<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/NCT03841201</url>
  </required_header>
  <id_info>
    <org_study_id>IMMUNIB</org_study_id>
    <nct_id>NCT03841201</nct_id>
  </id_info>
  <brief_title>Immunotherapy With Nivolumab in Combination With Lenvatinib for Advanced Stage Hepatocellular Carcinoma</brief_title>
  <official_title>IMMUNIB - An Open-label, Single-arm Phase II Study of Immunotherapy With Nivolumab in Combination With Lenvatinib for Advanced Stage Hepatocellular</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Eisai GmbH</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest</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>
      This is an exploratory, open-label, single arm, multicenter phase II trial for the evaluation&#xD;
      of efficacy and feasibility (as determined by safety and tolerability) of immunotherapy with&#xD;
      nivolumab in combination with lenvatinib for patients with multinodular, advanced stage&#xD;
      hepatocellular carcinoma in first line therapy&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 12, 2019</start_date>
  <completion_date type="Actual">May 2, 2023</completion_date>
  <primary_completion_date type="Actual">October 27, 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>
    <intervention_model_description>Open-label, single-arm, multicenter phase II trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective response rate (ORR) according to RECIST 1.1</measure>
    <time_frame>6 months</time_frame>
    <description>Number and percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety and tolerability (AEs, SAEs according to NCI-CTCAE V 4.03)</measure>
    <time_frame>6 months</time_frame>
    <description>Type, incidence and severity of AEs, SAEs according to NCI-CTCAE V 4.03</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR) according to iRECIST</measure>
    <time_frame>6 months</time_frame>
    <description>Number and percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) according to iRECIST</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time-to-progression (TTP)</measure>
    <time_frame>6 months</time_frame>
    <description>Time from the date of treatment allocation to the date of first observed disease progression (investigator assessment according to RECIST 1.1).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>6 months</time_frame>
    <description>Time from the date of treatment allocation to the date of first observed disease progression (investigator assessment according to RECIST 1.1) or death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>6 months</time_frame>
    <description>Time from the date of treatment allocation to the date of death (due to any cause).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Translational research</measure>
    <time_frame>6 months</time_frame>
    <description>Correlation of biomarkers potentially associated with clinical efficacy (OS, PFS and ORR) from lenvatinib plus nivolumab by molecular quantitation of mRNA expression of parameters like e.g. PD-1, PD-L1 and PD-L2, immune cell infiltrates (IGHM, CD3, CD8, FOXP3, CD68, CD205), chemokines (CXCL9, CXCL10, CXCL13) and invasion markers (MMP7, MMP9).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Advanced Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lenvatinib peroral qd (8 mg for patients with body weight &lt;60kg and 12 mg for patients with body weight ≥ 60kg)&#xD;
Nivolumab i.v. q2w (240mg fixed dose IV) max. 36 cycles</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenvatinib</intervention_name>
    <description>oral</description>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Study treatment</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>iv infusion</description>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Study treatment</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Fully-informed written consent.&#xD;
&#xD;
          2. Males and females ≥ 18 years of age&#xD;
&#xD;
             *There are no data that indicate special gender distribution. Therefore patients will&#xD;
             be enrolled in the study gender-independently.&#xD;
&#xD;
          3. Unresectable, multinodular tumour, not eligible for resection or local ablation&#xD;
&#xD;
          4. Histologically confirmed diagnosis of hepatocellular carcinoma&#xD;
&#xD;
          5. Has a Child-Pugh Classification score ≤ 6 for assessed liver function within 7 days&#xD;
             before allocation (Appendix 4: Child-Pugh Score)&#xD;
&#xD;
          6. At least one measurable site of disease as defined by RECIST 1.1 criteria with spiral&#xD;
             CT scan or MRI.&#xD;
&#xD;
          7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.&#xD;
&#xD;
          8. Life expectancy of at least 12 weeks.&#xD;
&#xD;
          9. Adequate bone marrow, hepatic and renal function including the following:&#xD;
&#xD;
               -  Haemoglobin ≥ 10.0 g/dL, absolute neutrophil count ≥ 1,500 /µL, platelets ≥70,000&#xD;
                  /µL;&#xD;
&#xD;
               -  Total bilirubin ≤ 3.0 mg/dL upper normal limit;&#xD;
&#xD;
               -  AST (SGOT), ALT (SGPT) ≤ 5 x upper normal limit;&#xD;
&#xD;
               -  International normalized ratio (INR) ≤1.25;&#xD;
&#xD;
               -  Albumin ≥ 30 g/dL;&#xD;
&#xD;
               -  Creatinine ≤ 1.5 x upper normal limit OR measured or calculated creatinine&#xD;
                  clearance (according to Cockcroft-Gault) ≥30 mL/min for participant with&#xD;
                  creatinine levels &gt;1.5 × institutional ULN (GFR can also be used in place of&#xD;
                  creatinine or CrCl)&#xD;
&#xD;
         10. Female patients with reproductive potential must have a negative urine or serum&#xD;
             pregnancy test within 7 days prior to start of trial. Women must not be breastfeeding.&#xD;
&#xD;
         11. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV)&#xD;
             infection, meets the following criteria:&#xD;
&#xD;
               -  Patients with HBV or HCV infection should be monitored for viral levels during&#xD;
                  study participation.&#xD;
&#xD;
               -  Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV&#xD;
                  DNA should have HBV DNA &lt; 100 IU/ml and should be managed per local treatment&#xD;
                  guidelines.&#xD;
&#xD;
             Controlled (treated) hepatitis B subjects will be allowed if they started treatment at&#xD;
             the time point of enrollment into the study by the latest and treatment is continued&#xD;
             during study participation and for ≥ 6 months after end of study treatment.&#xD;
&#xD;
             - HCV patients with with advanced HCC are mostly not treated for their HCV infection.&#xD;
             However, patients treated for HCV are considered suitable for inclusion if antiviral&#xD;
             therapy has been completed ≥ 30 days prior to first administration of study drug.&#xD;
&#xD;
         12. The patient is willing and able to comply with the protocol for the duration of the&#xD;
             study, including hospital visits for treatment and scheduled follow-up visits and&#xD;
             examinations.&#xD;
&#xD;
         13. WOCBP must agree to follow instructions for method(s) of contraception for a period of&#xD;
             30 days (duration of ovulatory cycle) plus the time required for the investigational&#xD;
             drug to undergo 5 half-lives. The terminal half-lives of nivolumab is approximately 25&#xD;
             days. WOCBP should use an adequate method to avoid pregnancy for approximately 5&#xD;
             months (30 days plus the time required for nivolumab to undergo 5 half-lives) after&#xD;
             the last dose of investigational drug.&#xD;
&#xD;
         14. Males who are sexually active with WOCBP must agree to follow instructions for&#xD;
             method(s) of contraception for a period of 90 days (duration of sperm turnover) plus&#xD;
             the time required for the investigational drug to undergo 5 half-lives. The terminal&#xD;
             half-lives of nivolumab is approximately 25 days. Males who are sexually active with&#xD;
             WOCBP must continue contraception for approximately 7 months (90 days plus the time&#xD;
             required for nivolumab to undergo 5 half-lives) after the last dose of investigational&#xD;
             drug. In addition, male subjects must be willing to refrain from sperm donation during&#xD;
             this time.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous systemic therapy in the first-line setting.&#xD;
&#xD;
          2. Patients on a liver transplantation list or with advanced liver disease as defined&#xD;
             below:&#xD;
&#xD;
               -  Encephalopathy&#xD;
&#xD;
               -  Untreatable Ascites.&#xD;
&#xD;
          3. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.&#xD;
&#xD;
          4. Prior organ allograft or allogeneic bone marrow transplantation.&#xD;
&#xD;
          5. Local therapies ongoing or completed &lt;4 weeks prior to the baseline scan.&#xD;
&#xD;
          6. Thrombotic or embolic events such as cerebrovascular accident (including transient&#xD;
             ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months&#xD;
             prior to the first dose of study drug with the exception of thrombosis of a segmental&#xD;
             portal vein.&#xD;
&#xD;
          7. Prior, systemic anti-cancer chemotherapy, radiotherapy administered &lt;4 weeks prior to&#xD;
             study entry, endocrine- or immunotherapy or use of other investigational agents.&#xD;
&#xD;
          8. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.&#xD;
&#xD;
          9. Major surgery within 4 weeks of starting the study. Patients must have recovered from&#xD;
             effects of major surgery.&#xD;
&#xD;
         10. Malignancies other than disease under study within 5 years prior to inclusion, with&#xD;
             the exception of those with a negligible risk of metastasis or death (e.g., expected&#xD;
             5-year OS &gt; 90%) treated with expected curative outcome (such as adequately treated&#xD;
             carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized&#xD;
             prostate cancer treated surgically with curative intent, ductal carcinoma in situ&#xD;
             treated surgically with curative intent)&#xD;
&#xD;
         11. Uncontrolled hypertension.&#xD;
&#xD;
         12. Clinically significant cardiovascular disease.&#xD;
&#xD;
         13. Any serious or uncontrolled medical disorder or active infection that, in the opinion&#xD;
             of the investigator, may increase the risk associated with study participation, study&#xD;
             drug administration, or would impair the ability of the subject to receive study drug.&#xD;
&#xD;
         14. Proteinuria (≥2g/24h)&#xD;
&#xD;
         15. Psychiatric disorders or altered mental status precluding understanding of the&#xD;
             informed consent process and/or compliance with the study protocol.&#xD;
&#xD;
         16. Subjects with a history of or current CNS metastases. A scan to confirm the absence of&#xD;
             brain metastases is not required. Patients with unknown CNS metastatic status and any&#xD;
             clinical signs indicative of CNS metastases are eligible if CNS metastases are&#xD;
             excluded using CT and/or MRI scans.&#xD;
&#xD;
         17. Pregnant or breast-feeding women.&#xD;
&#xD;
         18. Immunocompromised patients, e.g. patients who are known to be serologically positive&#xD;
             for human immunodeficiency virus (HIV).&#xD;
&#xD;
         19. Subjects with active, known, or suspected autoimmune disease. Subjects with Type I&#xD;
             diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only&#xD;
             requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or&#xD;
             alopecia) not requiring systemic treatment are permitted to enroll. For any cases of&#xD;
             uncertainty, it is recommended that the medical monitor be consulted prior to signing&#xD;
             informed consent.&#xD;
&#xD;
         20. Subjects with a condition requiring systemic treatment with either corticosteroids (&gt;&#xD;
             10 mg daily prednisone equivalents) or other immunosuppressive medications within 14&#xD;
             days of study drug administration. Inhaled or topical steroids, and adrenal&#xD;
             replacement doses &gt; 10 mg daily prednisone equivalents are permitted in the absence of&#xD;
             active autoimmune disease.&#xD;
&#xD;
         21. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4&#xD;
             antibody, or any other antibody or drug specifically targeting T-cell co-stimulation&#xD;
             or checkpoint pathways.&#xD;
&#xD;
         22. All toxicities attributed to prior anti-cancer therapy other than hearing loss,&#xD;
             alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4.03) or&#xD;
             baseline before administration of study drug.&#xD;
&#xD;
         23. &gt; Grade 1 peripheral neuropathy according to CTCAE version 4.03&#xD;
&#xD;
         24. Patients who have received a live vaccine within 30 days prior to enrolment.&#xD;
&#xD;
         25. History of allergy or hypersensitivity to study drugs or any constituent of the&#xD;
             products&#xD;
&#xD;
         26. Is currently participating in or has participated in a study of an investigational&#xD;
             agent or has used an investigational device within 4 weeks prior to the first dose of&#xD;
             study treatment.&#xD;
&#xD;
         27. Patient who has been incarcerated or involuntarily institutionalized by court order or&#xD;
             by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.&#xD;
&#xD;
         28. Patients who are unable to consent because they do not understand the nature,&#xD;
             significance and implications of the clinical trial and therefore cannot form a&#xD;
             rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Salah-Eddin Al-Batran, MD</last_name>
    <role>Study Director</role>
    <affiliation>Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hannover Medical School</name>
      <address>
        <city>Hannover</city>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>February 12, 2019</study_first_submitted>
  <study_first_submitted_qc>February 13, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <last_update_submitted>May 11, 2023</last_update_submitted>
  <last_update_submitted_qc>May 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 12, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>hepatocellular carcinoma</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Lenvatinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No IPD will be shared</ipd_description>
  </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/NCT03841201
org study id: IMMUNIB
nct id: NCT03841201
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This is an exploratory, open-label, single arm, multicenter phase II trial for the evaluation
      of efficacy and feasibility (as determined by safety and tolerability) of immunotherapy with
      nivolumab in combination with lenvatinib for patients with multinodular, advanced stage
      hepatocellular carcinoma in first line therapy
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Open-label, single-arm, multicenter phase II trial
primary purpose: Treatment
masking: None (Open Label)
measure: Objective response rate (ORR) according to RECIST 1.1
time frame: 6 months
description: Number and percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1
measure: Safety and tolerability (AEs, SAEs according to NCI-CTCAE V 4.03)
time frame: 6 months
description: Type, incidence and severity of AEs, SAEs according to NCI-CTCAE V 4.03
measure: Objective response rate (ORR) according to iRECIST
time frame: 6 months
description: Number and percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) according to iRECIST
measure: Time-to-progression (TTP)
time frame: 6 months
description: Time from the date of treatment allocation to the date of first observed disease progression (investigator assessment according to RECIST 1.1).
measure: Progression free survival (PFS)
time frame: 6 months
description: Time from the date of treatment allocation to the date of first observed disease progression (investigator assessment according to RECIST 1.1) or death from any cause.
measure: Overall survival (OS)
time frame: 6 months
description: Time from the date of treatment allocation to the date of death (due to any cause).
measure: Translational research
time frame: 6 months
description: Correlation of biomarkers potentially associated with clinical efficacy (OS, PFS and ORR) from lenvatinib plus nivolumab by molecular quantitation of mRNA expression of parameters like e.g. PD-1, PD-L1 and PD-L2, immune cell infiltrates (IGHM, CD3, CD8, FOXP3, CD68, CD205), chemokines (CXCL9, CXCL10, CXCL13) and invasion markers (MMP7, MMP9).
arm group label: Treatment
arm group type: Experimental
description: Lenvatinib peroral qd (8 mg for patients with body weight <60kg and 12 mg for patients with body weight ≥ 60kg)
Nivolumab i.v. q2w (240mg fixed dose IV) max. 36 cycles
intervention type: Drug
intervention name: Lenvatinib
description: oral
arm group label: Treatment
other name: Study treatment
intervention type: Drug
intervention name: Nivolumab
description: iv infusion
arm group label: Treatment
other name: Study treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Salah-Eddin Al-Batran, MD
role: Study Director
affiliation: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Nivolumab
mesh term: Lenvatinib
sharing ipd: No
ipd description: No IPD will be shared