<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/NCT04497038</url>
  </required_header>
  <id_info>
    <org_study_id>UMCC 2020.007</org_study_id>
    <secondary_id>HUM00176488</secondary_id>
    <nct_id>NCT04497038</nct_id>
  </id_info>
  <brief_title>Cabozantinib in Patients With Advanced Hepatocellular Carcinoma With Child Pugh Class B Cirrhosis After First-Line Therapy</brief_title>
  <official_title>Phase 1/2 Trial to Evaluate Cabozantinib in Patients With Advanced Hepatocellular Carcinoma With Child Pugh Class B Cirrhosis After First-Line Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan Rogel Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Exelixis</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Michigan Rogel Cancer Center</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study is to determine the safety and efficacy of cabozantinib in the&#xD;
      management of unresectable or metastatic hepatocellular carcinoma (HCC) with underlying&#xD;
      Child-Pugh class B cirrhosis.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 6, 2021</start_date>
  <completion_date type="Anticipated">December 2026</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 1/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>Maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D)</measure>
    <time_frame>Up to 29 days after initiating treatment</time_frame>
    <description>MTD/RP2D determined by dose limiting toxicities (DLT) during the first 29 days of therapy. DLTs are outlined in the protocol and assessed per the NCI CTCAE v5.0. The MTD/RP2D will be determined as the dose level with the highest probability of DLT not exceeding 35%.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>PFS defined as time from date of treatment to date of radiological or clinical progressing (leading to withdrawal from the study), or death from any cause, whichever comes first. PFS will be estimated using the product-limit method of Kaplan and Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median time to progression (TTP)</measure>
    <time_frame>Until date of last disease evaluation (up to 2 years)</time_frame>
    <description>TTP defined as time from date of treatment to date of radiological or clinical progression (leading to withdrawal from the study).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Patients will be followed for up to 2 years from treatment discontinuation or until death, whichever comes first, or 3 years after first date of treatment initiation for those that remain on treatment. OS will be estimated using the product-limit method of Kaplan and Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response rate (ORR) (partial response + complete response)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>ORR (PR + CR) per RECIST v1.1 criteria during active study treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic (PK) profile: Elimination clearance (L/hr)</measure>
    <time_frame>Up to 2 months</time_frame>
    <description>Blood draws pre-dose, every 2 weeks until the start of cycle 3</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">32</enrollment>
  <condition>Advanced Adult Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Cabozantinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cabozantinib 20-60 mg by mouth once daily.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabozantinib</intervention_name>
    <description>Patients will receive therapy with cabozantinib. Dosage in the trial will start at 40 mg PO daily. Each patient will be assessed for the development of toxicity according to the NCI Common Terminology Criteria for Adverse Events, version 5.0. Dose adjustments may be made per the Time-To-Event modification of the Continual Reassessment Method (TITE-CRM). The maximum dosage will be 60 mg PO daily and the minimum will be 20 mg PO daily.</description>
    <arm_group_label>Cabozantinib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have a radiologically consistent (early enhancement and delayed&#xD;
             enhancement washout) or pathologically confirmed diagnosis of hepatocellular carcinoma&#xD;
             that is not eligible for curative resection, transplantation, or ablative therapies.&#xD;
&#xD;
          -  Prior radiation, liver directed therapy (including bland, chemo- or radioembolization,&#xD;
             or ablation), or hepatic resection are permitted if ≥4 weeks from start of therapy.&#xD;
             Extra-hepatic palliative radiation is permitted if completed ≥2 weeks prior to first&#xD;
             dose of study therapy and the patient has recovered to ≤ grade 1 toxicity.&#xD;
&#xD;
          -  Patients must have radiographically measurable disease (RECIST1.1) in at least one&#xD;
             site not previously treated or with progression after radiation or liver directed&#xD;
             therapy (including bland, chemo- or radio-embolization, or ablation) either within the&#xD;
             liver or in a metastatic site.&#xD;
&#xD;
          -  Patients must have either progressed or deemed intolerant of first-line systemic&#xD;
             therapy. More than one line of systemic therapy is not permitted. The last dose should&#xD;
             be at least 2 weeks from first dose of study therapy. Prior treatment may not contain&#xD;
             cabozantinib.&#xD;
&#xD;
          -  Recovery to ≤ grade 1 from toxicities related to any prior treatments, unless the AEs&#xD;
             were clinically non-significant and/or stable on supportive therapy&#xD;
&#xD;
          -  Must have a Child-Pugh score of B7 or B8&#xD;
&#xD;
          -  Must have an ECOG performance status of 0-1.&#xD;
&#xD;
          -  Ability to understand and willingness to sign IRB-approved informed consent.&#xD;
&#xD;
          -  Willing to provide archived tissue, if available, from a previous diagnostic biopsy.&#xD;
&#xD;
          -  Must be able to tolerate CT and/or MRI with contrast.&#xD;
&#xD;
          -  Adequate organ function obtained ≤ 2 weeks prior to enrollment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Must not have uncontrolled ascites (requiring paracentesis within 3 months of&#xD;
             screening) or hepatic encephalopathy requiring hospitalization (within 6 months of&#xD;
             screening)&#xD;
&#xD;
          -  Must not have prior history of organ transplantation.&#xD;
&#xD;
          -  No known brain metastasis unless adequately treated with radiotherapy and/or surgery&#xD;
             and stable for at least 4 weeks before registration. Eligible subjects must have been&#xD;
             without corticosteroid treatment at the time of registration.&#xD;
&#xD;
          -  Must not have undergone a major surgery (e.g., GI surgery, removal or biopsy of brain&#xD;
             metastasis) within 8 weeks before first dose of study treatment. Complete wound&#xD;
             healing from major surgery must have occurred 1 month before first dose and from minor&#xD;
             surgery (e.g., simple excision, tooth extraction) at least 10 days before first dose.&#xD;
             Subjects with clinically relevant ongoing complications from prior surgery are not&#xD;
             eligible.&#xD;
&#xD;
          -  Must not have an active second malignancy other than non-melanoma skin cancer or&#xD;
             cervical carcinoma in situ. Patients with history of malignancy are eligible provided&#xD;
             primary treatment of that cancer was completed &gt; 1 year prior to enrollment and the&#xD;
             patient is free of clinical or radiologic evidence of recurrent or progressive&#xD;
             malignancy.&#xD;
&#xD;
          -  Must not have uncontrolled, significant intercurrent or recent illness including, but&#xD;
             not limited to the following conditions:&#xD;
&#xD;
               -  Cardiovascular disorders (Congestive heart failure or uncontrolled hypertension;&#xD;
                  or stroke, myocardial infarction, or other ischemic or thromboembolic event&#xD;
                  within 6 months before first dose)&#xD;
&#xD;
               -  Gastrointestinal disorders, including those associated with a high risk of&#xD;
                  perforation or fistula formation&#xD;
&#xD;
               -  Clinically significant hematuria, hematemesis, or hemoptysis of &gt; 0.5 teaspoon of&#xD;
                  red blood or other history of significant bleeding within 12 weeks before first&#xD;
                  dose&#xD;
&#xD;
               -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease&#xD;
                  manifestation&#xD;
&#xD;
               -  Lesions invading or encasing any major blood vessels except thromboses of&#xD;
                  portal/hepatic vasculature attributed to underlying liver disease and/or liver&#xD;
                  tumor&#xD;
&#xD;
               -  Other clinically significant disorders that would preclude safe study&#xD;
                  participation (serious non-healing wound/ulcer/bone fracture;&#xD;
                  uncompensated/symptomatic hypothyroidism; known HIV)&#xD;
&#xD;
          -  Must not have untreated or incompletely treated varices with bleeding or high risk for&#xD;
             bleeding. Subjects treated with adequate endoscopic therapy (in accordance with&#xD;
             institutional standards) without any episodes of recurrent overt GI bleeding requiring&#xD;
             transfusion or hospitalization for at least 6 months prior to study entry are eligible&#xD;
&#xD;
          -  Must not have a psychiatric illness, other significant medical illness, or social&#xD;
             situation (such as involuntary incarceration) which, in the investigator's opinion,&#xD;
             would limit compliance or ability to comply with study requirements&#xD;
&#xD;
          -  Women must not be pregnant or breastfeeding since cabozantinib may harm the fetus or&#xD;
             child.&#xD;
&#xD;
          -  Women of child-bearing potential (not surgically sterilized and between menarche and&#xD;
             1-year post menopause) and men must agree to use 2 methods of adequate contraception&#xD;
             (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the&#xD;
             duration of study participation, and for 4 months following completion of study&#xD;
             therapy. Should a woman become pregnant or suspect she is pregnant while participating&#xD;
             in this study, she should inform her treating physician immediately.&#xD;
&#xD;
          -  Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for&#xD;
             treatment of either a psychiatric or physical (e.g. infectious disease) illness would&#xD;
             be excluded.&#xD;
&#xD;
          -  Concomitant treatment with strong inducers or inhibitors of CYP3A4 is not allowed.&#xD;
             Patients must discontinue the drug(s) at least 14 days prior to first study dose on&#xD;
             the study.&#xD;
&#xD;
          -  Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin&#xD;
             and factor Xa inhibitors), or platelet inhibitors (e.g. clopidogrel) is not allowed.&#xD;
&#xD;
          -  Must not have corrected QT interval calculated by the Fridericia formula (QTcF) &gt; 500&#xD;
             ms per electrocardiogram (ECG) within 28 days before first dose of study treatment.&#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>Vaibhav Sahai, MBBS, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cancer Answer Line</last_name>
    <phone>800-865-1125</phone>
    <email>CancerAnswerLine@med.umich.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aparna Kalyan</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>University of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Andy Liao, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Michigan Rogel Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Thomas Enzler, MD</last_name>
      <phone>800-865-1125</phone>
      <email>CancerAnswerLine@med.umich.edu</email>
    </contact>
    <investigator>
      <last_name>Thomas Enzler, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>David Hsieh, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 29, 2020</study_first_submitted>
  <study_first_submitted_qc>July 31, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2020</study_first_posted>
  <last_update_submitted>August 30, 2023</last_update_submitted>
  <last_update_submitted_qc>August 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT04497038
org study id: UMCC 2020.007
secondary id: HUM00176488
nct id: NCT04497038
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The aim of this study is to determine the safety and efficacy of cabozantinib in the
      management of unresectable or metastatic hepatocellular carcinoma (HCC) with underlying
      Child-Pugh class B cirrhosis.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D)
time frame: Up to 29 days after initiating treatment
description: MTD/RP2D determined by dose limiting toxicities (DLT) during the first 29 days of therapy. DLTs are outlined in the protocol and assessed per the NCI CTCAE v5.0. The MTD/RP2D will be determined as the dose level with the highest probability of DLT not exceeding 35%.
measure: Progression-free survival (PFS)
time frame: Up to 3 years
description: PFS defined as time from date of treatment to date of radiological or clinical progressing (leading to withdrawal from the study), or death from any cause, whichever comes first. PFS will be estimated using the product-limit method of Kaplan and Meier.
measure: Median time to progression (TTP)
time frame: Until date of last disease evaluation (up to 2 years)
description: TTP defined as time from date of treatment to date of radiological or clinical progression (leading to withdrawal from the study).
measure: Overall survival (OS)
time frame: Up to 3 years
description: Patients will be followed for up to 2 years from treatment discontinuation or until death, whichever comes first, or 3 years after first date of treatment initiation for those that remain on treatment. OS will be estimated using the product-limit method of Kaplan and Meier.
measure: Overall response rate (ORR) (partial response + complete response)
time frame: Up to 2 years
description: ORR (PR + CR) per RECIST v1.1 criteria during active study treatment.
measure: Pharmacokinetic (PK) profile: Elimination clearance (L/hr)
time frame: Up to 2 months
description: Blood draws pre-dose, every 2 weeks until the start of cycle 3
arm group label: Cabozantinib
arm group type: Experimental
description: Cabozantinib 20-60 mg by mouth once daily.
intervention type: Drug
intervention name: Cabozantinib
description: Patients will receive therapy with cabozantinib. Dosage in the trial will start at 40 mg PO daily. Each patient will be assessed for the development of toxicity according to the NCI Common Terminology Criteria for Adverse Events, version 5.0. Dose adjustments may be made per the Time-To-Event modification of the Continual Reassessment Method (TITE-CRM). The maximum dosage will be 60 mg PO daily and the minimum will be 20 mg PO daily.
arm group label: Cabozantinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Vaibhav Sahai, MBBS, MS
role: Principal Investigator
affiliation: University of Michigan
last name: Cancer Answer Line
phone: 800-865-1125
email: CancerAnswerLine@med.umich.edu
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
sharing ipd: No