<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/NCT03008369</url>
  </required_header>
  <id_info>
    <org_study_id>MC1575</org_study_id>
    <secondary_id>NCI-2016-02032</secondary_id>
    <secondary_id>MC1575</secondary_id>
    <secondary_id>P30CA015083</secondary_id>
    <nct_id>NCT03008369</nct_id>
  </id_info>
  <brief_title>Lenvatinib in Treating Patients With Metastatic or Advanced Pheochromocytoma or Paraganglioma That Cannot Be Removed by Surgery</brief_title>
  <official_title>Phase II Trial of Lenvatinib in Metastatic or Advanced Pheochromocytoma and Paraganglioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well lenvatinib works in treating patients with&#xD;
      pheochromocytoma or paraganglioma that has spread to other places in the body or cannot be&#xD;
      removed by surgery. Lenvatinib may stop the growth of tumor cells by blocking some of the&#xD;
      enzymes needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the anti-tumor activity of lenvatinib (overall response rate; [ORR]) in&#xD;
      patients with metastatic or advanced unresectable pheochromocytomas and paragangliomas.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine progression-free survival (PFS). II. To determine overall survival (OS). III.&#xD;
      To determine duration of tumor response. IV. To determine safety and tolerability of&#xD;
      lenvatinib. V. To assess patient reported quality of life using EuroQol Five-Dimensional Five&#xD;
      Level Scale Questionnaire (EQ-5D-5L) and Functional Assessment of Cancer Therapy-General&#xD;
      (FACT-G).&#xD;
&#xD;
      TERTIARY OBJECTIVES:&#xD;
&#xD;
      I. For patients with secretory tumors, to examine changes in plasma metanephrine levels and&#xD;
      urinary catecholamine and/or metanephrine levels.&#xD;
&#xD;
      II. For patients with secretory tumors, to examine whether lenvatinib-induced changes in&#xD;
      plasma metanephrines and urinary catecholamine and/or metanephrine levels during the first&#xD;
      cycle of treatment may be associated with objective tumor response.&#xD;
&#xD;
      III. To examine associations between tumor response and somatic mutational status in archived&#xD;
      tumors, or germline mutational status (presence of SDHD, SDHB, RET, VHL, neurofibromatosis&#xD;
      type-1).&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive lenvatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28&#xD;
      days for up to 5 years in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 or 6 months for up to 5&#xD;
      years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 31, 2017</start_date>
  <completion_date type="Actual">September 28, 2022</completion_date>
  <primary_completion_date type="Actual">December 1, 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>Confirmed Tumor Response Rate</measure>
    <time_frame>Monthly, up to 17 months.</time_frame>
    <description>Will be defined as 100% times the number of eligible patients who has started lenvatinib and whose objective tumor status was a complete response or partial response on 2 consecutive evaluations at least 4 weeks apart (using Response Evaluation Criteria in Solid Tumors version 1.1 criteria) divided by the number of eligible patients who has started lenvatinib. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of Tumor Response</measure>
    <time_frame>Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months</time_frame>
    <description>Will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patients Evaluable for Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0</measure>
    <time_frame>Monthly, up to 17 months.</time_frame>
    <description>Adverse Events are fully reported in the adverse event section of the results. All adverse events will be graded. For each type of adverse event classified as either possibly, probably, or definitely related to study treatment, the proportion of patients experiencing a severe (grade 3 or higher) adverse event will be noted per cycle. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival Time</measure>
    <time_frame>Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months</time_frame>
    <description>Will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>Every month until off treatment, at off treatment, every 3 months until PD, at PD or up to 17 months</time_frame>
    <description>Will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life Assessed by EQ-5D and FACT-G</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Descriptive statistics, and scatter plots will form the basis of presentation of these data both overall and by other outcomes (toxicity, response and survival measures). Correlations between the quality of life outcomes and other outcome measures will be carried out by standard parametric and nonparametric tests (e.g. Pearson's and Spearman's rho). Comparison between continuous variables will be made with Wilcoxon rank sum tests, Fisher's exact tests will be used to determine differences between categorical variables, and Log-rank test will be used to test differences between time-to-event ou</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Changes in Urinary Catecholamine and Metanephrine Levels</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Wilcoxon rank sum tests will be used to examine whether fold changes in a given biomarker during the first cycle of treatment differs between whose tumor responded to treatment and those whose tumor did not. Time series plots will be constructed.</description>
  </other_outcome>
  <other_outcome>
    <measure>Germline Mutational Status in Peripheral Blood Mononuclear Cells</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).</description>
  </other_outcome>
  <other_outcome>
    <measure>Somatic Mutational Status in Peripheral Blood Mononuclear Cells</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Will examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Malignant Adrenal Gland Pheochromocytoma</condition>
  <condition>Malignant Paraganglioma</condition>
  <condition>Metastatic Adrenal Gland Pheochromocytoma</condition>
  <arm_group>
    <arm_group_label>Treatment (lenvatinib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (lenvatinib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenvatinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (lenvatinib)</arm_group_label>
    <other_name>E7080</other_name>
    <other_name>ER-203492-00</other_name>
    <other_name>Multi-Kinase Inhibitor E7080</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Quality-of-Life Assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (lenvatinib)</arm_group_label>
    <other_name>Quality of Life Assessment</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed malignant secretory or non-secretory&#xD;
             pheochromocytoma or paraganglioma that is unresectable and deemed inappropriate for&#xD;
             alternative local regional therapeutic approaches&#xD;
&#xD;
          -  Measurable disease&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2&#xD;
&#xD;
          -  Life expectancy &gt; 24 weeks&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1500/mm^3&#xD;
&#xD;
          -  White blood cell (WBC) count &gt;= 3,000/mm^3&#xD;
&#xD;
          -  Platelet count &gt;= 100,000/mm^3&#xD;
&#xD;
          -  Hemoglobin &gt;= 9.0 g/dL (5.6 mmol/L); NOTE: transfusions are not allowed =&lt; 7 days&#xD;
             prior to registration&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 X upper limit of normal (ULN) (or total bilirubin =&lt; 3.0 X ULN&#xD;
             with direct bilirubin =&lt; 1.5 X ULN in patients with well-documented Gilbert's&#xD;
             Syndrome)&#xD;
&#xD;
          -  Aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]) =&lt; 2.5 X&#xD;
             ULN&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 x ULN&#xD;
&#xD;
          -  Urine protein/creatinine ratio =&lt; 1 OR 24-hour urine protein &lt; 1.5 gram&#xD;
&#xD;
          -  Negative pregnancy test done =&lt; 7 days prior to registration, for women of&#xD;
             childbearing potential only&#xD;
&#xD;
          -  Blood pressure (BP) &lt; 150 mmHg (systolic) and &lt; 90 mmHg (diastolic); initiation or&#xD;
             adjustment of BP medication is permitted prior to registration provided that the&#xD;
             average of three BP readings at a visit prior to registration is &lt; 150/90 mmHg; NOTE:&#xD;
             all patients with secretory pheochromocytoma or paraganglioma are REQUIRED to: 1) be&#xD;
             evaluated in consultation by a hypertension specialist with specific experience in the&#xD;
             management of hypertension in the setting of catecholamine-secreting tumors (usually&#xD;
             an endocrinologist, nephrologist, or a cardiologist), and in the setting of&#xD;
             hormone-associated hypertension) receive alpha- and beta-adrenergic blockade for at&#xD;
             least 7-14 days prior to initiation of lenvatinib; the hypertension specialist of&#xD;
             record for each patient should be committed to closely following the patient during&#xD;
             the clinical study with evaluation by said specialist required at cycle 1 and 2 and&#xD;
             thereafter on an as needed basis&#xD;
&#xD;
          -  Provide written informed consent&#xD;
&#xD;
          -  Willing to return to enrolling institution for follow-up (during the active monitoring&#xD;
             phase of the study)&#xD;
&#xD;
          -  Ability to complete questionnaire(s) by themselves or with assistance&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any of the following:&#xD;
&#xD;
               -  Pregnant women&#xD;
&#xD;
               -  Nursing women&#xD;
&#xD;
               -  Men or women of childbearing potential who are unwilling to employ adequate&#xD;
                  contraception&#xD;
&#xD;
          -  Chemotherapy/systemic therapy, radiotherapy, immunotherapy or surgery =&lt; 21 days prior&#xD;
             to registration or kinase inhibitor therapy =&lt; 14 days prior to registration or&#xD;
             failure to recover from toxicities (to grade 1 or below) from treatment; NOTE:&#xD;
             concurrent therapy with octreotide is allowed providing that tumor progression on this&#xD;
             therapy has been demonstrated; concurrent therapy with bisphosphonates (e.g.&#xD;
             zoledronic acid) or denosumab is also allowed; NOTE: an unlimited number of prior&#xD;
             chemotherapeutic or biologic therapies for malignant pheochromocytoma or paraganglioma&#xD;
             is permitted; this includes prior anti-angiogenesis therapies such as tyrosine kinase&#xD;
             inhibitors&#xD;
&#xD;
          -  Active or uncontrolled intercurrent illness including, but not limited to, ongoing or&#xD;
             active infection, symptomatic congestive heart failure, unstable angina pectoris,&#xD;
             cardiac arrhythmia, or psychiatric illness/social situations that would limit&#xD;
             compliance with study requirements&#xD;
&#xD;
          -  Receiving any other investigational agent&#xD;
&#xD;
          -  Current use of warfarin for any reason; NOTE: if patient can be safely transitioned to&#xD;
             another anticoagulant, they may be eligible provided other criteria are satisfied&#xD;
&#xD;
          -  Any of the following:&#xD;
&#xD;
               -  Correct QT (QTc) prolongation (defined as a QTc interval &gt;= 500 msecs)&#xD;
&#xD;
               -  Left ventricular ejection fraction (LVEF) &lt; institutional lower limits of normal&#xD;
                  (LLN)&#xD;
&#xD;
               -  Frequent ventricular ectopy&#xD;
&#xD;
               -  Evidence of ongoing myocardial ischemia&#xD;
&#xD;
          -  Receiving any medications or substances with risk of torsades de pointes; NOTE:&#xD;
             medications or substances with known risk of torsades de pointes are prohibited;&#xD;
             consult pharmacist for review if needed&#xD;
&#xD;
          -  Known active and/or untreated brain metastases&#xD;
&#xD;
          -  Known severe allergic or other prohibitive reactions to other tyrosine kinase&#xD;
             inhibitors (TKI)&#xD;
&#xD;
          -  Prior treatment with lenvatinib&#xD;
&#xD;
          -  Any of the following conditions:&#xD;
&#xD;
               -  Active peptic ulcer disease&#xD;
&#xD;
               -  Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other&#xD;
                  gastrointestinal conditions which increase the risk of perforation&#xD;
&#xD;
               -  History of new abdominal fistula, gastrointestinal perforation or intra-abdominal&#xD;
                  abscess =&lt; 84 days prior to registration; NOTE: enrollment of patients with&#xD;
                  chronic/canalized fistulous tracts (present for &gt; 84 days) is allowed&#xD;
&#xD;
               -  Serious or non-healing wound, ulcer, or bone fracture&#xD;
&#xD;
               -  History of familial QTc prolongation syndrome&#xD;
&#xD;
          -  Any of the following conditions =&lt; 6 months prior to registration:&#xD;
&#xD;
               -  Cerebrovascular accident (CVA) or transient ischemic attack (TIA)&#xD;
&#xD;
               -  Serious or unstable cardiac arrhythmia&#xD;
&#xD;
               -  Admission for unstable angina or myocardial infarction&#xD;
&#xD;
               -  Cardiac angioplasty or stenting&#xD;
&#xD;
               -  Coronary artery bypass graft surgery&#xD;
&#xD;
               -  Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been&#xD;
                  treated with therapeutic anticoagulation =&lt; 30 days&#xD;
&#xD;
               -  Arterial thrombosis&#xD;
&#xD;
               -  Symptomatic peripheral vascular disease&#xD;
&#xD;
          -  Other active malignancy =&lt; 2 years prior to registration; EXCEPTIONS: non-melanotic&#xD;
             skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior&#xD;
             malignancy, they must not be receiving other specific treatment for their cancer;&#xD;
             NOTE: adjuvant anti-estrogen/hormonal therapy for breast cancer is allowed&#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>Ashish Chintakuntlawar</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.mayo.edu/research/clinical-trials</url>
    <description>Mayo Clinic Clinical Trials</description>
  </link>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <results_first_submitted>July 1, 2020</results_first_submitted>
  <results_first_submitted_qc>April 22, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">May 14, 2021</results_first_posted>
  <last_update_submitted>September 28, 2022</last_update_submitted>
  <last_update_submitted_qc>September 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 6, 2022</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>Pheochromocytoma</mesh_term>
    <mesh_term>Paraganglioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lenvatinib</mesh_term>
  </intervention_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>September 18, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/69/NCT03008369/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment (Lenvatinib)</title>
          <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.</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 (Lenvatinib)</title>
          <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Lenvatinib: Given PO Quality-of-Life Assessment: Ancillary 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>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50" lower_limit="44" upper_limit="59"/>
                  </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </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_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Confirmed Tumor Response Rate</title>
        <description>Will be defined as 100% times the number of eligible patients who has started lenvatinib and whose objective tumor status was a complete response or partial response on 2 consecutive evaluations at least 4 weeks apart (using Response Evaluation Criteria in Solid Tumors version 1.1 criteria) divided by the number of eligible patients who has started lenvatinib. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR</description>
        <time_frame>Monthly, up to 17 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lenvatinib)</title>
            <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Confirmed Tumor Response Rate</title>
          <description>Will be defined as 100% times the number of eligible patients who has started lenvatinib and whose objective tumor status was a complete response or partial response on 2 consecutive evaluations at least 4 weeks apart (using Response Evaluation Criteria in Solid Tumors version 1.1 criteria) divided by the number of eligible patients who has started lenvatinib. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Tumor Response</title>
        <description>Will be estimated using the Kaplan-Meier method.</description>
        <time_frame>Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months</time_frame>
        <population>All treated patients</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lenvatinib)</title>
            <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Tumor Response</title>
          <description>Will be estimated using the Kaplan-Meier method.</description>
          <population>All treated patients</population>
          <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="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.7" lower_limit="9.7" upper_limit="NA">Upper limit not reached due to insufficient number of participants with events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Patients Evaluable for Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0</title>
        <description>Adverse Events are fully reported in the adverse event section of the results. All adverse events will be graded. For each type of adverse event classified as either possibly, probably, or definitely related to study treatment, the proportion of patients experiencing a severe (grade 3 or higher) adverse event will be noted per cycle. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns.</description>
        <time_frame>Monthly, up to 17 months.</time_frame>
        <population>All treated patients</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lenvatinib)</title>
            <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Patients Evaluable for Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0</title>
          <description>Adverse Events are fully reported in the adverse event section of the results. All adverse events will be graded. For each type of adverse event classified as either possibly, probably, or definitely related to study treatment, the proportion of patients experiencing a severe (grade 3 or higher) adverse event will be noted per cycle. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns.</description>
          <population>All treated patients</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="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival Time</title>
        <description>Will be estimated using the Kaplan-Meier method.</description>
        <time_frame>Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months</time_frame>
        <population>All treated patients</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lenvatinib)</title>
            <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival Time</title>
          <description>Will be estimated using the Kaplan-Meier method.</description>
          <population>All treated patients</population>
          <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="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Kaplan-Meier median, lower limit, and upper limit not reached due to insufficient number of participants with events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival</title>
        <description>Will be estimated using the Kaplan-Meier method.</description>
        <time_frame>Every month until off treatment, at off treatment, every 3 months until PD, at PD or up to 17 months</time_frame>
        <population>All treated patients</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lenvatinib)</title>
            <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival</title>
          <description>Will be estimated using the Kaplan-Meier method.</description>
          <population>All treated patients</population>
          <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="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.5" lower_limit="5.5" upper_limit="NA">Upper limit not reached due to insufficient number of participants with events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Quality of Life Assessed by EQ-5D and FACT-G</title>
        <description>Descriptive statistics, and scatter plots will form the basis of presentation of these data both overall and by other outcomes (toxicity, response and survival measures). Correlations between the quality of life outcomes and other outcome measures will be carried out by standard parametric and nonparametric tests (e.g. Pearson's and Spearman's rho). Comparison between continuous variables will be made with Wilcoxon rank sum tests, Fisher's exact tests will be used to determine differences between categorical variables, and Log-rank test will be used to test differences between time-to-event ou</description>
        <time_frame>Up to 5 years</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Changes in Urinary Catecholamine and Metanephrine Levels</title>
        <description>Wilcoxon rank sum tests will be used to examine whether fold changes in a given biomarker during the first cycle of treatment differs between whose tumor responded to treatment and those whose tumor did not. Time series plots will be constructed.</description>
        <time_frame>Up to 5 years</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Germline Mutational Status in Peripheral Blood Mononuclear Cells</title>
        <description>Will examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).</description>
        <time_frame>Up to 5 years</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Somatic Mutational Status in Peripheral Blood Mononuclear Cells</title>
        <description>Will examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).</description>
        <time_frame>Up to 5 years</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Monthly, up to 17 months.</time_frame>
      <desc>Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0</desc>
      <group_list>
        <group group_id="E1">
          <title>Treatment (Lenvatinib)</title>
          <description>Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Lenvatinib: Given PO Quality-of-Life Assessment: Ancillary studies</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 12</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>Gastrointestinal disorders - Oth spec</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>MedDRA 12</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>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</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>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="12" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</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="11" subjects_affected="2" 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>Fatigue</sub_title>
                <counts group_id="E1" events="19" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <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>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Musculoskeletal, conn tissue - Oth spec</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="15" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrm</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" 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="17" subjects_affected="2" subjects_at_risk="3"/>
              </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>Ashish Vitthalrao Chintakuntlawar, MBBS, Ph.D.</name_or_title>
      <organization>Mayo Clinic</organization>
      <phone>5072930504</phone>
      <email>Chintakuntlawar.Ashish@mayo.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/NCT03008369
org study id: MC1575
secondary id: NCI-2016-02032
secondary id: MC1575
secondary id: P30CA015083
nct id: NCT03008369
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well lenvatinib works in treating patients with
      pheochromocytoma or paraganglioma that has spread to other places in the body or cannot be
      removed by surgery. Lenvatinib may stop the growth of tumor cells by blocking some of the
      enzymes needed for cell growth.
PRIMARY OBJECTIVES:

      I. To determine the anti-tumor activity of lenvatinib (overall response rate; [ORR]) in
      patients with metastatic or advanced unresectable pheochromocytomas and paragangliomas.

      SECONDARY OBJECTIVES:

      I. To determine progression-free survival (PFS). II. To determine overall survival (OS). III.
      To determine duration of tumor response. IV. To determine safety and tolerability of
      lenvatinib. V. To assess patient reported quality of life using EuroQol Five-Dimensional Five
      Level Scale Questionnaire (EQ-5D-5L) and Functional Assessment of Cancer Therapy-General
      (FACT-G).

      TERTIARY OBJECTIVES:

      I. For patients with secretory tumors, to examine changes in plasma metanephrine levels and
      urinary catecholamine and/or metanephrine levels.

      II. For patients with secretory tumors, to examine whether lenvatinib-induced changes in
      plasma metanephrines and urinary catecholamine and/or metanephrine levels during the first
      cycle of treatment may be associated with objective tumor response.

      III. To examine associations between tumor response and somatic mutational status in archived
      tumors, or germline mutational status (presence of SDHD, SDHB, RET, VHL, neurofibromatosis
      type-1).

      OUTLINE:

      Patients receive lenvatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28
      days for up to 5 years in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 or 6 months for up to 5
      years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Confirmed Tumor Response Rate
time frame: Monthly, up to 17 months.
description: Will be defined as 100% times the number of eligible patients who has started lenvatinib and whose objective tumor status was a complete response or partial response on 2 consecutive evaluations at least 4 weeks apart (using Response Evaluation Criteria in Solid Tumors version 1.1 criteria) divided by the number of eligible patients who has started lenvatinib. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
measure: Duration of Tumor Response
time frame: Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months
description: Will be estimated using the Kaplan-Meier method.
measure: Patients Evaluable for Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0
time frame: Monthly, up to 17 months.
description: Adverse Events are fully reported in the adverse event section of the results. All adverse events will be graded. For each type of adverse event classified as either possibly, probably, or definitely related to study treatment, the proportion of patients experiencing a severe (grade 3 or higher) adverse event will be noted per cycle. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns.
measure: Overall Survival Time
time frame: Every month until off treatment, at off treatment, every 3 months until PD, at PD, every 6 months after PD up to 17 months
description: Will be estimated using the Kaplan-Meier method.
measure: Progression-free Survival
time frame: Every month until off treatment, at off treatment, every 3 months until PD, at PD or up to 17 months
description: Will be estimated using the Kaplan-Meier method.
measure: Quality of Life Assessed by EQ-5D and FACT-G
time frame: Up to 5 years
description: Descriptive statistics, and scatter plots will form the basis of presentation of these data both overall and by other outcomes (toxicity, response and survival measures). Correlations between the quality of life outcomes and other outcome measures will be carried out by standard parametric and nonparametric tests (e.g. Pearson's and Spearman's rho). Comparison between continuous variables will be made with Wilcoxon rank sum tests, Fisher's exact tests will be used to determine differences between categorical variables, and Log-rank test will be used to test differences between time-to-event ou
measure: Changes in Urinary Catecholamine and Metanephrine Levels
time frame: Up to 5 years
description: Wilcoxon rank sum tests will be used to examine whether fold changes in a given biomarker during the first cycle of treatment differs between whose tumor responded to treatment and those whose tumor did not. Time series plots will be constructed.
measure: Germline Mutational Status in Peripheral Blood Mononuclear Cells
time frame: Up to 5 years
description: Will examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).
measure: Somatic Mutational Status in Peripheral Blood Mononuclear Cells
time frame: Up to 5 years
description: Will examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).
arm group label: Treatment (lenvatinib)
arm group type: Experimental
description: Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (lenvatinib)
intervention type: Drug
intervention name: Lenvatinib
description: Given PO
arm group label: Treatment (lenvatinib)
other name: E7080
other name: ER-203492-00
other name: Multi-Kinase Inhibitor E7080
intervention type: Other
intervention name: Quality-of-Life Assessment
description: Ancillary studies
arm group label: Treatment (lenvatinib)
other name: Quality of Life Assessment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ashish Chintakuntlawar
role: Principal Investigator
affiliation: Mayo Clinic
facility: 
country: United States
url: https://www.mayo.edu/research/clinical-trials
description: Mayo Clinic Clinical Trials
responsible party type: Sponsor
mesh term: Pheochromocytoma
mesh term: Paraganglioma
mesh term: Lenvatinib
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 