<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/NCT04442581</url>
  </required_header>
  <id_info>
    <org_study_id>RG1007034</org_study_id>
    <secondary_id>NCI-2020-03968</secondary_id>
    <secondary_id>10548</secondary_id>
    <nct_id>NCT04442581</nct_id>
  </id_info>
  <brief_title>Cabozantinib and Pembrolizumab for the First-Line Treatment of Advanced Liver Cancer</brief_title>
  <official_title>A Phase 2 Trial of Cabozantinib and Pembrolizumab in the First-Line Treatment of Advanced Hepatocellular Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Exelixis</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Washington</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well cabozantinib and pembrolizumab work for the first-line&#xD;
      treatment of patients with liver cancer who are not eligible for local therapy (i.e. advanced&#xD;
      stage). Cabozantinib may stop the growth of tumor cells by blocking some cell surface&#xD;
      receptors and signaling pathways inside the tumor cells. Immunotherapy with monoclonal&#xD;
      antibodies, such as pembrolizumab, may help the body's immune system attack the cancer.&#xD;
      Giving cabozantinib and pembrolizumab together may work better in treating patients with&#xD;
      advanced liver cancer compared to cabozantinib or pembrolizumab alone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OUTLINE:&#xD;
&#xD;
      Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-21 and&#xD;
      pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up&#xD;
      to 2 years in the absence of disease progression or unacceptable toxicity. Disease assessment&#xD;
      by imaging will be performed every 9 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Terminated due to slow accrual&#xD;
  </why_stopped>
  <start_date type="Actual">April 20, 2021</start_date>
  <completion_date type="Actual">March 8, 2022</completion_date>
  <primary_completion_date type="Actual">December 13, 2021</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>Number of Participants With Objective Response (Complete or Partial Response)</measure>
    <time_frame>Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.</time_frame>
    <description>Will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (by blinded central review). Assessment of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 of target lesions by cross sectional imaging (either CT or MRI), defined as the following: 1.) Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall Response Rate is defined as percentage of CR + PR.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Disease Control (Complete + Partial Response + Stable Disease)</measure>
    <time_frame>Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.</time_frame>
    <description>Will be assessed per RECIST v1.1 and iRECIST. Assessment of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 of target lesions by cross sectional imaging (either CT or MRI), defined as the following: 1.) Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall Response Rate is defined as percentage of CR + PR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time in Months With Progression-free Survival</measure>
    <time_frame>Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.</time_frame>
    <description>Defined as time from study registration to radiographic progression per RECIST v1.1 (blinded central assessment), clinical progression, or death of any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival Time in Months</measure>
    <time_frame>Survival assessed from study registration through study completion, 10 months 16 days.</time_frame>
    <description>Defined as time from study registration to death of any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events</measure>
    <time_frame>Adverse events monitored from time of informed consent through the last follow-up visit or 30 days after the date of the last dose of cabozantinib or pembrolizumab treatment, whichever occurs last, up to 10 months 16 days</time_frame>
    <description>Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Advanced Hepatocellular Carcinoma</condition>
  <condition>BCLC Stage B Hepatocellular Carcinoma</condition>
  <condition>BCLC Stage C Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment (cabozantinib S-malate, pembrolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabozantinib S-malate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (cabozantinib S-malate, pembrolizumab)</arm_group_label>
    <other_name>BMS-907351</other_name>
    <other_name>Cabometyx</other_name>
    <other_name>Cometriq</other_name>
    <other_name>XL-184</other_name>
    <other_name>XL184</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (cabozantinib S-malate, pembrolizumab)</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>Lambrolizumab</other_name>
    <other_name>MK-3475</other_name>
    <other_name>SCH 900475</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Must have a histologically confirmed diagnosis of HCC or a non-invasive diagnosis of&#xD;
             HCC as per the American Association for the Study of Liver Diseases (AASLD) criteria&#xD;
&#xD;
               -  If available, archival tissue must be submitted&#xD;
&#xD;
               -  Mixed HCC-cholangiocarcinoma is not allowed&#xD;
&#xD;
          -  Patient has Barcelona Clinic Liver Cancer (BCLC) stage C disease, or BCLC stage B&#xD;
             disease that is not amenable to locoregional therapy or refractory to locoregional&#xD;
             therapy, and not amenable to curative treatment&#xD;
&#xD;
               -  Previous locoregional therapy is allowed (e.g. surgical resection, external beam&#xD;
                  radiation, catheter-based therapy), and patients must have evidence of disease&#xD;
                  progression from locoregional therapy&#xD;
&#xD;
          -  Must have measurable disease by RECIST v1.1&#xD;
&#xD;
               -  Lesions that were previously radiated or ablated cannot be target lesions unless&#xD;
                  there was subsequent radiographic progression at those sites&#xD;
&#xD;
          -  No prior systemic therapy for HCC. Prior chemotherapy given locally into the liver&#xD;
             (e.g. transarterial chemoembolization [TACE]) is allowed&#xD;
&#xD;
          -  Must have Child-Pugh class A hepatic function within 7 days prior to first dose of&#xD;
             study intervention&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1&#xD;
&#xD;
          -  Life expectancy of at least 12 weeks&#xD;
&#xD;
          -  Recovery to baseline or =&lt; grade 1 toxicities (CTCAE v5) related to any prior&#xD;
             treatments, unless adverse events (AEs) are clinically nonsignificant and/or stable on&#xD;
             supportive therapy&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1500/mm^3 without granulocyte colony-stimulating&#xD;
             factor support (within 14 days before first dose of study treatment)&#xD;
&#xD;
          -  Platelets &gt;= 60,000/mm^3 without transfusion (within 14 days before first dose of&#xD;
             study treatment)&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL (&gt;= 90 g/L) without transfusion or erythropoietin (EPO)&#xD;
             dependency (within 14 days before first dose of study treatment)&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =&lt; 5 x upper limit&#xD;
             of normal (ULN) (within 14 days before first dose of study treatment)&#xD;
&#xD;
          -  Total bilirubin =&lt; 2 mg/dL OR direct bilirubin =&lt; ULN for participants with total&#xD;
             bilirubin levels &gt; 2 mg/dL (within 14 days before first dose of study treatment)&#xD;
&#xD;
          -  Serum albumin &gt;= 2.8 g/dl (&gt;= 28 g/L) without albumin infusion (within 14 days before&#xD;
             first dose of study treatment)&#xD;
&#xD;
          -  Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin&#xD;
             time (PTT) test =&lt; 1.5 x ULN (within 14 days before first dose of study treatment)&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 x ULN or calculated creatinine clearance &gt;= 40 mL/min using&#xD;
             the Cockcroft-Gault equation (within 14 days before first dose of study treatment)&#xD;
&#xD;
          -  Urine protein/creatinine ratio (UPCR) =&lt; 1 mg/mg (=&lt; 113.2 mg/mmol) or 24 hour(h)&#xD;
             urine protein =&lt; 1 g (within 14 days before first dose of study treatment)&#xD;
&#xD;
          -  Hemoglobin A1c (HbA1c) =&lt; 8% within 28 days before randomization or fasting serum&#xD;
             glucose =&lt; 160 mg/dL (within 14 days before first dose of study treatment)&#xD;
&#xD;
          -  Patients with positive hepatitis B surface antigen (HBsAg) and/or hepatitis B virus&#xD;
             (HBV) viral load &gt; 100 IU/mL at the time of enrollment are eligible to enroll on study&#xD;
             if they meet the following criteria:&#xD;
&#xD;
               -  Anti-HBV therapy as per institutional practice must be given at least 4 weeks and&#xD;
                  HBV viral load must be &lt; 100 IU/mL prior to initiating study treatment. Patients&#xD;
                  on active HBV therapy with viral loads &lt; 100 IU/mL should remain on the same&#xD;
                  therapy throughout study treatment&#xD;
&#xD;
               -  Note: Patients with positive anti-hepatitis B core antibody (HBcAb), negative&#xD;
                  HBsAg, and negative or positive anti-hepatitis B surface antibody, and who have&#xD;
                  an HBV viral load &lt; 100 IU/mL do not require anti-viral prophylaxis&#xD;
&#xD;
          -  Patients with past or ongoing hepatitis C infection (HCV) are eligible to enroll on&#xD;
             study, with or without prior anti-viral treatment, as long as the other eligibility&#xD;
             criteria are met. Treated patients must have completed their anti-viral treatment at&#xD;
             least 1 month prior to initiating study treatment&#xD;
&#xD;
          -  Sexually active fertile subjects and their partners must agree to use effective&#xD;
             methods of contraception during the course of the study and for at least 4 months&#xD;
             after the last dose cabozantinib. They must also refrain from donating sperm during&#xD;
             this time period&#xD;
&#xD;
          -  Female subjects of childbearing potential must not be pregnant at screening and not&#xD;
             breastfeeding. Females of childbearing potential are defined as premenopausal females&#xD;
             capable of becoming pregnant (i.e. females who have had any evidence of menses in the&#xD;
             past 12 months, with the exception of those who had prior hysterectomy)&#xD;
&#xD;
               -  Women who have been amenorrheic for 12 or more months are still considered to be&#xD;
                  of childbearing potential if the amenorrhea is possibly due to prior&#xD;
                  chemotherapy, antiestrogens, low body weight, ovarian suppression or other&#xD;
                  reasons&#xD;
&#xD;
          -  Capable of understanding and complying with the protocol requirements and must provide&#xD;
             written informed consent/assent for the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior treatment with any systemic therapy for HCC, including anti-VEGF therapy or any&#xD;
             systemic investigational agent&#xD;
&#xD;
               -  If the patient previously received systemic treatment for reasons other than HCC:&#xD;
                  small molecule kinase inhibitors are not allowed within 2 weeks and&#xD;
                  cytotoxic/biologic agents are not allowed within 4 weeks of study treatment&#xD;
&#xD;
          -  Prior exposure to immune checkpoint inhibitors or other immunotherapeutic agents&#xD;
&#xD;
          -  Currently participating in or has participated in a study of an investigational agent&#xD;
             or device within 4 weeks prior to the first dose of study treatment&#xD;
&#xD;
          -  Major surgery within 6 weeks or minor surgery (e.g. dental extraction) within 10 days&#xD;
             prior to first dose of study treatment&#xD;
&#xD;
               -  Complete wound healing from major surgery must have occurred at least 1 month&#xD;
                  before first dose and from minor surgery (e.g. simple excision, tooth extraction)&#xD;
                  at least 7 days before first dose. Subjects with clinically relevant ongoing&#xD;
                  complications from prior surgery are not eligible&#xD;
&#xD;
          -  Local liver-directed therapy within 4 weeks of initiating study treatment&#xD;
&#xD;
          -  Palliative radiation for the purpose of symptomatic relief to non-liver and&#xD;
             non-central nervous system (CNS) disease within 2 weeks of starting treatment. Other&#xD;
             radiation treatments within 4 weeks of starting treatment&#xD;
&#xD;
               -  Patients must have recovered from all radiation-related toxicities, not require&#xD;
                  corticosteroids, and have not had radiation pneumonitis&#xD;
&#xD;
          -  Prior liver or other allogenic tissue/organ transplantation&#xD;
&#xD;
          -  History of primary immunodeficiency&#xD;
&#xD;
          -  Active autoimmune or inflammatory disease that has required systemic treatment in the&#xD;
             past 2 years (i.e. with use of disease-modifying agents, corticosteroids or&#xD;
             immunosuppressive drugs). This includes, but is not limited to, inflammatory bowel&#xD;
             disease, celiac disease, systemic lupus erythematosus, rheumatoid arthritis,&#xD;
             myasthenia gravis, Graves' disease, etc.&#xD;
&#xD;
               -  The following autoimmune conditions are allowed: vitiligo or alopecia;&#xD;
                  hypothyroidism on stable hormone replacement therapy; psoriasis/eczema not&#xD;
                  requiring systemic treatment&#xD;
&#xD;
               -  Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid&#xD;
                  replacement therapy for adrenal or pituitary insufficiency) is not considered a&#xD;
                  form of systemic treatment and is allowed&#xD;
&#xD;
          -  Chronic use of systemic steroid (in dosing exceeding 10 mg daily of prednisone&#xD;
             equivalent) or immunosuppressive therapy or use within 14 days prior to enrollment&#xD;
&#xD;
               -  The following treatments are allowed: intranasal, inhaled, topical or local&#xD;
                  steroid injections; systemic corticosteroids at physiologic doses equivalent to&#xD;
                  no more than prednisone 10 mg/day; steroids as premedication for contrast dye&#xD;
                  allergy&#xD;
&#xD;
          -  History of (non-infectious) pneumonitis that required steroids or has current&#xD;
             pneumonitis&#xD;
&#xD;
          -  History of hepatic encephalopathy or treatment to prevent or control encephalopathy&#xD;
             within the past 12 months. Subjects on lactulose and/or rifaximin to control hepatic&#xD;
             encephalopathy are not allowed&#xD;
&#xD;
          -  Esophageal or gastric variceal bleeding within the past 6 months. All subjects will be&#xD;
             screened for esophageal varices unless performed in the last 6 months before study&#xD;
             treatment. If varices are present, they should be treated according to institutional&#xD;
             standards before starting study treatment&#xD;
&#xD;
          -  Uncontrolled ascites, clinically significant or symptomatic ascites requiring&#xD;
             paracenteses or increasing doses of diuretics within the past 3 months&#xD;
&#xD;
               -  Patients who are on stable diuretic doses for at least 3 months are eligible if&#xD;
                  they meet other eligibility criteria&#xD;
&#xD;
               -  Asymptomatic ascites detected on imaging are allowed&#xD;
&#xD;
          -  Has known history or any evidence of CNS metastases and/or carcinomatous meningitis.&#xD;
             Subjects with previously treated brain metastases may participate provided they are&#xD;
             asymptomatic and radiologically stable (i.e. without progression for at least 4 weeks&#xD;
             by repeat imaging [which must be performed during study screening], clinically stable,&#xD;
             and without the need steroids for at least 4 weeks prior to first dose of study&#xD;
             treatment)&#xD;
&#xD;
          -  Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin&#xD;
             and factor Xa inhibitors) or platelet inhibitors (e.g. clopidogrel). Allowed&#xD;
             anticoagulants are the following:&#xD;
&#xD;
               -  Low-dose aspirin for cardioprotection (per local applicable guidelines) is&#xD;
                  permitted&#xD;
&#xD;
               -  Low molecular weight heparin (LMWH) is permitted&#xD;
&#xD;
               -  Anticoagulation with therapeutic doses of LMWH is allowed in subjects without&#xD;
                  known brain metastases who are on a stable dose of LMWH for at least 4 weeks&#xD;
                  before first dose of study treatment, and who have had no clinically significant&#xD;
                  hemorrhagic complications from the anticoagulation regimen or the tumor&#xD;
&#xD;
          -  The subject has uncontrolled, significant intercurrent or recent illness including,&#xD;
             but not limited to, the following conditions:&#xD;
&#xD;
               -  Cardiovascular disorders:&#xD;
&#xD;
                    -  Congestive heart failure New York Heart Association class 3 or 4, unstable&#xD;
                       angina pectoris, serious cardiac arrhythmias with risk of hemodynamic&#xD;
                       instability within 12 months before the first dose of study treatment&#xD;
&#xD;
                    -  Uncontrolled hypertension defined as sustained blood pressure (BP) &gt; 150 mm&#xD;
                       Hg systolic or &gt; 95 mm Hg diastolic despite optimal antihypertensive&#xD;
                       treatment, and/or change in antihypertensive medications within 1 week&#xD;
                       before starting treatment. Note: eligibility of a subject receiving 4 or&#xD;
                       more antihypertensive medications prior to study entry will require approval&#xD;
                       from the principal investigator (PI)&#xD;
&#xD;
                    -  Stroke (including transient ischemic attack [TIA]), myocardial infarction&#xD;
                       (MI), or other ischemic event, or arterial thromboembolic within 12 months&#xD;
                       before the first dose&#xD;
&#xD;
                    -  Asymptomatic venous thromboembolic event (e.g. deep venous thrombosis,&#xD;
                       pulmonary embolism) is allowed if the patient has been stable on&#xD;
                       anticoagulation with LMWH for at least 4 weeks&#xD;
&#xD;
               -  Gastrointestinal (GI) disorders including those associated with a high risk of&#xD;
                  perforation or fistula formation:&#xD;
&#xD;
                    -  The subject has evidence of tumor invading the GI tract, active peptic ulcer&#xD;
                       disease, inflammatory bowel disease (e.g. Crohn's disease), GI&#xD;
                       malabsorption, diverticulitis, cholecystitis, symptomatic cholangitis or&#xD;
                       appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct&#xD;
                       or common bile duct, or gastric outlet obstruction&#xD;
&#xD;
                    -  Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal&#xD;
                       abscess within 6 months before first dose&#xD;
&#xD;
                         -  Note: Complete healing of an intra-abdominal abscess must be confirmed&#xD;
                            before first dose&#xD;
&#xD;
               -  Clinically significant hematuria, hematemesis, or hemoptysis of &gt; 0.5 teaspoon&#xD;
                  (2.5 ml) of red blood, other history of significant bleeding (e.g. pulmonary&#xD;
                  hemorrhage) within 12 weeks before first dose, or known thrombotic disorder&#xD;
&#xD;
               -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease&#xD;
                  manifestation&#xD;
&#xD;
               -  Lesions invading any major blood vessels, including main portal vein, inferior&#xD;
                  vena cava, or cardiac involvement of HCC based on imaging&#xD;
&#xD;
                    -  Note: Main and branch portal vein and hepatic vein invasion is allowed&#xD;
&#xD;
               -  Ongoing active infection requiring antibiotics. Antibiotics must be completed at&#xD;
                  least 7 days before initiating study treatment&#xD;
&#xD;
               -  Known active tuberculosis&#xD;
&#xD;
               -  Serious non-healing wound, ulcer, or bone fracture&#xD;
&#xD;
          -  Patients with proteinuria &gt; 1+ on urine dipstick testing will undergo 24-hour urine&#xD;
             collection for quantitative assessment of proteinuria. Participants with urine protein&#xD;
             &gt;= 1 g/24 hours will be ineligible&#xD;
&#xD;
          -  Corrected QT interval calculated by the Fridericia formula (QTcF) &gt; 480 ms per&#xD;
             electrocardiogram (EKG) within 28 days before first dose of study treatment&#xD;
&#xD;
               -  Note: If a single EKG shows a QTcF with an absolute value &gt; 500 ms, two&#xD;
                  additional EKGs at intervals of approximately 3 min must be performed within 30&#xD;
                  min after the initial EKG, and the average of these three consecutive results for&#xD;
                  QTcF will be used to determine eligibility&#xD;
&#xD;
          -  Inability to swallow tablets or any other condition that might interfere with oral&#xD;
             absorption of medications&#xD;
&#xD;
          -  Previously identified allergy or hypersensitivity to study drugs and/or any of their&#xD;
             excipients&#xD;
&#xD;
          -  Ongoing secondary malignancy that is progressing and/or has required active treatment&#xD;
             within the past year. Adjuvant treatment for resected breast cancer is allowed&#xD;
&#xD;
               -  Subjects with basal cell carcinoma of the skin, squamous cell carcinoma or the&#xD;
                  skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that&#xD;
                  have undergone potentially therapy are allowed&#xD;
&#xD;
          -  Has a known history of human immunodeficiency virus (HIV) infection. Note: HIV testing&#xD;
             is not mandated for screening&#xD;
&#xD;
          -  Co-infection with HBV (HBsAg [+] and /or detectable HBV DNA) and HCV (anti-HCV Ab [+]&#xD;
             and detectable HCV ribonucleic acid [RNA]) at study entry&#xD;
&#xD;
          -  Co-infection with HBV and hepatitis D virus (HDV) at study entry&#xD;
&#xD;
          -  Live attenuated vaccine within 30 days prior to first dose of study treatment.&#xD;
             Examples of live vaccines include, but are not limited to, the following: measles,&#xD;
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus&#xD;
             Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection&#xD;
             are generally killed virus vaccines and are allowed; however, intranasal influenza&#xD;
             vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed&#xD;
&#xD;
          -  Pregnant or lactating females&#xD;
&#xD;
          -  Known psychiatric illness, substance abuse disorder, or other condition that would&#xD;
             interfere with the ability to comply with the requirements of the study&#xD;
&#xD;
          -  Has history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the study, interfere with the subject's&#xD;
             participation for the full duration of the study, or is not in the best interest of&#xD;
             the subject 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>
  <overall_official>
    <last_name>Gentry George King</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fred Hutch/University of Washington Cancer Consortium</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Fred Hutch/University of Washington Cancer Consortium</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>June 18, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 22, 2020</study_first_posted>
  <results_first_submitted>December 12, 2022</results_first_submitted>
  <results_first_submitted_qc>March 13, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">April 5, 2023</results_first_posted>
  <last_update_submitted>March 13, 2023</last_update_submitted>
  <last_update_submitted_qc>March 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Washington</investigator_affiliation>
    <investigator_full_name>Gentry George King</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </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>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 3, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/81/NCT04442581/Prot_SAP_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form: Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 13, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/81/NCT04442581/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment (Cabozantinib S-malate, Pembrolizumab)</title>
          <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
Cabozantinib S-malate: Given PO&#xD;
Pembrolizumab: Given IV</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Stage 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Stage 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment (Cabozantinib S-malate, Pembrolizumab)</title>
          <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
Cabozantinib S-malate: Given PO&#xD;
Pembrolizumab: Given IV</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Objective Response (Complete or Partial Response)</title>
        <description>Will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (by blinded central review). Assessment of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 of target lesions by cross sectional imaging (either CT or MRI), defined as the following: 1.) Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall Response Rate is defined as percentage of CR + PR.</description>
        <time_frame>Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Cabozantinib S-malate, Pembrolizumab)</title>
            <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
Cabozantinib S-malate: Given PO&#xD;
Pembrolizumab: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Objective Response (Complete or Partial Response)</title>
          <description>Will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (by blinded central review). Assessment of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 of target lesions by cross sectional imaging (either CT or MRI), defined as the following: 1.) Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall Response Rate is defined as percentage of CR + PR.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Disease Control (Complete + Partial Response + Stable Disease)</title>
        <description>Will be assessed per RECIST v1.1 and iRECIST. Assessment of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 of target lesions by cross sectional imaging (either CT or MRI), defined as the following: 1.) Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall Response Rate is defined as percentage of CR + PR.</description>
        <time_frame>Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Cabozantinib S-malate, Pembrolizumab)</title>
            <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
Cabozantinib S-malate: Given PO&#xD;
Pembrolizumab: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Disease Control (Complete + Partial Response + Stable Disease)</title>
          <description>Will be assessed per RECIST v1.1 and iRECIST. Assessment of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 of target lesions by cross sectional imaging (either CT or MRI), defined as the following: 1.) Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall Response Rate is defined as percentage of CR + PR.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time in Months With Progression-free Survival</title>
        <description>Defined as time from study registration to radiographic progression per RECIST v1.1 (blinded central assessment), clinical progression, or death of any cause.</description>
        <time_frame>Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Cabozantinib S-malate, Pembrolizumab)</title>
            <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
Cabozantinib S-malate: Given PO&#xD;
Pembrolizumab: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Time in Months With Progression-free Survival</title>
          <description>Defined as time from study registration to radiographic progression per RECIST v1.1 (blinded central assessment), clinical progression, or death of any cause.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.26" lower_limit="4" upper_limit="10.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival Time in Months</title>
        <description>Defined as time from study registration to death of any cause.</description>
        <time_frame>Survival assessed from study registration through study completion, 10 months 16 days.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Cabozantinib S-malate, Pembrolizumab)</title>
            <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
Cabozantinib S-malate: Given PO&#xD;
Pembrolizumab: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival Time in Months</title>
          <description>Defined as time from study registration to death of any cause.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.26" lower_limit="8" upper_limit="10.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events</title>
        <description>Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.</description>
        <time_frame>Adverse events monitored from time of informed consent through the last follow-up visit or 30 days after the date of the last dose of cabozantinib or pembrolizumab treatment, whichever occurs last, up to 10 months 16 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Cabozantinib S-malate, Pembrolizumab)</title>
            <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
Cabozantinib S-malate: Given PO&#xD;
Pembrolizumab: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events</title>
          <description>Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events monitored from time of informed consent through the last follow-up visit or 30 days after the date of the last dose of cabozantinib or pembrolizumab treatment, whichever occurs last, up to 10 months 16 days.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment (Cabozantinib S-malate, Pembrolizumab)</title>
          <description>Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.&#xD;
Cabozantinib S-malate: Given PO&#xD;
Pembrolizumab: Given IV</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>General Weakness/Poor Performance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Necrotizing fasciitis</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Neutrophil Count Decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>White Blood Cell Count Decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood Lactate Dehydrogenase Increase</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Thyroid Stimulating Hormone Increase</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Dry Mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Glossitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Alanine transaminase Increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Creatinine Increase</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Madeline Jacoby</name_or_title>
      <organization>University of Washington</organization>
      <phone>2026068246</phone>
      <email>mjacoby@seattlecca.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT04442581
org study id: RG1007034
secondary id: NCI-2020-03968
secondary id: 10548
nct id: NCT04442581
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well cabozantinib and pembrolizumab work for the first-line
      treatment of patients with liver cancer who are not eligible for local therapy (i.e. advanced
      stage). Cabozantinib may stop the growth of tumor cells by blocking some cell surface
      receptors and signaling pathways inside the tumor cells. Immunotherapy with monoclonal
      antibodies, such as pembrolizumab, may help the body's immune system attack the cancer.
      Giving cabozantinib and pembrolizumab together may work better in treating patients with
      advanced liver cancer compared to cabozantinib or pembrolizumab alone.
OUTLINE:

      Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-21 and
      pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up
      to 2 years in the absence of disease progression or unacceptable toxicity. Disease assessment
      by imaging will be performed every 9 weeks.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Objective Response (Complete or Partial Response)
time frame: Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.
description: Will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (by blinded central review). Assessment of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 of target lesions by cross sectional imaging (either CT or MRI), defined as the following: 1.) Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall Response Rate is defined as percentage of CR + PR.
measure: Number of Participants With Disease Control (Complete + Partial Response + Stable Disease)
time frame: Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.
description: Will be assessed per RECIST v1.1 and iRECIST. Assessment of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 of target lesions by cross sectional imaging (either CT or MRI), defined as the following: 1.) Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Overall Response Rate is defined as percentage of CR + PR.
measure: Time in Months With Progression-free Survival
time frame: Assessed at baseline, every 2 cycles until cycle 4, then every 3 cycles until disease progression, up to 10 months 16 days.
description: Defined as time from study registration to radiographic progression per RECIST v1.1 (blinded central assessment), clinical progression, or death of any cause.
measure: Overall Survival Time in Months
time frame: Survival assessed from study registration through study completion, 10 months 16 days.
description: Defined as time from study registration to death of any cause.
measure: Number of Participants With Adverse Events
time frame: Adverse events monitored from time of informed consent through the last follow-up visit or 30 days after the date of the last dose of cabozantinib or pembrolizumab treatment, whichever occurs last, up to 10 months 16 days
description: Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.
arm group label: Treatment (cabozantinib S-malate, pembrolizumab)
arm group type: Experimental
description: Patients receive cabozantinib S-malate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Cabozantinib S-malate
description: Given PO
arm group label: Treatment (cabozantinib S-malate, pembrolizumab)
other name: BMS-907351
other name: Cabometyx
other name: Cometriq
other name: XL-184
other name: XL184
intervention type: Biological
intervention name: Pembrolizumab
description: Given IV
arm group label: Treatment (cabozantinib S-malate, pembrolizumab)
other name: Keytruda
other name: Lambrolizumab
other name: MK-3475
other name: SCH 900475
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gentry George King
role: Principal Investigator
affiliation: Fred Hutch/University of Washington Cancer Consortium
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Washington
investigator full name: Gentry George King
investigator title: Assistant Professor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Pembrolizumab
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 