<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/NCT02227914</url>
  </required_header>
  <id_info>
    <org_study_id>OPZ011</org_study_id>
    <secondary_id>2014-003149-85</secondary_id>
    <nct_id>NCT02227914</nct_id>
  </id_info>
  <brief_title>Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma</brief_title>
  <official_title>Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Amgen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of Phase 1b of the study is to determine the maximum tolerated dose,&#xD;
      pharmacokinetics (PK) and pharmacodynamics (PDn) and assess the safety, tolerability and&#xD;
      activity of oprozomib in combination with sorafenib in subjects with advanced hepatocellular&#xD;
      carcinoma (HCC).&#xD;
&#xD;
      The purpose of Phase 2 of the study is to evaluate the efficacy of oprozomib in combination&#xD;
      with sorafenib versus sorafenib alone and to compare the key outcome measures for subjects&#xD;
      with advanced HCC.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Study stopped due to administrative reasons&#xD;
  </why_stopped>
  <start_date>December 2014</start_date>
  <completion_date type="Actual">March 2015</completion_date>
  <primary_completion_date type="Actual">March 2015</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>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) - Phase 1b</measure>
    <time_frame>16 months</time_frame>
    <description>To determine the maximum tolerated dose (MTD) and identify the recommended Phase 2 dose (RP2D) of oprozomib in combination with sorafenib in subjects with advanced hepatocellular carcinoma (HCC).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time To Progression (TTP) - Phase 2</measure>
    <time_frame>16 months</time_frame>
    <description>To evaluate the efficacy of oprozomib in combination with sorafenib versus sorafenib alone in subjects with advanced HCC, as measured by time to progression (TTP), defined as time from randomization to disease progression.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 1b &amp; Phase 2</measure>
    <time_frame>Until 30 days after the end of study (32 months)</time_frame>
    <description>Number of patients that experience Adverse Events (AEs). Adverse Events (AEs) and Serious Adverse Events (SAEs) graded according to the NCI-CTCAE (Version 4.03).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) parameters - Phase 1b</measure>
    <time_frame>16 months</time_frame>
    <description>Evaluate population pharmacokinetic (PK) parameters, including maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the curve at the last measurable time point (AUC0-t), and area under the curve extrapolated to infinity (AUC0-inf) using noncompartmental methods.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic (PDn) parameter - Phase 1b</measure>
    <time_frame>16 months</time_frame>
    <description>The extent of inactivation of proteasome activity in red blood cells (RBCs) after oprozomib dosing will be monitored as a PDn parameter. Pharmacodynamic inhibition will be listed by dose cohort, exposure, and response status.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR) - Phase 2</measure>
    <time_frame>16 months</time_frame>
    <description>To estimate the overall response rate (ORR), defined as the proportion of subjects with a best overall response of complete response (CR) and partial response (PR) for subjects receiving oprozomib in combination with sorafenib and for subjects receiving sorafenib alone.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS) - Phase 2</measure>
    <time_frame>16 months</time_frame>
    <description>Progression-free survival (PFS), defined as time from randomization to the earlier of PD or death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) - Phase 2</measure>
    <time_frame>16 months</time_frame>
    <description>Overall survival (OS) is defined as time from randomization to death due to any cause.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Advanced Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Oprozomib with Sorafenib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1b:&#xD;
Oprozomib doses will be escalated in sequential groups of at least 2 subjects. Study subjects will receive oprozomib at dose levels of 90, 120, 150, 180, 210, or 240 mg + sorafenib to reach the dose levels of 600 or 800 mg total daily dose until the maximum tolerated dose (MTD) is reached.&#xD;
Phase 2:&#xD;
Study subjects who meet the entry criteria will receive oprozomib + sorafenib at the RP2D (recommended Phase 2 dose) established in the Phase 1b portion of the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sorafenib</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Phase 2:&#xD;
Study subjects who meet the entry criteria will receive sorafenib 400 mg twice a day (800 mg total daily dose).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oprozomib</intervention_name>
    <description>Study subjects will receive oprozomib tablets once a day on Days 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle</description>
    <arm_group_label>Oprozomib with Sorafenib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sorafenib</intervention_name>
    <description>Study subjects will receive sorafenib tablets twice a day for Days 1-28</description>
    <arm_group_label>Oprozomib with Sorafenib</arm_group_label>
    <arm_group_label>Sorafenib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          1. Patients with advanced HCC&#xD;
&#xD;
          2. For the Phase 2 portion of the study, at least 1 measurable tumor lesion according to&#xD;
             Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, which has not been&#xD;
             previously treated with local therapy&#xD;
&#xD;
          3. Cirrhotic status of Child-Pugh Class A only&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1&#xD;
&#xD;
          5. The following laboratory parameters:&#xD;
&#xD;
               -  Albumin ≥ 2.8 g/dL&#xD;
&#xD;
               -  Platelet count ≥ 60,000/mm3&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1500/mm3&#xD;
&#xD;
               -  Hemoglobin ≥ 8.5 g/dL&#xD;
&#xD;
               -  Total bilirubin ≤ 3 mg/dL&#xD;
&#xD;
               -  Alanine aminotransaminase (ALT) and aspartate aminotransferase (AST) ≤ 3 times&#xD;
                  upper limit of normal (ULN)&#xD;
&#xD;
               -  Amylase and lipase ≤ 1.5 times ULN&#xD;
&#xD;
               -  Calculated or measured creatinine clearance (CrCl) ≥ 30 mL/min&#xD;
&#xD;
               -  Prothrombin time (PT)-international normalized ratio (INR) ≤ 2.3 or PT ≤ 6&#xD;
                  seconds above control&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          1. Previous or concurrent cancer that is distinct in primary site or histology from HCC,&#xD;
             EXCEPT cervical and breast carcinoma in situ, adequately treated basal cell or&#xD;
             squamous cell carcinoma of the skin, or superficial bladder tumors (Ta, Tis &amp; T1)&#xD;
&#xD;
          2. Renal failure requiring hemo- or peritoneal dialysis&#xD;
&#xD;
          3. History of cardiac disease&#xD;
&#xD;
          4. Active clinically serious infections. Hepatitis B is allowed if no active replication&#xD;
             is present. Hepatitis C is allowed if no antiviral treatment is required&#xD;
&#xD;
          5. Known history of human immunodeficiency virus (HIV) infection&#xD;
&#xD;
          6. Known history or symptomatic metastatic brain or meningeal tumors&#xD;
&#xD;
          7. Clinically significant gastrointestinal (GI) bleeding, serious nonhealing wound and&#xD;
             ulcer within 3 months prior to study entry, or bone fracture within 30 days prior to&#xD;
             study entry&#xD;
&#xD;
          8. History of organ allograft&#xD;
&#xD;
          9. Known or suspected allergy to the investigational agent or any agent given in&#xD;
             association with this trial&#xD;
&#xD;
         10. Inability to swallow medication, inability or unwillingness to comply with the drug&#xD;
             administration requirements, or GI condition that could interfere with the oral&#xD;
             absorption or tolerance of treatment&#xD;
&#xD;
         11. Uncontrolled diabetes&#xD;
&#xD;
         12. Any contraindication to oral hydration (e.g., preexisting cardiac impairment or fluid&#xD;
             restriction)&#xD;
&#xD;
         13. Uncontrolled ascites&#xD;
&#xD;
         14. Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE ≥ Grade 2&#xD;
             dyspnea).&#xD;
&#xD;
         15. Women who are pregnant and/or breastfeeding&#xD;
&#xD;
         16. Prior use of any systemic anticancer chemotherapy for HCC&#xD;
&#xD;
         17. Prior use of systemic investigational agents for HCC&#xD;
&#xD;
         18. Concomitant treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors&#xD;
&#xD;
         19. Known hypersensitivity or intolerance to dexamethasone or 5-HT3 antagonist&#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>MD</last_name>
    <role>Study Director</role>
    <affiliation>Amgen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lahey Hospital &amp; Medical Center</name>
      <address>
        <city>Burlington</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rocky Mountain Cancer Centers</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami Hospital &amp; Clinics</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Chicago Medical Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ohio State University, Martha Morehouse Medical Plaza</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin Comprehensive Cancer Center</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>August 26, 2014</study_first_submitted>
  <study_first_submitted_qc>August 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 28, 2014</study_first_posted>
  <last_update_submitted>April 28, 2017</last_update_submitted>
  <last_update_submitted_qc>April 28, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 2, 2017</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sorafenib</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02227914
org study id: OPZ011
secondary id: 2014-003149-85
nct id: NCT02227914
lead sponsor: 
has dmc: Yes
The purpose of Phase 1b of the study is to determine the maximum tolerated dose,
      pharmacokinetics (PK) and pharmacodynamics (PDn) and assess the safety, tolerability and
      activity of oprozomib in combination with sorafenib in subjects with advanced hepatocellular
      carcinoma (HCC).

      The purpose of Phase 2 of the study is to evaluate the efficacy of oprozomib in combination
      with sorafenib versus sorafenib alone and to compare the key outcome measures for subjects
      with advanced HCC.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) - Phase 1b
time frame: 16 months
description: To determine the maximum tolerated dose (MTD) and identify the recommended Phase 2 dose (RP2D) of oprozomib in combination with sorafenib in subjects with advanced hepatocellular carcinoma (HCC).
measure: Time To Progression (TTP) - Phase 2
time frame: 16 months
description: To evaluate the efficacy of oprozomib in combination with sorafenib versus sorafenib alone in subjects with advanced HCC, as measured by time to progression (TTP), defined as time from randomization to disease progression.
measure: Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 1b & Phase 2
time frame: Until 30 days after the end of study (32 months)
description: Number of patients that experience Adverse Events (AEs). Adverse Events (AEs) and Serious Adverse Events (SAEs) graded according to the NCI-CTCAE (Version 4.03).
measure: Pharmacokinetics (PK) parameters - Phase 1b
time frame: 16 months
description: Evaluate population pharmacokinetic (PK) parameters, including maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the curve at the last measurable time point (AUC0-t), and area under the curve extrapolated to infinity (AUC0-inf) using noncompartmental methods.
measure: Pharmacodynamic (PDn) parameter - Phase 1b
time frame: 16 months
description: The extent of inactivation of proteasome activity in red blood cells (RBCs) after oprozomib dosing will be monitored as a PDn parameter. Pharmacodynamic inhibition will be listed by dose cohort, exposure, and response status.
measure: Overall Response Rate (ORR) - Phase 2
time frame: 16 months
description: To estimate the overall response rate (ORR), defined as the proportion of subjects with a best overall response of complete response (CR) and partial response (PR) for subjects receiving oprozomib in combination with sorafenib and for subjects receiving sorafenib alone.
measure: Progression-free Survival (PFS) - Phase 2
time frame: 16 months
description: Progression-free survival (PFS), defined as time from randomization to the earlier of PD or death due to any cause.
measure: Overall Survival (OS) - Phase 2
time frame: 16 months
description: Overall survival (OS) is defined as time from randomization to death due to any cause.
arm group label: Oprozomib with Sorafenib
arm group type: Experimental
description: Phase 1b:
Oprozomib doses will be escalated in sequential groups of at least 2 subjects. Study subjects will receive oprozomib at dose levels of 90, 120, 150, 180, 210, or 240 mg + sorafenib to reach the dose levels of 600 or 800 mg total daily dose until the maximum tolerated dose (MTD) is reached.
Phase 2:
Study subjects who meet the entry criteria will receive oprozomib + sorafenib at the RP2D (recommended Phase 2 dose) established in the Phase 1b portion of the study.
arm group label: Sorafenib
arm group type: Active Comparator
description: Phase 2:
Study subjects who meet the entry criteria will receive sorafenib 400 mg twice a day (800 mg total daily dose).
intervention type: Drug
intervention name: Oprozomib
description: Study subjects will receive oprozomib tablets once a day on Days 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle
arm group label: Oprozomib with Sorafenib
intervention type: Drug
intervention name: Sorafenib
description: Study subjects will receive sorafenib tablets twice a day for Days 1-28
arm group label: Oprozomib with Sorafenib
arm group label: Sorafenib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: MD
role: Study Director
affiliation: Amgen
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Sorafenib