;
          6. No previous immunotherapy for uveal melanoma metastases.&#xD;
&#xD;
          7. Female patient of childbearing potential should have a negative urine or serum&#xD;
             pregnancy test within 72 hours prior to receiving the first treatment. If the urine&#xD;
             test is positive or cannot be confirmed as negative, a serum pregnancy test will be&#xD;
             required&#xD;
&#xD;
          8. Female patients of childbearing potential must be willing to use an adequate method of&#xD;
             contraception, for the course of the study through 120 days after the last dose of&#xD;
             study medication. Note: Abstinence is acceptable if this is the usual lifestyle and&#xD;
             preferred contraception for the subject&#xD;
&#xD;
          9. Male patients of childbearing potential must agree to use an adequate method of&#xD;
             contraception, starting with the first dose of study therapy through 120 days after&#xD;
             the last dose of study therapy. Abstinence is acceptable if this is the usual&#xD;
             lifestyle and preferred contraception for the subject&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Life expectancy of less than 3 months&#xD;
&#xD;
          2. Body mass index above 35&#xD;
&#xD;
          3. More than 50% of the liver volume replaced by tumor as measured by CT or MRI&#xD;
&#xD;
          4. Known congestive heart failure with an LVEF &lt;40%&#xD;
&#xD;
          5. COPD or other chronic pulmonary disease with PFT's indicating an FEV&lt; 50% predicted&#xD;
             for age&#xD;
&#xD;
          6. Interstitial lung disease (ILD) or (non-infectious) pneumonitis&#xD;
&#xD;
          7. Reduced renal function defined as S-Creatinine &gt;=1.5xULN or Creatinine Clearance &lt; 40&#xD;
             mL/min, calculated using the Cockroft and Gault formula&#xD;
&#xD;
          8. Reduced hepatic function (defined as AST, ALT, bilirubin&gt;3*ULN and PK-INR&gt;1.5) or&#xD;
             medical history of liver cirrhosis or portal hypertension&#xD;
&#xD;
          9. Hemoglobin &lt;90 g/L or platelets &lt;100x109/L or neutrophils &lt;1.5x109/L&#xD;
&#xD;
         10. Use of live vaccines four weeks before or after the last study treatment&#xD;
&#xD;
         11. History of severe hypersensitivity reactions to mAbs&#xD;
&#xD;
         12. Known human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome&#xD;
             (AIDS), hepatitis B or hepatitis C&#xD;
&#xD;
         13. Active autoimmune disease or a history of known or suspected autoimmune disease&#xD;
&#xD;
         14. A condition requiring systemic treatment with either corticosteroids (&gt;10 mg daily&#xD;
             prednisone equivalents) or other immunosuppressive medications within 14 days of study&#xD;
             drug administration. Inhaled or topical steroids and adrenal replacement doses &gt;10 mg&#xD;
             daily prednisone equivalents are permitted in the absence of active autoimmune&#xD;
             disease.&#xD;
&#xD;
         15. Concomitant therapy with any other anti-cancer therapy, concurrent medical conditions&#xD;
             requiring use of immunosuppressive medications or use of other investigational drugs&#xD;
&#xD;
         16. Has a known additional malignancy that is progressing or requires active treatment.&#xD;
&#xD;
         17. Pregnant or breastfeeding or expecting to conceive or father children within the&#xD;
             projected duration of the study, starting with the screening visit through 120 days&#xD;
             after the last dose of study drug.&#xD;
&#xD;
         18. A history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the study, interfere with the patient's&#xD;
             participation for the full duration of the study, or is not in the best interest of&#xD;
             the patient to participate, in the opinion of the treating investigator&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Sahlgrenska University Hospital</name>
      <address>
        <city>Gothenburg</city>
        <zip>413 45</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>July 5, 2020</study_first_submitted>
  <study_first_submitted_qc>July 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <last_update_submitted>October 26, 2022</last_update_submitted>
  <last_update_submitted_qc>October 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sahlgrenska University Hospital, Sweden</investigator_affiliation>
    <investigator_full_name>Roger Olofsson Bagge, MD, PhD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Uveal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</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/NCT04463368
org study id: CA184-587
nct id: NCT04463368
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Uveal melanoma is the most common primary intraocular malignancy in adults. Despite
      successful control of the primary tumour, metastatic disease will develop in approximately
      35%-50% of the patients within 10 years. The liver is the most common site for metastases,
      and about 50% of the patients will have isolated liver metastases. Isolated hepatic perfusion
      is a regional treatment where the liver is completely isolated from the systemic circulation,
      allowing a high concentration of chemotherapy to be perfused through the liver with minimal
      systemic exposure. The introduction of modern immunotherapy in the treatment arsenal for
      cutaneous melanoma also creates hope for patients with uveal melanoma metastases. However,
      the results of immunotherapy have so far been disappointing. The reason for the low efficacy
      could be that uveal melanoma develops in the immune privileged eye.

      The hypothesis in this trial is that isolated hepatic perfusion with melphalan causes an
      immunogenic type of cell death by local tumour destruction while leaving the immune-system
      intact. This will cause an activation of the immune-system and the addition of ipilimumab and
      nivolumab will enhance this effect, ultimately increasing the treatment efficacy.

      The primary objective of this trial is to evaluate the safety and tolerability of isolated
      hepatic perfusion together with ipilimumab and nivolumab when given at the same time or as a
      sequenced regimen. The study design is a phase I randomized controlled, multicentre,
      open-label trial. Active follow-up will be performed for 2 years. Patients will be randomized
      after diagnoses of metastatic disease to one of the following treatment arms:

      Arm A. Patients will be treated with IHP followed by 4 courses of ipilimumab 3mg/kg and
      nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.

      Arm B. Patients will be treated with 1 course of ipilimumab 3mg/kg and nivolumab 1mg/kg
      followed by IHP after 3 weeks and then another 3 courses of ipilimumab 3mg/kg and nivolumab
      1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
time frame: 1 year
description: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
measure: Objective response rate (ORR)
time frame: 2 years
description: Evaluation of objective response rate (ORR)
measure: Clinical benefit rate (CBR)
time frame: 2 years
description: Evaluation of clinical benefit rate (CBR)
measure: Progression-free survival (PFS)
time frame: 2 years
description: Evaluation of progression-free survival (PFS)
measure: Hepatic progression-free survival (hPFS)
time frame: 2 years
description: Evaluation of hepatic progression-free survival (hPFS)
measure: Overall survival (OS)
time frame: 2 years
description: Evaluation of overall survival (OS)
measure: Time to response (TTR)
time frame: 2 years
description: Evaluation of time to response (TTR)
measure: Duration of response (DOR)
time frame: 2 years
description: Evaluation of duration of response (DOR)
arm group label: Arm A
arm group type: Experimental
description: Patients will be treated with IHP followed by 4 courses of ipilimumab 3mg/kg and nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.
arm group label: Arm B
arm group type: Experimental
description: Patients will be treated with 1 course of ipilimumab 3mg/kg and nivolumab 1mg/kg followed by IHP after 3 weeks and then another 3 courses of ipilimumab 3mg/kg and nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.
intervention type: Procedure
intervention name: Isolated hepatic perfusion
description: The procedure is performed under general anaesthesia. The caval vein is isolated infrahepatically above the renal veins and suprahepatically between the diaphragm and the pericardium. A catheter is placed in the retrohepatic portion of the caval vein for perfusion outflow. The portal vein is clamped and the proper hepatic artery is cannulated via the gastroduodenal artery. The liver perfusion is performed at a rate of 8- 9 ml/kg/min with a target liver temperature of 40 degrees Celsius. The leakage from the system was continuously recorded using Technetium labelled albumin (Vasculosis) injected into the perfusion circuit. Melphalan (1 mg/kg bodyweight divided into two doses, given 30 minutes apart) is added to the perfusion system. The perfusion is then continued for 60 minutes, after which the perfusion was discontinued.
arm group label: Arm A
arm group label: Arm B
intervention type: Drug
intervention name: Ipilimumab
description: 4 courses of ipilimumab 3mg/kg every third week
arm group label: Arm A
arm group label: Arm B
intervention type: Drug
intervention name: Nivolumab
description: 4 courses of nivolumab 1mg/kg every third week
arm group label: Arm A
arm group label: Arm B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Sweden
responsible party type: Principal Investigator
investigator affiliation: Sahlgrenska University Hospital, Sweden
investigator full name: Roger Olofsson Bagge, MD, PhD
investigator title: Principal Investigator
mesh term: Melanoma
mesh term: Neoplasm Metastasis
mesh term: Uveal Neoplasms
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: Undecided