<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/NCT01687673</url>
  </required_header>
  <id_info>
    <org_study_id>124511</org_study_id>
    <secondary_id>NCI-2012-02021</secondary_id>
    <nct_id>NCT01687673</nct_id>
  </id_info>
  <brief_title>Phase II Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma</brief_title>
  <official_title>Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Robert H. Lurie Cancer Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This Phase II trial is being developed following the completion of a Phase I study of the&#xD;
      combination of temsirolimus and sorafenib in 25 first-line therapy patients with advanced&#xD;
      hepatocellular carcinoma (December 2009 through April 2012). The maximum tolerated dose (MTD)&#xD;
      and recommended phase II dose (RP2D) of the combination of temsirolimus is 10 mg IV weekly&#xD;
      plus sorafenib 200 mg (oral, twice daily).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The hypothesis of this single-arm phase II study is that the combination of temsirolimus and&#xD;
      sorafenib will achieve a clinically-meaningful median time to progression (TTP) of at least 6&#xD;
      months, with null hypothesis of less than or equal to 3 months, in first-line systemic&#xD;
      therapy for patients with advanced Hepatocellular carcinoma (HCC). A randomized trial would&#xD;
      be required to formally compare the efficacy of this combination to sorafenib alone and will&#xD;
      be indicated if this phase II study achieves a median TTP of at least 6 months. An interim&#xD;
      safety analysis will employ stopping rules after 30% of planned patients have been treated&#xD;
      with at least one dose of protocol therapy to ensure the combination does not confer&#xD;
      excessive toxicity.&#xD;
&#xD;
      A key aspect of this study will be the requirement of histologic confirmation along with&#xD;
      adequate archival tissue for correlative tissue analyses to explore new biomarkers of&#xD;
      response to mammalian target of rapamycin (mTOR) inhibition. Circulating biomarker data&#xD;
      including enumeration of circulating tumor cells (CTC) and measurement of the tumor marker&#xD;
      Alpha-fetoprotein (AFP) will be performed at specific time points to evaluate for predictive&#xD;
      value. Specimen banking of tissue, serum, and peripheral blood mononuclear cells will be&#xD;
      undertaken to enable future novel biomarker studies. Modified RECIST will be performed in&#xD;
      addition to standard RECIST 1.1 to explore for improved imaging predictors of response.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 5, 2012</start_date>
  <completion_date type="Actual">January 9, 2020</completion_date>
  <primary_completion_date type="Actual">April 26, 2016</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>Median Time to Progression (TTP)</measure>
    <time_frame>24 months</time_frame>
    <description>Median TTP will be calculated in months from date of first dose of protocol therapy to date of removal from study for progression, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of the target lesions (SLD), taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions . Kaplan-Meier methods will be used to summarize the primary endpoint</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response Rate (RR)</measure>
    <time_frame>24 months</time_frame>
    <description>Response Rate (RR) is defined as any patient whom has a documented complete response (CR) or partial response (PR) per RECIST version 1.1 criteria. Results will be reported by number of participants for each response type: CR or PR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Progression Free Survival (PFS)</measure>
    <time_frame>24 months</time_frame>
    <description>Median PFS will be calculated in months from date of first dose of protocol therapy to date of documented disease progression or death from any cause, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Kaplan-Meier methods will be used to summarize time-to-event outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival (OS)</measure>
    <time_frame>60 months</time_frame>
    <description>Median OS for all enrolled patients (intention-to-treat) will be calculated from date of first dose of protocol therapy until date of death, using chart review and/or follow up phone calls to determine date of death in patients after removal from study. The survival of patients still alive after 5 years of follow up post study discontinuation will be censored.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Treatment Failure (TTF)</measure>
    <time_frame>24 months</time_frame>
    <description>TTF will be measured from date of first dose of protocol therapy to date of study discontinuation for progression, death, or toxicity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With a Demonstrated Alpha-fetoprotein (AFP) Response</measure>
    <time_frame>24 months</time_frame>
    <description>In patients with baseline AFP &gt;= 20 ng/mL, AFP response will be measured by the percent change from baseline value to the value at the time of best AFP response. The number of participants with ≥ 50% decline from baseline will be measured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients Whom Required a Dose Reduction</measure>
    <time_frame>24 months</time_frame>
    <description>The number of patients whom required a dose reduction due to toxicity as classified by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be reported</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients Whom Required a Treatment Delay</measure>
    <time_frame>24 months</time_frame>
    <description>The number of patients whom required a treatment delay due to toxicity as classified by the CTCAE version 4.0 will be reported</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Whom Discontinued Treatment Due to Intolerable Toxicity</measure>
    <time_frame>24 months</time_frame>
    <description>The number of participants whom discontinued treatment due to toxicity as classified by the CTCAE version 4.0 will be reported</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Combination temsirolimus plus sorafenib</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Temsirolimus</intervention_name>
    <description>10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.</description>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sorafenib:</intervention_name>
    <description>200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA&#xD;
&#xD;
          1. Patients must have histologically diagnosed American Joint Committee on Cancer (AJCC)&#xD;
             stage II, III, or IV hepatocellular carcinoma (HCC) not eligible for curative&#xD;
             resection, transplantation, or ablative therapies&#xD;
&#xD;
          2. Radiographically measurable disease by RECIST version 1.1 in at least one site not&#xD;
             previously treated with chemoembolization, radioembolization, or other local ablative&#xD;
             procedures (i.e. must have at least one measurable target lesion, either within the&#xD;
             liver or in a measurable metastatic site); a new area of tumor progression within or&#xD;
             adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is&#xD;
             acceptable&#xD;
&#xD;
          3. No prior systemic cytotoxic chemotherapy or targeted therapy (including sorafenib) for&#xD;
             HCC&#xD;
&#xD;
          4. Prior chemoembolization, local ablative therapies, or hepatic resection permitted if&#xD;
             completed ≥ 4 weeks prior to study enrollment if patient has recovered with ≤ grade 1&#xD;
             toxicity and if measurable disease (criterion 2) is present&#xD;
&#xD;
          5. Prior radiation for bone or brain metastases is permitted if patient is now&#xD;
             asymptomatic and has completed all radiation and steroid therapy (if applicable) for&#xD;
             brain or bone metastases ≥ 2 weeks prior to study enrollment.&#xD;
&#xD;
          6. Age ≥ 18 years.&#xD;
&#xD;
          7. Child-Pugh score of A or B with ≤ 7 points and meeting laboratory eligibility for all&#xD;
             parameters&#xD;
&#xD;
          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          9. Life expectancy greater than 3 months&#xD;
&#xD;
         10. Treatment with appropriate antiviral therapy for patients with active hepatitis B&#xD;
             Virus (HBV) infection is required&#xD;
&#xD;
         11. Treatment for clinically-significant hyperglycemia, hyperlipidemia, or hypertension&#xD;
             that develops on study is required&#xD;
&#xD;
         12. Baseline blood pressure must be adequately controlled with or without antihypertensive&#xD;
             medications prior to enrollment (systolic ≤ 150 mm Hg, diastolic ≤ 90 mm Hg)&#xD;
&#xD;
         13. Baseline cholesterol must be &lt; 350 mg/dL and triglycerides &lt; 300 mg/dL (with or&#xD;
             without the use of antihyperlipidemic medications)&#xD;
&#xD;
         14. Baseline fasting blood glucose must be ≤ 140 mg/dL and hemoglobin A1c less than 7.5%&#xD;
             (with or without the use of anti-diabetic medications)&#xD;
&#xD;
         15. Adequate baseline organ and marrow function as defined below&#xD;
&#xD;
             Adequate bone marrow function:&#xD;
&#xD;
             absolute neutrophil count &gt; = 1,000/microliter (mcL) platelets ≥ 75,000/mcL hemoglobin&#xD;
             ≥ 8.5 g/dL&#xD;
&#xD;
             Adequate hepatic function:&#xD;
&#xD;
             total bilirubin ≤ 2 mg/dL or ≤ 1.5 times ULN aspartate aminotransferase (AST) / serum&#xD;
             glutamic-oxaloacetic transaminase (SGOT) &amp; alanine aminotransferase (ALT) / serum&#xD;
             glutamic-pyruvic transaminase (SGPT) ≤ 5 X upper limit of normal (ULN) International&#xD;
             Normalized Ratio (INR) &lt;=1. 5 X ULN&#xD;
&#xD;
             Adequate renal function:&#xD;
&#xD;
             albumin ≥ 2.8 g/dL creatinine ≤1. 5 X ULN&#xD;
&#xD;
         16. Able to tolerate oral therapy.&#xD;
&#xD;
         17. Ability to understand and willingness to provide informed consent, and the willingness&#xD;
             to comply with the requirements of the protocol. Informed consent may be obtained with&#xD;
             the assistance of a medical translator according to institutional policies.&#xD;
&#xD;
         18. The effects of temsirolimus on the developing human fetus are unknown. For this reason&#xD;
             and because sorafenib - also being used in this trial - is known to be teratogenic,&#xD;
             women of child-bearing potential must have a negative pregnancy test within 14 days of&#xD;
             study enrollment.&#xD;
&#xD;
             Also, women of child-bearing potential and men must agree to use two methods adequate&#xD;
             contraception (hormonal plus barrier or two forms of barrier) or abstinence prior to&#xD;
             study entry and for the duration of study participation. Should a woman become&#xD;
             pregnant or suspect she is pregnant while she or her partner is participating in this&#xD;
             study, she needs to inform her treating physician immediately. Men treated or enrolled&#xD;
             on this protocol must also agree to use adequate contraception prior to the study, or&#xD;
             be surgically sterile, for the duration of study participation, and for 3 months after&#xD;
             completion of study drug administration.&#xD;
&#xD;
         19. Eligibility of patients receiving any medications or substances known to affect or&#xD;
             with potential to affect the activity or pharmacokinetics of temsirolimus and/or&#xD;
             sorafenib will be determined following review of the case by the Study Chair. Efforts&#xD;
             should be made to switch patients who are taking enzyme-inducing anti-convulsant&#xD;
             agents to other medications.&#xD;
&#xD;
         20. mixed histology (mixed HCC-cholangiocarcinoma) tumors if deemed appropriate for HCC&#xD;
             therapy by treating MD&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Mixed tumor histology or fibrolamellar variant tumors are excluded.&#xD;
&#xD;
          2. Prior systemic or antiangiogenic therapy for HCC (including thalidomide, sorafenib,&#xD;
             sunitinib, or bevacizumab). Prior systemic therapy for other diagnoses is permitted if&#xD;
             greater than 6 months have elapsed since last dose, any prior toxicity has recovered&#xD;
             to ≤ grade 1 by CTCAE v4.0, and treatment was not discontinued for toxicity.&#xD;
&#xD;
          3. Prior treatment with mTOR inhibitor or other molecularly targeted therapy.&#xD;
&#xD;
          4. Prior systemic cytotoxic therapies for HCC (chemoembolization is permitted if&#xD;
             inclusion criteria are met).&#xD;
&#xD;
          5. Treatment with other investigational agents.&#xD;
&#xD;
          6. Immunosuppressive medications including systemic corticosteroids unless used for&#xD;
             adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis&#xD;
             exacerbation (≤ 2 weeks), or antiemesis&#xD;
&#xD;
          7. Patients with known HIV infection are ineligible due to risk of pharmacokinetic&#xD;
             interactions between anti-retroviral therapy and the study drugs, as well as potential&#xD;
             for significant immunosuppression and serious infections with mTOR inhibition.&#xD;
&#xD;
          8. Patients who have undergone liver transplantation are excluded.&#xD;
&#xD;
          9. Uncontrolled hypertension (&gt; 150/90 mmHg).&#xD;
&#xD;
         10. Uncontrolled hyperlipidemia (total cholesterol &gt; 350 or triglycerides &gt; 300).&#xD;
&#xD;
         11. Symptomatic brain or bone metastases; prior radiation and/or steroid therapy for brain&#xD;
             or bone metastases (if applicable) must be completed ≥ 2 weeks prior to study&#xD;
             enrollment.&#xD;
&#xD;
         12. History of seizure disorder requiring antiepileptic medication or brain metastases&#xD;
             with seizures.&#xD;
&#xD;
         13. Serious non-healing wound, ulcer, bone fracture, or abscess.&#xD;
&#xD;
         14. Major surgical procedure less than 4 weeks from start of protocol treatment.&#xD;
&#xD;
         15. Patients requiring chronic anticoagulation with warfarin are excluded. Patients&#xD;
             treated with low molecular weight heparin or unfractionated heparin are eligible if on&#xD;
             a stable dose without evidence of clinically significant bleeding for at least 2 weeks&#xD;
             prior to enrollment.&#xD;
&#xD;
         16. Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in&#xD;
             situ. (Patients with history of malignancy are not considered to have a &quot;currently&#xD;
             active&quot; malignancy if they have completed therapy and are now considered by their&#xD;
             physician to be at less than 30% risk for relapse.)&#xD;
&#xD;
         17. Uncontrolled intercurrent illness including, but not limited to: Ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris,&#xD;
             uncontrolled cardiac arrhythmia, uncontrolled peripheral vascular disease, myocardial&#xD;
             infarction within preceding 12 months, cerebrovascular accident within preceding 12&#xD;
             months, pulmonary disease impairing functional status or requiring oxygen, impairment&#xD;
             in gastrointestinal function that may affect or alter absorption of oral medications&#xD;
             (such as malabsorption or history of gastrectomy or bowel resection).&#xD;
&#xD;
         18. Patients will be excluded if there is any history of allergic reaction(s) attributed&#xD;
             to compounds of similar composition to temsirolimus, sorafenib, their metabolites, or&#xD;
             any component of their formulation (including excipients and polysorbate 80). This&#xD;
             includes hypersensitivity to macrolide antibiotics due to potential for&#xD;
             cross-reactivity with temsirolimus.&#xD;
&#xD;
         19. Pregnant or lactating women are excluded from this study because temsirolimus and&#xD;
             sorafenib are drugs with the potential for teratogenic or abortifacient effects.&#xD;
             Because there is an unknown but potential risk for adverse events in nursing infants&#xD;
             secondary to treatment of the mother with temsirolimus or sorafenib, breastfeeding&#xD;
             should be discontinued if the mother is receiving temsirolimus/sorafenib treatment.&#xD;
&#xD;
         20. Patients who require prohibited medications with potential for serious interactions&#xD;
             with protocol therapy, and who cannot have therapeutic substitution are excluded.&#xD;
             Patients receiving any medications or substances that are inhibitors or inducers of&#xD;
             CYP450 enzyme(s) are ineligible. Lists of prohibited medications and substances known,&#xD;
             or with the potential to interact with the specified CYP450 enzyme(s) isoenzymes are&#xD;
             provided in Appendices 6-9 Prohibited Medications&#xD;
&#xD;
         21. Psychiatric illness, other significant medical illness, or social situation which, in&#xD;
             the investigator's opinion, would limit compliance or ability to comply with study&#xD;
             requirements.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kate Kelley, MD</last_name>
    <role>Study Chair</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kate Kelley, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Robert H Lurie Comprehensive Cancer Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>September 11, 2012</study_first_submitted>
  <study_first_submitted_qc>September 18, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 19, 2012</study_first_posted>
  <results_first_submitted>October 21, 2020</results_first_submitted>
  <results_first_submitted_qc>November 12, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">December 7, 2020</results_first_posted>
  <disposition_first_submitted>January 30, 2019</disposition_first_submitted>
  <disposition_first_submitted_qc>January 30, 2019</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">February 1, 2019</disposition_first_posted>
  <last_update_submitted>November 12, 2020</last_update_submitted>
  <last_update_submitted_qc>November 12, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Advanced HCC</keyword>
  <keyword>Temsirolimus</keyword>
  <keyword>TORISEL</keyword>
  <keyword>Sorafenib</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Sorafenib</mesh_term>
    <mesh_term>Temsirolimus</mesh_term>
    <mesh_term>MTOR Inhibitors</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>November 17, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/73/NCT01687673/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment</title>
          <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="29"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment</title>
          <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="29"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61" lower_limit="33" upper_limit="78"/>
                  </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="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                  </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="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                  </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="10"/>
                  </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="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </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="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Baseline Alpha-fetoprotein (AFP)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>&lt; 400 nanograms per millilitre (ng/mL)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>&gt;= 400 ng/mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Median Time to Progression (TTP)</title>
        <description>Median TTP will be calculated in months from date of first dose of protocol therapy to date of removal from study for progression, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of the target lesions (SLD), taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions . Kaplan-Meier methods will be used to summarize the primary endpoint</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Time to Progression (TTP)</title>
          <description>Median TTP will be calculated in months from date of first dose of protocol therapy to date of removal from study for progression, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of the target lesions (SLD), taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions . Kaplan-Meier methods will be used to summarize the primary endpoint</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7" lower_limit="2.2" upper_limit="5.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Response Rate (RR)</title>
        <description>Response Rate (RR) is defined as any patient whom has a documented complete response (CR) or partial response (PR) per RECIST version 1.1 criteria. Results will be reported by number of participants for each response type: CR or PR.</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Response Rate (RR)</title>
          <description>Response Rate (RR) is defined as any patient whom has a documented complete response (CR) or partial response (PR) per RECIST version 1.1 criteria. Results will be reported by number of participants for each response type: CR or PR.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response</title>
              <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>Median Progression Free Survival (PFS)</title>
        <description>Median PFS will be calculated in months from date of first dose of protocol therapy to date of documented disease progression or death from any cause, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Kaplan-Meier methods will be used to summarize time-to-event outcomes.</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Progression Free Survival (PFS)</title>
          <description>Median PFS will be calculated in months from date of first dose of protocol therapy to date of documented disease progression or death from any cause, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Kaplan-Meier methods will be used to summarize time-to-event outcomes.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7" lower_limit="2.2" upper_limit="5.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Overall Survival (OS)</title>
        <description>Median OS for all enrolled patients (intention-to-treat) will be calculated from date of first dose of protocol therapy until date of death, using chart review and/or follow up phone calls to determine date of death in patients after removal from study. The survival of patients still alive after 5 years of follow up post study discontinuation will be censored.</description>
        <time_frame>60 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Overall Survival (OS)</title>
          <description>Median OS for all enrolled patients (intention-to-treat) will be calculated from date of first dose of protocol therapy until date of death, using chart review and/or follow up phone calls to determine date of death in patients after removal from study. The survival of patients still alive after 5 years of follow up post study discontinuation will be censored.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.8" lower_limit="6.8" upper_limit="14.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Treatment Failure (TTF)</title>
        <description>TTF will be measured from date of first dose of protocol therapy to date of study discontinuation for progression, death, or toxicity.</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Treatment Failure (TTF)</title>
          <description>TTF will be measured from date of first dose of protocol therapy to date of study discontinuation for progression, death, or toxicity.</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="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.1" lower_limit="0.7" upper_limit="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With a Demonstrated Alpha-fetoprotein (AFP) Response</title>
        <description>In patients with baseline AFP &gt;= 20 ng/mL, AFP response will be measured by the percent change from baseline value to the value at the time of best AFP response. The number of participants with ≥ 50% decline from baseline will be measured.</description>
        <time_frame>24 months</time_frame>
        <population>Only 21 patients had AFP response data available at time of best AFP response</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With a Demonstrated Alpha-fetoprotein (AFP) Response</title>
          <description>In patients with baseline AFP &gt;= 20 ng/mL, AFP response will be measured by the percent change from baseline value to the value at the time of best AFP response. The number of participants with ≥ 50% decline from baseline will be measured.</description>
          <population>Only 21 patients had AFP response data available at time of best AFP response</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients Whom Required a Dose Reduction</title>
        <description>The number of patients whom required a dose reduction due to toxicity as classified by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be reported</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Whom Required a Dose Reduction</title>
          <description>The number of patients whom required a dose reduction due to toxicity as classified by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be reported</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="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients Whom Required a Treatment Delay</title>
        <description>The number of patients whom required a treatment delay due to toxicity as classified by the CTCAE version 4.0 will be reported</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Whom Required a Treatment Delay</title>
          <description>The number of patients whom required a treatment delay due to toxicity as classified by the CTCAE version 4.0 will be reported</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="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Whom Discontinued Treatment Due to Intolerable Toxicity</title>
        <description>The number of participants whom discontinued treatment due to toxicity as classified by the CTCAE version 4.0 will be reported</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Whom Discontinued Treatment Due to Intolerable Toxicity</title>
          <description>The number of participants whom discontinued treatment due to toxicity as classified by the CTCAE version 4.0 will be reported</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="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 60 months</time_frame>
      <desc>Only patients actively treated with a combination of Temsirolimus and Sorafenib were evaluated for safety.</desc>
      <group_list>
        <group group_id="E1">
          <title>Treatment</title>
          <description>Combination temsirolimus plus sorafenib&#xD;
Temsirolimus: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.&#xD;
Sorafenib:: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</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="27" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (4.0)</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="20" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="3" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenic purpura</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="11" subjects_affected="8" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="22" subjects_affected="10" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="11" subjects_affected="7" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Cholesterol high</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="50" subjects_affected="17" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="6" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="14" subjects_affected="8" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="28"/>
              </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>Dr. R. Katie Kelley, MD</name_or_title>
      <organization>University of California, San Francisco</organization>
      <phone>(415) 353-9888</phone>
      <email>Katie.Kelley@ucsf.edu</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/NCT01687673
org study id: 124511
secondary id: NCI-2012-02021
nct id: NCT01687673
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This Phase II trial is being developed following the completion of a Phase I study of the
      combination of temsirolimus and sorafenib in 25 first-line therapy patients with advanced
      hepatocellular carcinoma (December 2009 through April 2012). The maximum tolerated dose (MTD)
      and recommended phase II dose (RP2D) of the combination of temsirolimus is 10 mg IV weekly
      plus sorafenib 200 mg (oral, twice daily).
The hypothesis of this single-arm phase II study is that the combination of temsirolimus and
      sorafenib will achieve a clinically-meaningful median time to progression (TTP) of at least 6
      months, with null hypothesis of less than or equal to 3 months, in first-line systemic
      therapy for patients with advanced Hepatocellular carcinoma (HCC). A randomized trial would
      be required to formally compare the efficacy of this combination to sorafenib alone and will
      be indicated if this phase II study achieves a median TTP of at least 6 months. An interim
      safety analysis will employ stopping rules after 30% of planned patients have been treated
      with at least one dose of protocol therapy to ensure the combination does not confer
      excessive toxicity.

      A key aspect of this study will be the requirement of histologic confirmation along with
      adequate archival tissue for correlative tissue analyses to explore new biomarkers of
      response to mammalian target of rapamycin (mTOR) inhibition. Circulating biomarker data
      including enumeration of circulating tumor cells (CTC) and measurement of the tumor marker
      Alpha-fetoprotein (AFP) will be performed at specific time points to evaluate for predictive
      value. Specimen banking of tissue, serum, and peripheral blood mononuclear cells will be
      undertaken to enable future novel biomarker studies. Modified RECIST will be performed in
      addition to standard RECIST 1.1 to explore for improved imaging predictors of response.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Median Time to Progression (TTP)
time frame: 24 months
description: Median TTP will be calculated in months from date of first dose of protocol therapy to date of removal from study for progression, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of the target lesions (SLD), taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions . Kaplan-Meier methods will be used to summarize the primary endpoint
measure: Response Rate (RR)
time frame: 24 months
description: Response Rate (RR) is defined as any patient whom has a documented complete response (CR) or partial response (PR) per RECIST version 1.1 criteria. Results will be reported by number of participants for each response type: CR or PR.
measure: Median Progression Free Survival (PFS)
time frame: 24 months
description: Median PFS will be calculated in months from date of first dose of protocol therapy to date of documented disease progression or death from any cause, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Kaplan-Meier methods will be used to summarize time-to-event outcomes.
measure: Median Overall Survival (OS)
time frame: 60 months
description: Median OS for all enrolled patients (intention-to-treat) will be calculated from date of first dose of protocol therapy until date of death, using chart review and/or follow up phone calls to determine date of death in patients after removal from study. The survival of patients still alive after 5 years of follow up post study discontinuation will be censored.
measure: Time to Treatment Failure (TTF)
time frame: 24 months
description: TTF will be measured from date of first dose of protocol therapy to date of study discontinuation for progression, death, or toxicity.
measure: Number of Patients With a Demonstrated Alpha-fetoprotein (AFP) Response
time frame: 24 months
description: In patients with baseline AFP >= 20 ng/mL, AFP response will be measured by the percent change from baseline value to the value at the time of best AFP response. The number of participants with ≥ 50% decline from baseline will be measured.
measure: Number of Patients Whom Required a Dose Reduction
time frame: 24 months
description: The number of patients whom required a dose reduction due to toxicity as classified by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be reported
measure: Number of Patients Whom Required a Treatment Delay
time frame: 24 months
description: The number of patients whom required a treatment delay due to toxicity as classified by the CTCAE version 4.0 will be reported
measure: Number of Participants Whom Discontinued Treatment Due to Intolerable Toxicity
time frame: 24 months
description: The number of participants whom discontinued treatment due to toxicity as classified by the CTCAE version 4.0 will be reported
arm group label: Treatment
arm group type: Experimental
description: Combination temsirolimus plus sorafenib
intervention type: Drug
intervention name: Temsirolimus
description: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.
arm group label: Treatment
intervention type: Drug
intervention name: Sorafenib:
description: 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.
arm group label: Treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Kate Kelley, MD
role: Study Chair
affiliation: University of California, San Francisco
last name: Kate Kelley, MD
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Sirolimus
mesh term: Sorafenib
mesh term: Temsirolimus
mesh term: MTOR Inhibitors
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 