<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/NCT02259725</url>
  </required_header>
  <id_info>
    <org_study_id>0S-14-3</org_study_id>
    <secondary_id>NCI-2014-01996</secondary_id>
    <secondary_id>HS-14-00583</secondary_id>
    <secondary_id>0S-14-3</secondary_id>
    <secondary_id>P30CA014089</secondary_id>
    <nct_id>NCT02259725</nct_id>
  </id_info>
  <brief_title>Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors</brief_title>
  <official_title>Phase II Study of Single Agent Regorafenib in Patients With Advanced/Metastatic Neuroendocrine Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Southern California</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Southern California</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies regorafenib in treating patients with neuroendocrine tumors that&#xD;
      have spread from the primary site (place where it started) to other places in the body.&#xD;
      Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for&#xD;
      cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To assess progression-free survival (PFS) in advanced/metastatic in patients with&#xD;
      carcinoid or pancreatic islet cell tumors.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess overall survival and response rate in advanced/metastatic poor prognosis in&#xD;
      patients with carcinoid or pancreatic islet cell tumors.&#xD;
&#xD;
      II. To assess the toxicity of patients treated with regorafenib. III. To explore markers of&#xD;
      angiogenesis as they relate to outcome in carcinoid and pancreatic islet cell tumors.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Courses repeat every&#xD;
      28 days in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 16, 2016</start_date>
  <completion_date type="Actual">August 20, 2020</completion_date>
  <primary_completion_date type="Actual">August 20, 2020</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>PFS</measure>
    <time_frame>Time from start of treatment to time of progression or death on study whichever comes first, assessed at 6 months</time_frame>
    <description>Two parallel Simon's 2-stage phase II trials will be conducted to evaluate the efficacy of regorafenib in patients with advanced carcinoid (cohort A) or pancreatic islet cell tumors (cohort B). Will be summarized as a proportion of patients who are alive and progression-free among all patients in the primary data analysis set. The 95% confidence intervals (CIs) will be calculated using the Wilson method. Will be analyzed using Kaplan-Meier (KM) curves. The median PFS and 95% CIs will be calculated. The probability of 6-month PFS will be estimated from the KM curve too.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Will be calculated as a proportion of patients who have either a complete or partial response among all patients in the primary data analysis set. The 95% CIs will be given.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>From start of treatment until death due to any cause, assessed up to 4 years</time_frame>
    <description>The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Toxicity profile will be summarized by attribution: regorafenib-related and all reported, course: course 1 and all courses, type, and grade: grade 1-2, 3-4, and 5.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Biomarkers Such as Messenger Ribonucleic Acid (mRNA) Levels or Germline Variations of Genes Related to Angiogenesis</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>The associations between biomarkers and clinical outcomes (6-month PFS, response, PFS, and overall survival) will be analyzed in univariate analysis first using appropriate methods. Multivariable analyses will be conducted to evaluate the independent effect of a marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values will be adjusted for multiple comparisons.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Gastrinoma</condition>
  <condition>Glucagonoma</condition>
  <condition>Insulinoma</condition>
  <condition>Metastatic Gastrointestinal Carcinoid Tumor</condition>
  <condition>Pancreatic Polypeptide Tumor</condition>
  <condition>Pulmonary Carcinoid Tumor</condition>
  <condition>Recurrent Gastrointestinal Carcinoid Tumor</condition>
  <condition>Recurrent Islet Cell Carcinoma</condition>
  <condition>Somatostatinoma</condition>
  <arm_group>
    <arm_group_label>Treatment (regorafenib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>regorafenib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (regorafenib)</arm_group_label>
    <other_name>BAY 73-4506</other_name>
    <other_name>multikinase inhibitor BAY 73-4506</other_name>
    <other_name>Stivarga</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (regorafenib)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Advanced metastatic, progressing carcinoid or pancreatic islet cell cancers&#xD;
&#xD;
          -  No prior targeted treatment (tx) or anti-angiogenic therapy; patients may have&#xD;
             received one line of prior therapy with octreotide, locoregional therapy; continuation&#xD;
             of concurrent octreotide is allowed; patients will be maintained on octreotide&#xD;
             (sandostatin) for the duration of their treatment&#xD;
&#xD;
          -  Life expectancy of at least 12 weeks (3 months)&#xD;
&#xD;
          -  Subjects must be able to understand and be willing to sign the written informed&#xD;
             consent form (ICF); a signed ICF must be appropriately obtained prior to the conduct&#xD;
             of any trial-specific procedure&#xD;
&#xD;
          -  All acute toxic effects of any prior treatment have resolved to National Cancer&#xD;
             Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v)4.0&#xD;
             grade 1 or less at the time of signing the informed consent form (ICF); exceptions to&#xD;
             this include alopecia&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x the upper limits of normal (ULN)&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =&lt; 2.5 x ULN (=&lt; 5&#xD;
             x ULN for subjects with liver involvement of their cancer)&#xD;
&#xD;
          -  Alkaline phosphastase limit =&lt; 2.5 x ULN (=&lt; 5 x ULN for subjects with liver&#xD;
             involvement of their cancer)&#xD;
&#xD;
          -  Lipase =&lt; 1.5 x the ULN&#xD;
&#xD;
          -  Amylase =&lt; 1.5 x the ULN&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 x the ULN&#xD;
&#xD;
          -  International normalized ratio (INR)/ partial thromboplastin time (PTT) &lt; 1.5 x ULN;&#xD;
             (subjects who are treated with an agent such as warfarin or heparin will be allowed to&#xD;
             participate provided that no prior evidence of underlying abnormality in coagulation&#xD;
             parameters exists; close monitoring [day 5 of cycle 1 and day 1 of each cycle] is&#xD;
             mandatory) will be performed until INR/PTT is stable based on a measurement that is&#xD;
             pre-dose as defined by the local standard of care)&#xD;
&#xD;
          -  Platelet count &gt;= 100,000 /mm^3&#xD;
&#xD;
          -  Hemoglobin (Hb) &gt;= 9 g/dL&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,500/mm^3; blood transfusion to meet the inclusion&#xD;
             criteria will not be allowed&#xD;
&#xD;
          -  Glomerular filtration rate (GFR) &gt;= 30 ml/min/1.73 m^2 according to the Modified Diet&#xD;
             in Renal Disease (MDRD) abbreviated formula&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test performed&#xD;
             within 7 days prior to the start of study drug; post-menopausal women (defined as no&#xD;
             menses for at least 1 year) and surgically sterilized women are not required to&#xD;
             undergo a pregnancy test; the definition of adequate contraception will be based on&#xD;
             the judgement of the investigator&#xD;
&#xD;
          -  Subjects (men and women) of childbearing potential must agree to use adequate&#xD;
             contraception beginning at the signing of the ICF until at least 3 months after the&#xD;
             last dose of study drug; the definition of adequate contraception will be based on the&#xD;
             judgment of the principal investigator or a designated associate&#xD;
&#xD;
          -  Subject must be able to swallow and retain oral medication&#xD;
&#xD;
          -  Southwest Oncology Group (SWOG) performance status 0-1&#xD;
&#xD;
          -  Patients must have measurable disease&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous assignment to treatment during this study; subjects permanently withdrawn&#xD;
             from study participation will not be allowed to re-enter study&#xD;
&#xD;
          -  Uncontrolled hypertension (systolic pressure &gt; 140 mm Hg or diastolic pressure &gt; 90 mm&#xD;
             Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management&#xD;
&#xD;
          -  Active or clinically significant cardiac disease including:&#xD;
&#xD;
               -  Congestive heart failure - New York Heart Association (NYHA) &gt; class II&#xD;
&#xD;
               -  Active coronary artery disease&#xD;
&#xD;
               -  Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or&#xD;
                  digoxin&#xD;
&#xD;
               -  Unstable angina (anginal symptoms at rest), new-onset angina within 3 months&#xD;
                  before randomization, or myocardial infarction within 6 months before&#xD;
                  randomization&#xD;
&#xD;
          -  Evidence or history of bleeding diathesis or coagulopathy&#xD;
&#xD;
          -  Any hemorrhage or bleeding event &gt;= NCI-CTCAE grade 3 within 4 weeks prior to start of&#xD;
             study medication&#xD;
&#xD;
          -  Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular&#xD;
             accident (including transient ischemic attacks) deep vein thrombosis or pulmonary&#xD;
             embolism within 6 months of start of study treatment&#xD;
&#xD;
          -  Subjects with any previously untreated or concurrent cancer that is distinct in&#xD;
             primary site or histology from carcinoid or pancreatic islet cancer except cervical&#xD;
             cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor; subjects&#xD;
             surviving a cancer that was curatively treated and without evidence of disease for&#xD;
             more than 3 years before randomization are allowed; all cancer treatments must be&#xD;
             completed at least 3 years prior to study entry (i.e., signature date of the informed&#xD;
             consent form)&#xD;
&#xD;
          -  Patients with pheochromocytoma&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV) infection or current chronic or&#xD;
             active hepatitis B or C infection requiring treatment with antiviral therapy&#xD;
&#xD;
          -  Ongoing infection &gt; grade 2 NCI-CTCAE v4.0&#xD;
&#xD;
          -  Presence of a non-healing wound, non-healing ulcer, or bone fracture&#xD;
&#xD;
          -  Renal failure requiring hemo-or peritoneal dialysis&#xD;
&#xD;
          -  Dehydration grade &gt;= 1 NCI-CTCAE v4.0&#xD;
&#xD;
          -  Patients with seizure disorder requiring medication&#xD;
&#xD;
          -  Persistent proteinuria &gt;= grade 3 NCI-CTCAE v4.0 (&gt; 3.5 g/24 hrs, measured by urine&#xD;
             protein:creatinine ratio on a random urine sample)&#xD;
&#xD;
          -  Interstitial lung disease with ongoing signs and symptoms at the time of informed&#xD;
             consent&#xD;
&#xD;
          -  Pleural effusion or ascites that causes respiratory compromise (&gt;= NCI-CTCAE version&#xD;
             4.0 grade 2 dyspnea)&#xD;
&#xD;
          -  History of organ allograft (including corneal transplant)&#xD;
&#xD;
          -  Known or suspected allergy or hypersensitivity to any of the study drugs, study drug&#xD;
             classes, or excipients of the formulations given during the course of this trial&#xD;
&#xD;
          -  Any malabsorption condition&#xD;
&#xD;
          -  Women who are pregnant or breast-feeding&#xD;
&#xD;
          -  Any condition which, in the investigator's opinion, makes the subject unsuitable for&#xD;
             trial participation&#xD;
&#xD;
          -  Substance abuse, medical, psychological or social conditions that may interfere with&#xD;
             the subject's participation in the study or evaluation of the study results&#xD;
&#xD;
          -  Patients with known brain metastases should be excluded from this clinical trial&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to regorafenib or other agents used in study&#xD;
&#xD;
          -  Uncontrolled, intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Excluded therapies and medications, previous and concomitant&#xD;
&#xD;
               -  Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,&#xD;
                  immunotherapy, biologic therapy, or tumor embolization) other than study&#xD;
                  treatment (regorafenib)&#xD;
&#xD;
               -  Prior use of regorafenib&#xD;
&#xD;
               -  Concurrent use of chemotherapy, radiotherapy or another investigational drug or&#xD;
                  device therapy (i.e., outside of study treatment) during, or within 4 weeks of&#xD;
                  trial entry (signing of the ICF)&#xD;
&#xD;
               -  Major surgical procedure, open biopsy, or significant traumatic injury within 28&#xD;
                  days before start of study medication&#xD;
&#xD;
               -  Use of any herbal remedy (e.g. St. John's wort [Hypericum perforatum])&#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>Syma Iqbal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southern California</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Arizona</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85259</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC Norris Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hoag Memorial Hospital Presbyterian</name>
      <address>
        <city>Newport Beach</city>
        <state>California</state>
        <zip>92663</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC Norris Oncology Hematology-Newport Beach</name>
      <address>
        <city>Newport Beach</city>
        <state>California</state>
        <zip>92663</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Cancer Care Alliance</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>October 3, 2014</study_first_submitted>
  <study_first_submitted_qc>October 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 8, 2014</study_first_posted>
  <results_first_submitted>November 15, 2021</results_first_submitted>
  <results_first_submitted_qc>November 15, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">December 15, 2021</results_first_posted>
  <last_update_submitted>November 15, 2021</last_update_submitted>
  <last_update_submitted_qc>November 15, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 15, 2021</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>Neoplasms</mesh_term>
    <mesh_term>Neuroendocrine Tumors</mesh_term>
    <mesh_term>Carcinoid Tumor</mesh_term>
    <mesh_term>Malignant Carcinoid Syndrome</mesh_term>
    <mesh_term>Gastrointestinal Neoplasms</mesh_term>
    <mesh_term>Insulinoma</mesh_term>
    <mesh_term>Carcinoma, Islet Cell</mesh_term>
    <mesh_term>Gastrinoma</mesh_term>
    <mesh_term>Glucagonoma</mesh_term>
    <mesh_term>Somatostatinoma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <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>March 13, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/25/NCT02259725/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study began recruiting in August 2016 and ended in January 2019. All subjects were seen and treated either at USC Norris Comprehensive Cancer Center or at LAC+USC Medical Center.</recruitment_details>
      <pre_assignment_details>There were no pre-assignment criteria. All subjects were given the same treatment.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Treatment (Regorafenib)</title>
          <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
regorafenib: Given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment (Regorafenib)</title>
          <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
regorafenib: Given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </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="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </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="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>PFS</title>
        <description>Two parallel Simon's 2-stage phase II trials will be conducted to evaluate the efficacy of regorafenib in patients with advanced carcinoid (cohort A) or pancreatic islet cell tumors (cohort B). Will be summarized as a proportion of patients who are alive and progression-free among all patients in the primary data analysis set. The 95% confidence intervals (CIs) will be calculated using the Wilson method. Will be analyzed using Kaplan-Meier (KM) curves. The median PFS and 95% CIs will be calculated. The probability of 6-month PFS will be estimated from the KM curve too.</description>
        <time_frame>Time from start of treatment to time of progression or death on study whichever comes first, assessed at 6 months</time_frame>
        <population>No analysis done. Only 3 subjects were enrolled out of accrual goal of 24 subjects.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Regorafenib)</title>
            <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
regorafenib: Given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>PFS</title>
          <description>Two parallel Simon's 2-stage phase II trials will be conducted to evaluate the efficacy of regorafenib in patients with advanced carcinoid (cohort A) or pancreatic islet cell tumors (cohort B). Will be summarized as a proportion of patients who are alive and progression-free among all patients in the primary data analysis set. The 95% confidence intervals (CIs) will be calculated using the Wilson method. Will be analyzed using Kaplan-Meier (KM) curves. The median PFS and 95% CIs will be calculated. The probability of 6-month PFS will be estimated from the KM curve too.</description>
          <population>No analysis done. Only 3 subjects were enrolled out of accrual goal of 24 subjects.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee</title>
        <description>Will be calculated as a proportion of patients who have either a complete or partial response among all patients in the primary data analysis set. The 95% CIs will be given.</description>
        <time_frame>Up to 4 years</time_frame>
        <population>No analysis was done. Only 3 subjects were enrolled out of accrual goal of 24 subjects.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Regorafenib)</title>
            <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
regorafenib: Given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee</title>
          <description>Will be calculated as a proportion of patients who have either a complete or partial response among all patients in the primary data analysis set. The 95% CIs will be given.</description>
          <population>No analysis was done. Only 3 subjects were enrolled out of accrual goal of 24 subjects.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves.</description>
        <time_frame>From start of treatment until death due to any cause, assessed up to 4 years</time_frame>
        <population>Due to insufficient accrual (only 3 accrued), no analysis was performed.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Regorafenib)</title>
            <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
regorafenib: Given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves.</description>
          <population>Due to insufficient accrual (only 3 accrued), no analysis was performed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0</title>
        <description>Toxicity profile will be summarized by attribution: regorafenib-related and all reported, course: course 1 and all courses, type, and grade: grade 1-2, 3-4, and 5.</description>
        <time_frame>Up to 4 years</time_frame>
        <population>Data not collected</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Regorafenib)</title>
            <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
regorafenib: Given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0</title>
          <description>Toxicity profile will be summarized by attribution: regorafenib-related and all reported, course: course 1 and all courses, type, and grade: grade 1-2, 3-4, and 5.</description>
          <population>Data not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Biomarkers Such as Messenger Ribonucleic Acid (mRNA) Levels or Germline Variations of Genes Related to Angiogenesis</title>
        <description>The associations between biomarkers and clinical outcomes (6-month PFS, response, PFS, and overall survival) will be analyzed in univariate analysis first using appropriate methods. Multivariable analyses will be conducted to evaluate the independent effect of a marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values will be adjusted for multiple comparisons.</description>
        <time_frame>Up to 4 years</time_frame>
        <population>Analysis not done. Only 3 subjects were enrolled out of the accrual goal of subjects.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Regorafenib)</title>
            <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
regorafenib: Given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Biomarkers Such as Messenger Ribonucleic Acid (mRNA) Levels or Germline Variations of Genes Related to Angiogenesis</title>
          <description>The associations between biomarkers and clinical outcomes (6-month PFS, response, PFS, and overall survival) will be analyzed in univariate analysis first using appropriate methods. Multivariable analyses will be conducted to evaluate the independent effect of a marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values will be adjusted for multiple comparisons.</description>
          <population>Analysis not done. Only 3 subjects were enrolled out of the accrual goal of subjects.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected from the time the subject received the initial study drug administration and continued throughout the study until 30 days after the last dose or until resolution of adverse event if beyond 30 days after last dose.</time_frame>
      <desc>Adverse events are assessed during regularly scheduled follow up.</desc>
      <group_list>
        <group group_id="E1">
          <title>Treatment (Regorafenib)</title>
          <description>Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
regorafenib: Given PO&#xD;
laboratory biomarker analysis: Correlative studies</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="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="3" subjects_at_risk="3"/>
              </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="1" subjects_affected="1" subjects_at_risk="3"/>
              </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="3"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Stomach pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </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="3"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Testicular pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Victoria Soto</name_or_title>
      <organization>USC / Norris Comprehensive Cancer Center</organization>
      <phone>3238653000</phone>
      <email>soto_v@med.usc.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/NCT02259725
org study id: 0S-14-3
secondary id: NCI-2014-01996
secondary id: HS-14-00583
secondary id: 0S-14-3
secondary id: P30CA014089
nct id: NCT02259725
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies regorafenib in treating patients with neuroendocrine tumors that
      have spread from the primary site (place where it started) to other places in the body.
      Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for
      cell growth.
PRIMARY OBJECTIVES:

      I. To assess progression-free survival (PFS) in advanced/metastatic in patients with
      carcinoid or pancreatic islet cell tumors.

      SECONDARY OBJECTIVES:

      I. To assess overall survival and response rate in advanced/metastatic poor prognosis in
      patients with carcinoid or pancreatic islet cell tumors.

      II. To assess the toxicity of patients treated with regorafenib. III. To explore markers of
      angiogenesis as they relate to outcome in carcinoid and pancreatic islet cell tumors.

      OUTLINE:

      Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Courses repeat every
      28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: PFS
time frame: Time from start of treatment to time of progression or death on study whichever comes first, assessed at 6 months
description: Two parallel Simon's 2-stage phase II trials will be conducted to evaluate the efficacy of regorafenib in patients with advanced carcinoid (cohort A) or pancreatic islet cell tumors (cohort B). Will be summarized as a proportion of patients who are alive and progression-free among all patients in the primary data analysis set. The 95% confidence intervals (CIs) will be calculated using the Wilson method. Will be analyzed using Kaplan-Meier (KM) curves. The median PFS and 95% CIs will be calculated. The probability of 6-month PFS will be estimated from the KM curve too.
measure: Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee
time frame: Up to 4 years
description: Will be calculated as a proportion of patients who have either a complete or partial response among all patients in the primary data analysis set. The 95% CIs will be given.
measure: Overall Survival
time frame: From start of treatment until death due to any cause, assessed up to 4 years
description: The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves.
measure: Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
time frame: Up to 4 years
description: Toxicity profile will be summarized by attribution: regorafenib-related and all reported, course: course 1 and all courses, type, and grade: grade 1-2, 3-4, and 5.
measure: Biomarkers Such as Messenger Ribonucleic Acid (mRNA) Levels or Germline Variations of Genes Related to Angiogenesis
time frame: Up to 4 years
description: The associations between biomarkers and clinical outcomes (6-month PFS, response, PFS, and overall survival) will be analyzed in univariate analysis first using appropriate methods. Multivariable analyses will be conducted to evaluate the independent effect of a marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values will be adjusted for multiple comparisons.
arm group label: Treatment (regorafenib)
arm group type: Experimental
description: Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: regorafenib
description: Given PO
arm group label: Treatment (regorafenib)
other name: BAY 73-4506
other name: multikinase inhibitor BAY 73-4506
other name: Stivarga
intervention type: Other
intervention name: laboratory biomarker analysis
description: Correlative studies
arm group label: Treatment (regorafenib)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Syma Iqbal, MD
role: Principal Investigator
affiliation: University of Southern California
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Neuroendocrine Tumors
mesh term: Carcinoid Tumor
mesh term: Malignant Carcinoid Syndrome
mesh term: Gastrointestinal Neoplasms
mesh term: Insulinoma
mesh term: Carcinoma, Islet Cell
mesh term: Gastrinoma
mesh term: Glucagonoma
mesh term: Somatostatinoma
mesh term: Recurrence
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 