<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/NCT01688999</url>
  </required_header>
  <id_info>
    <org_study_id>120205</org_study_id>
    <secondary_id>12-C-0205</secondary_id>
    <nct_id>NCT01688999</nct_id>
  </id_info>
  <brief_title>Cabozantinib for Advanced Urothelial Cancer</brief_title>
  <official_title>A Phase II Study of Cabozantinib (XL184) in Patients With Advanced/Metastatic Urothelial Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <has_dmc>No</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>
      Background:&#xD;
&#xD;
      - Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is&#xD;
      approved for medullary thyroid cancer. However, studies have shown that prostate and ovarian&#xD;
      tumors respond to it. Researchers want see if cabozantinib can be a safe and effective&#xD;
      treatment for urothelial cancer.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To test the safety and effectiveness of cabozantinib for advanced urothelial cancer.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Individuals at least 18 years of age who have advanced urothelial cancer that has not&#xD;
      responded to standard treatments.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with a physical exam and medical history. Blood and urine&#xD;
           samples will be collected. Tumor tissue samples will also be collected. Imaging studies&#xD;
           will also be performed.&#xD;
&#xD;
        -  Participants will take cabozantinib by mouth once per day on each day of a 28-day cycle.&#xD;
&#xD;
        -  Treatment will be monitored with frequent blood tests and imaging studies.&#xD;
&#xD;
        -  Participants will continue to take the study drug for as long as their cancer does not&#xD;
           worsen and side effects are not too severe.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common&#xD;
           malignancy in men and the ninth most common in women with an estimated 69,250 new cases&#xD;
           and 14,990 deaths in the year 2011&#xD;
&#xD;
        -  There is no Food and Drug Administration (FDA)-approved second line drug for patients&#xD;
           with metastatic Urothelial Cancer (UC)&#xD;
&#xD;
        -  Multiple lines of evidence support targeting angiogenesis in UC&#xD;
&#xD;
        -  In human bladder cancer, overexpression of tyrosine-protein kinase (c-Met)/Axl/platelet&#xD;
           derived growth factor receptor- (PDGFR)-alpha or c-Met alone showed significant&#xD;
           correlation with poor survival&#xD;
&#xD;
        -  Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases&#xD;
           with growth-promoting and angiogenic properties.&#xD;
&#xD;
        -  The primary targets of cabozantinib are mesenchymal epithelial transition factor (MET),&#xD;
           vascular endothelial factor receptor 2 (VEGFR2), and rearranged during transfection&#xD;
           (RET)&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To determine the response rate of cabozantinib in patients with progressive urothelial&#xD;
      cancer who have received prior cytotoxic chemotherapy&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic,&#xD;
           progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.&#xD;
&#xD;
        -  Patients in cohort 2 must have a histologically confirmed diagnosis of bone only&#xD;
           metastatic, urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.&#xD;
&#xD;
        -  Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional&#xD;
           cell carcinoma cancer (including but not limited to squamous cell, neuroendocrine,&#xD;
           adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or&#xD;
           renal pelvis.&#xD;
&#xD;
        -  Patients must have been previously treated, as defined by treatment with at least one&#xD;
           prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of&#xD;
           prior cytotoxic agents.&#xD;
&#xD;
        -  18 years of age or older.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  A maximum of 71subjects will be enrolled in this open label, non-randomized, phase II&#xD;
           trial of 60 mg each day of cabozantinib. Up to 50 patients will be accrued to cohort 1&#xD;
           (metastatic, progressive urothelial cancer. The remainder will be enrolled on&#xD;
           exploratory cohorts 2 &amp; 3, bone only metastatic urothelial disease and non transitional&#xD;
           cell carcinoma (TCC) bladder cancer respectively, during the time the study is accruing&#xD;
           patients for cohort 1. Note: Patients who tolerate cabozantinib at 60 mg daily during&#xD;
           the first 2 cycles (first restaging time period) without (Bullet) grade 2 toxicity may&#xD;
           undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator.&#xD;
&#xD;
        -  A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error&#xD;
           probabilities. Initially 21 subjects will be enrolled and followed for progression. If 2&#xD;
           or more of cohort 1 subjects experiences a response, enrollment will continue until a&#xD;
           total of 41 evaluable subjects with progressive urothelial cancer have been entered. 2-3&#xD;
           patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the&#xD;
           accrual period.&#xD;
&#xD;
        -  Each patient will undergo response evaluation assessments with chest abdomen pelvis&#xD;
           computed tomography (CAP CT) (or magnetic resonance imaging (MRI)) with or without&#xD;
           18F-Sodium Fluoride (Na18F) positron emission tomography (PET CT) every 8 weeks while on&#xD;
           active protocol therapy starting at baseline. Patients will undergo investigational&#xD;
           Fludeoxyglucose, (FDG) PET/CT and PET/MRI (optional) at baseline, week 4 and week 8.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 11, 2012</start_date>
  <completion_date type="Actual">September 14, 2020</completion_date>
  <primary_completion_date type="Actual">December 11, 2017</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>Percentage of Participants With Overall Response</measure>
    <time_frame>Median follow-up was 61.2 months</time_frame>
    <description>Complete Response (CR) or Partial Response (PR) to Cabozantinib (XL184) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Median follow-up was 61.2 months</time_frame>
    <description>Measure the timing from the study start until death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>Median follow-up was 61.2 months</time_frame>
    <description>Measure the timing of maintaining stable disease or partial response until disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest um diameters while on study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib</measure>
    <time_frame>Median follow-up was 61.2 months</time_frame>
    <description>Grade 4 toxicity hypomagnesium experienced by participants related to Cabozantinib. Grade 4 toxicity is life-threatening consequences; urgent intervention indicated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution</measure>
    <time_frame>Median follow-up was 61.2 months</time_frame>
    <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">69</enrollment>
  <condition>Urothelial Carcinoma</condition>
  <condition>Urethral Neoplasms</condition>
  <condition>Urinary Bladder Neoplasms</condition>
  <condition>Kidney Neoplasms</condition>
  <arm_group>
    <arm_group_label>Cabozantinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Administered orally at a dose of 60 mg once daily on each day of a 28-day cycle.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabozantinib</intervention_name>
    <description>60 mg by mouth (PO) daily each 28 day cycle. Treatment continues until toxicity or disease progression.</description>
    <arm_group_label>Cabozantinib</arm_group_label>
    <other_name>Cometriq</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        Cohort 1 only (urothelial progressive disease)&#xD;
&#xD;
          -  Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the&#xD;
             bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any&#xD;
             Clinical Laboratory Improvement Amendments (CLIA) certified lab.&#xD;
&#xD;
          -  Patients must have progressive metastatic disease. Progressive disease will be defined&#xD;
             as new or progressive lesions on cross-sectional imaging.&#xD;
&#xD;
          -  Patients must have at least one measurable site of disease&#xD;
&#xD;
        Cohort 2 only (Bone-only)&#xD;
&#xD;
          -  Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the&#xD;
             bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA&#xD;
             certified lab.&#xD;
&#xD;
          -  Patients must not have measurable progressive disease&#xD;
&#xD;
          -  Patient must have appearance of at least one new bone lesion.&#xD;
&#xD;
        Cohort 3 (Rare histologies)&#xD;
&#xD;
          -  Patient must have a histologically confirmed diagnosis of non-transitional cell&#xD;
             carcinoma of the bladder, urethra, ureter, or renal pelvis including but not limited&#xD;
             to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid.&#xD;
             Confirmation may be obtained from any CLIA certified lab.&#xD;
&#xD;
          -  Patients must have progressive metastatic disease. Progressive disease will be defined&#xD;
             as new or progressive lesions on cross-sectional imaging.&#xD;
&#xD;
          -  Patients must have at least one measurable site of disease&#xD;
&#xD;
        All cohorts&#xD;
&#xD;
          -  Patients must have been previously treated, as defined by treatment with at least one&#xD;
             prior cytotoxic regimen or agent.&#xD;
&#xD;
          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are&#xD;
             currently available on the use of cabozantinib in patients &lt;18 years of age, children&#xD;
             are excluded from this study, but may be eligible for future pediatric trials.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2&#xD;
             (Karnofsky greater than or equal to 60%&#xD;
&#xD;
          -  Adequate organ function as defined by the following criteria:&#xD;
&#xD;
          -  Hemoglobin greater than or equal to 9 g/dL&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) greater than or equal to 1500/microL&#xD;
&#xD;
          -  Platelets greater than or equal to 75,000/L&#xD;
&#xD;
          -  Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and&#xD;
             serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) less than&#xD;
             or equal to 3.0 times upper limit of normal (ULN); less than or equal to 5.0 times ULN&#xD;
             in cases of liver metastases&#xD;
&#xD;
          -  Total serum bilirubin less than or equal to 1.5 times the upper limit of normal (ULN).&#xD;
             For subjects with known Gilberts disease or similar syndrome with slow conjugation of&#xD;
             bilirubin, total bilirubin less than or equal to 3.0 mg/dL&#xD;
&#xD;
          -  Serum creatinine less than or equal to 1.5 X institutional upper limits of normal or&#xD;
             for patients with creatinine levels above 1.5 x institutional normal: creatinine&#xD;
             clearance greater than or equal to 50 mL/min/1.73 m^2 by 24 hour urine collection or&#xD;
             estimated creatinine clearance of greater than or equal to 50 mL/min. For creatinine&#xD;
             clearance estimation , the Cockcroft and Gault equation should be used:&#xD;
&#xD;
          -  Male: Creatinine Clearance (CrCl) (mL/min) = (140 - age) times wt (kg)/ (serum&#xD;
             creatinine times 72)&#xD;
&#xD;
          -  Female: Multiply above result by 0.85&#xD;
&#xD;
          -  Urine protein/creatinine ratio (UPCR) less than or equal to 2&#xD;
&#xD;
          -  Patient must be able to provide either archival tumor samples (haematoxylin and eosin&#xD;
             (H&amp;E) slides and one paraffin block or 10 unstained slides) or undergo tumor biopsy.&#xD;
&#xD;
          -  Patient must be capable of understanding and complying with protocol requirements and&#xD;
             is willing to give informed consent&#xD;
&#xD;
          -  The effects of XL184 on the developing human fetus are unknown. For this reason and&#xD;
             because tyrosine kinase inhibitors agents are known to be teratogenic, women of&#xD;
             childbearing potential and men must agree to use adequate contraception prior to study&#xD;
             entry and for the duration of study participation. Should a woman become pregnant or&#xD;
             suspect she is pregnant while she or her partner is participating in this study, she&#xD;
             should inform her treating physician immediately. Men treated or enrolled on this&#xD;
             protocol must also agree to use adequate contraception prior to the study, for the&#xD;
             duration of study participation, and 4 months after completion of XL184&#xD;
             administration.&#xD;
&#xD;
        Sexually active subjects (men and women) must agree to use medically accepted barrier&#xD;
        methods of contraception (e.g., male or female condom) during the course of the study and&#xD;
        for 4 months after the last dose of study drug(s), even if oral contraceptives are also&#xD;
        used. All subjects of reproductive potential must agree to use both a barrier method and a&#xD;
        second method of birth control during the course of the study and for 4 months after the&#xD;
        last dose of study drug(s).&#xD;
&#xD;
        - Women of childbearing potential must have a negative pregnancy test at screening. Women&#xD;
        of childbearing potential include women who have experienced menarche and who have not&#xD;
        undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or&#xD;
        bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as amenorrhea&#xD;
        greater than or equal to 12 consecutive months. Note: women who have been amenorrheic for&#xD;
        12 or more months are still considered to be of childbearing potential if the amenorrhea is&#xD;
        possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other&#xD;
        reversible reason.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  The subject has received cytotoxic chemotherapy (including investigational cytotoxic&#xD;
             chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or&#xD;
             nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.&#xD;
&#xD;
          -  Prior treatment with cabozantinib&#xD;
&#xD;
          -  Prior treatment with other small molecule inhibitors of Vascular Endothelial Growth&#xD;
             Factor Receptors (VEGFR) within less than or equal to 2 years of study enrollment.&#xD;
&#xD;
          -  The subject has received radiation therapy:&#xD;
&#xD;
          -  to the thoracic cavity or gastrointestinal tract within 3 months before the first dose&#xD;
             of study treatment&#xD;
&#xD;
          -  to bone or brain metastasis within 14 days before the first dose of study treatment&#xD;
&#xD;
          -  to any other site(s) within 28 days before the first dose of study treatment&#xD;
&#xD;
          -  The subject has received radionuclide treatment within 6 weeks before the first dose&#xD;
             of study treatment&#xD;
&#xD;
          -  The subject has received prior treatment with a small molecule kinase inhibitor or a&#xD;
             hormonal therapy (including investigational kinase inhibitors or hormones) within 14&#xD;
             days or five half-lives of the compound or active metabolites, whichever is longer,&#xD;
             before the first dose of study treatment.&#xD;
&#xD;
          -  The subject has received any other type of investigational agent within 28 days before&#xD;
             the first dose of study treatment.&#xD;
&#xD;
          -  The subject has not recovered to baseline or Common Terminology Criteria in Adverse&#xD;
             Events (CTCAE). Grade 1 from toxicity due to all prior therapies except alopecia and&#xD;
             other non-clinically significant AEs.&#xD;
&#xD;
          -  The subject has a primary brain tumor&#xD;
&#xD;
          -  The subject has active brain metastases, leptomeningeal or epidural disease (Note:&#xD;
             Subjects with brain metastases previously treated with whole brain radiation or&#xD;
             radiosurgery or subjects with epidural disease previously treated with radiation or&#xD;
             surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks&#xD;
             before starting study treatment are eligible. Neurosurgical resection of brain&#xD;
             metastases or brain biopsy is permitted if completed at least 3 months before starting&#xD;
             study treatment. Baseline brain scans are not required to confirm eligibility.)&#xD;
&#xD;
          -  The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial&#xD;
             thromboplastin time (PTT) test greater than or equal to 1.3 times the laboratory upper&#xD;
             limit of normal (ULN) within 7 days before the first dose of study treatment.&#xD;
&#xD;
          -  The subject requires treatment, in therapeutic doses, with oral anticoagulants such as&#xD;
             warfarin prior to initiation of protocol therapy. Low dose aspirin (less than or equal&#xD;
             to 81 mg/day), lowdose warfarin (less than or equal to 1 mg/day), and low molecular&#xD;
             weight heparin (LMWH) are permitted. Subjects will be permitted to use anticoagulation&#xD;
             as described if treatment is required while they are enrolled on the protocol.&#xD;
&#xD;
          -  The subject requires chronic concomitant treatment of strong Cytochrome P450 3A4&#xD;
             (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,&#xD;
             rifapentine, phenobarbital, and St. John's Wort).&#xD;
&#xD;
        Because the lists of these agents are constantly changing, it is important to regularly&#xD;
        consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/;&#xD;
        medical reference texts such as the Physicians Desk Reference may also provide this&#xD;
        information. As part of the enrollment/informed consent procedures, the patient will be&#xD;
        counseled on the risk of interactions with other agents, and what to do if new medications&#xD;
        need to be prescribed or if the patient is considering a new over-the counter medicine or&#xD;
        herbal product.&#xD;
&#xD;
          -  The subject has experienced any of the following within 3 months before the first dose&#xD;
             of study treatment:&#xD;
&#xD;
          -  clinically-significant hematemesis or gastrointestinal bleeding&#xD;
&#xD;
          -  hemoptysis of greater than or equal to 0.5 teaspoon (greater than or equal to 2.5 mL)&#xD;
             of red blood&#xD;
&#xD;
          -  any other signs indicative of pulmonary hemorrhage&#xD;
&#xD;
          -  The subject has tumor invading (or concern for invasion) major blood vessels&#xD;
&#xD;
          -  Other severe acute or chronic medical or psychiatric condition, or laboratory&#xD;
             abnormality that may increase the risk associated with study participation or study&#xD;
             drug administration, or may interfere with the interpretation of study results, and in&#xD;
             the judgment of the Investigator would make the patient inappropriate for entry into&#xD;
             this study.&#xD;
&#xD;
          -  The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus,&#xD;
             stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or&#xD;
             endobronchial tumor within 28 days before the first dose of cabozantinib.&#xD;
&#xD;
          -  The subject is unable to swallow tablets&#xD;
&#xD;
          -  The subject has a corrected Q wave, T wave (QT) interval calculated by the Fridericia&#xD;
             formula (QTcF) &gt;500 ms within 28 days before treatment initiation.&#xD;
&#xD;
          -  The subject has a previously identified allergy or hypersensitivity to components of&#xD;
             the study treatment formulation.&#xD;
&#xD;
          -  The subject is unable or unwilling to abide by the study protocol or cooperate fully&#xD;
             with the investigator or designee.&#xD;
&#xD;
          -  The subject has had within 2 years before the start of study treatment evidence of&#xD;
             another malignancy which required systemic treatment&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             the study agents. In addition, these patients are at increased risk of lethal&#xD;
             infections when treated with marrow-suppressive therapy. Appropriate studies will be&#xD;
             undertaken in patients receiving combination antiretroviral therapy when indicated.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrea B Apolo, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2012-C-0205.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <link>
    <url>http://medicine.iupui.edu/clinpharm/ddis/</url>
    <description>http://medicine.iupui.edu/clinpharm/ddis/</description>
  </link>
  <reference>
    <citation>Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49. doi: 10.3322/caac.20006. Epub 2009 May 27.</citation>
    <PMID>19474385</PMID>
  </reference>
  <reference>
    <citation>McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. doi: 10.1200/JCO.1997.15.5.1853.</citation>
    <PMID>9164195</PMID>
  </reference>
  <reference>
    <citation>Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. doi: 10.1200/JCO.2002.20.4.937.</citation>
    <PMID>11844814</PMID>
  </reference>
  <results_reference>
    <citation>Apolo AB, Nadal R, Tomita Y, Davarpanah NN, Cordes LM, Steinberg SM, Cao L, Parnes HL, Costello R, Merino MJ, Folio LR, Lindenberg L, Raffeld M, Lin J, Lee MJ, Lee S, Alarcon SV, Yuno A, Dawson NA, Allette K, Roy A, De Silva D, Lee MM, Sissung TM, Figg WD, Agarwal PK, Wright JJ, Ning YM, Gulley JL, Dahut WL, Bottaro DP, Trepel JB. Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial. Lancet Oncol. 2020 Aug;21(8):1099-1109. doi: 10.1016/S1470-2045(20)30202-3. Epub 2020 Jul 6.</citation>
    <PMID>32645282</PMID>
  </results_reference>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>September 14, 2012</study_first_submitted>
  <study_first_submitted_qc>September 14, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 20, 2012</study_first_posted>
  <results_first_submitted>December 13, 2019</results_first_submitted>
  <results_first_submitted_qc>September 14, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 6, 2020</results_first_posted>
  <last_update_submitted>September 22, 2022</last_update_submitted>
  <last_update_submitted_qc>September 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cancer Institute (NCI)</investigator_affiliation>
    <investigator_full_name>Andrea Apolo, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Kidney Cancer</keyword>
  <keyword>Tyrosine Kinase Inhibitor</keyword>
  <keyword>Bladder Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Transitional Cell</mesh_term>
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
    <mesh_term>Kidney Neoplasms</mesh_term>
    <mesh_term>Urethral Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 10, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/99/NCT01688999/Prot_SAP_002.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 28, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/99/NCT01688999/ICF_003.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Cohort 1 - (Urothelial Progressive Disease)</title>
          <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
        </group>
        <group group_id="P2">
          <title>Cohort 2 (Bone-only)</title>
          <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
        </group>
        <group group_id="P3">
          <title>Cohort 3 (Rare Histologies)</title>
          <description>Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
                <participants group_id="P2" count="6"/>
                <participants group_id="P3" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="42"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Ineligible/Not treated</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Age, Categorical is not reported because it was not captured by cohorts.</population>
      <group_list>
        <group group_id="B1">
          <title>Cohort 1 - (Urothelial Progressive Disease)</title>
          <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
        </group>
        <group group_id="B2">
          <title>Cohort 2 (Bone-only)</title>
          <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
        </group>
        <group group_id="B3">
          <title>Cohort 3 (Rare Histologies)</title>
          <description>Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="50"/>
            <count group_id="B2" value="6"/>
            <count group_id="B3" value="13"/>
            <count group_id="B4" value="69"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="50"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="69"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="63" lower_limit="35" upper_limit="82"/>
                    <measurement group_id="B2" value="66" lower_limit="54" upper_limit="70"/>
                    <measurement group_id="B3" value="57" lower_limit="22" upper_limit="74"/>
                    <measurement group_id="B4" value="63" lower_limit="22" upper_limit="82"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="50"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="69"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <population>Race/Ethnicity was not captured for one participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>White</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="49"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="68"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="41"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>African American</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="49"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="68"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="49"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="68"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="49"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="68"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="50"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="69"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Primary Tumor Site</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Bladder</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="50"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="69"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="12"/>
                    <measurement group_id="B4" value="47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Upper tract:renal pelvis or ureter</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="50"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="69"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Bladder &amp; upper tract</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="50"/>
                    <count group_id="B2" value="6"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="69"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With Overall Response</title>
        <description>Complete Response (CR) or Partial Response (PR) to Cabozantinib (XL184) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
        <time_frame>Median follow-up was 61.2 months</time_frame>
        <population>42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - (Urothelial Progressive Disease)</title>
            <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 (Bone-only)</title>
            <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 (Rare Histologies)</title>
            <description>Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Overall Response</title>
          <description>Complete Response (CR) or Partial Response (PR) to Cabozantinib (XL184) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
          <population>42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.1" lower_limit="8.6" upper_limit="34.1"/>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">The percentage and 95% CI cannot be calculated for this cohort because the participants had no measurable disease.</measurement>
                    <measurement group_id="O3" value="NA" lower_limit="NA" upper_limit="NA">The percentage and 95% CI cannot be calculated for this cohort because the participants had no measurable disease.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Measure the timing from the study start until death.</description>
        <time_frame>Median follow-up was 61.2 months</time_frame>
        <population>42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - (Urothelial Progressive Disease)</title>
            <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 (Bone-only)</title>
            <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 (Rare Histologies)</title>
            <description>Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Measure the timing from the study start until death.</description>
          <population>42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.</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="42"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.1" lower_limit="5.2" upper_limit="10.3"/>
                    <measurement group_id="O2" value="9.3" lower_limit="4.6" upper_limit="12.5"/>
                    <measurement group_id="O3" value="5.8" lower_limit="2.6" upper_limit="8.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival</title>
        <description>Measure the timing of maintaining stable disease or partial response until disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest um diameters while on study.</description>
        <time_frame>Median follow-up was 61.2 months</time_frame>
        <population>42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - (Urothelial Progressive Disease)</title>
            <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 (Bone-only)</title>
            <description>Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 (Rare Histologies)</title>
            <description>Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival</title>
          <description>Measure the timing of maintaining stable disease or partial response until disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest um diameters while on study.</description>
          <population>42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.</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="42"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7" lower_limit="3.1" upper_limit="6.4"/>
                    <measurement group_id="O2" value="5.3" lower_limit="1.8" upper_limit="8.3"/>
                    <measurement group_id="O3" value="2.9" lower_limit="1.8" upper_limit="3.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib</title>
        <description>Grade 4 toxicity hypomagnesium experienced by participants related to Cabozantinib. Grade 4 toxicity is life-threatening consequences; urgent intervention indicated.</description>
        <time_frame>Median follow-up was 61.2 months</time_frame>
        <population>We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>All Participants</title>
            <description>Cohort 1 - (urothelial progressive disease) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.&#xD;
Cohort 2 (Bone-only) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.&#xD;
Cohort 3 (Rare histologies) Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib</title>
          <description>Grade 4 toxicity hypomagnesium experienced by participants related to Cabozantinib. Grade 4 toxicity is life-threatening consequences; urgent intervention indicated.</description>
          <population>We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.</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="68"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution</title>
        <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
        <time_frame>Median follow-up was 61.2 months</time_frame>
        <population>We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>All Participants</title>
            <description>Cohort 1 - (urothelial progressive disease) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.&#xD;
Cohort 2 (Bone-only) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.&#xD;
Cohort 3 (Rare histologies) Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution</title>
          <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
          <population>We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.</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="68"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Median follow-up was 61.2 months</time_frame>
      <desc>All serious and non-serious adverse events are reported regardless of attribution. We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>All Participants</title>
          <description>Cohort 1 - (urothelial progressive disease) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.&#xD;
Cohort 2 (Bone-only) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.&#xD;
Cohort 3 (Rare histologies) Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.</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="66" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="66" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other, pulmonary embolus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Endocrine disorders - Other, thyroiditis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Duodenal obstruction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Gastric hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Rectal fistula</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaphylaxis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="13" subjects_affected="5" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>hip pain, leg pain</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify</sub_title>
                <description>Death progressive disease</description>
                <counts group_id="E1" events="66" subjects_affected="66" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Stroke</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </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="67" subjects_at_risk="68"/>
              </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="52" subjects_affected="21" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other, hematemesis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Transient ischemic attacks</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Endocrine disorders - Other, thyroiditis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="27" subjects_affected="21" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Anal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Anal ulcer</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="17" subjects_affected="17" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="63" subjects_affected="35" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Gastroparesis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Gingival pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="19" subjects_affected="14" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="26" subjects_affected="23" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Oral dysesthesia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Rectal fistula</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Rectal hemorrhage</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Rectal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Tooth discoloration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="48" subjects_affected="28" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="9" subjects_affected="8" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="11" subjects_affected="10" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections and infestations - Other, URI</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Laryngitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Lip infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Rhinitis infective</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Stoma site infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, umbilical fungal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Injury, poisoning and procedural complications - Other, R. mediport</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Wound complication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="59" subjects_affected="35" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="28" subjects_affected="19" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="59" subjects_affected="37" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="40" subjects_affected="18" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="16" subjects_affected="8" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="13" subjects_affected="9" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="23" subjects_affected="13" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="52" subjects_affected="33" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="18" subjects_affected="8" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="40" subjects_affected="22" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="19" subjects_affected="15" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="5" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="34" subjects_affected="15" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="36" subjects_affected="11" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="61" subjects_affected="13" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="22" subjects_affected="14" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="62" subjects_affected="29" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal soft tissue necrosis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="15" subjects_affected="14" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Buttock pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>cramping - hands and legs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Scalp pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>hands/finger cramping</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>hip pain, leg pain</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>muscle spasms</description>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, thoracic muscle spasms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Concentration impairment</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="20" subjects_affected="19" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Sinus pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Bladder spasm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="14" subjects_affected="14" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="11" subjects_affected="6" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Urinary tract pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Genital edema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Scrotal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Vaginal discharge</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Laryngeal inflammation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Postnasal drip</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="68"/>
              </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="7" subjects_affected="7" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="77" subjects_affected="37" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Rash pustular</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Scrotal infection</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, specify</sub_title>
                <description>hair whitening</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin hypopigmentation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, abrasion - lft. ankle</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, fever blisters on lip</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, Inguinal rash</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, outer stoma bleeding</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, Pustule R. buttock</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, Scrotal erythema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, Stoma ileal conduit</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="11" subjects_affected="10" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Vascular access complication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </event>
              <event>
                <sub_title>Vascular disorders - Other, L. PE</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="68"/>
              </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>Dr. Andrea Apolo</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>301-480-0536</phone>
      <email>apoloab@nih.gov</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/NCT01688999
org study id: 120205
secondary id: 12-C-0205
nct id: NCT01688999
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is
      approved for medullary thyroid cancer. However, studies have shown that prostate and ovarian
      tumors respond to it. Researchers want see if cabozantinib can be a safe and effective
      treatment for urothelial cancer.

      Objectives:

      - To test the safety and effectiveness of cabozantinib for advanced urothelial cancer.

      Eligibility:

      - Individuals at least 18 years of age who have advanced urothelial cancer that has not
      responded to standard treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected. Tumor tissue samples will also be collected. Imaging studies
           will also be performed.

        -  Participants will take cabozantinib by mouth once per day on each day of a 28-day cycle.

        -  Treatment will be monitored with frequent blood tests and imaging studies.

        -  Participants will continue to take the study drug for as long as their cancer does not
           worsen and side effects are not too severe.
Background:

        -  In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common
           malignancy in men and the ninth most common in women with an estimated 69,250 new cases
           and 14,990 deaths in the year 2011

        -  There is no Food and Drug Administration (FDA)-approved second line drug for patients
           with metastatic Urothelial Cancer (UC)

        -  Multiple lines of evidence support targeting angiogenesis in UC

        -  In human bladder cancer, overexpression of tyrosine-protein kinase (c-Met)/Axl/platelet
           derived growth factor receptor- (PDGFR)-alpha or c-Met alone showed significant
           correlation with poor survival

        -  Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases
           with growth-promoting and angiogenic properties.

        -  The primary targets of cabozantinib are mesenchymal epithelial transition factor (MET),
           vascular endothelial factor receptor 2 (VEGFR2), and rearranged during transfection
           (RET)

      Objectives:

      - To determine the response rate of cabozantinib in patients with progressive urothelial
      cancer who have received prior cytotoxic chemotherapy

      Eligibility:

        -  Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic,
           progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.

        -  Patients in cohort 2 must have a histologically confirmed diagnosis of bone only
           metastatic, urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.

        -  Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional
           cell carcinoma cancer (including but not limited to squamous cell, neuroendocrine,
           adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or
           renal pelvis.

        -  Patients must have been previously treated, as defined by treatment with at least one
           prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of
           prior cytotoxic agents.

        -  18 years of age or older.

      Design:

        -  A maximum of 71subjects will be enrolled in this open label, non-randomized, phase II
           trial of 60 mg each day of cabozantinib. Up to 50 patients will be accrued to cohort 1
           (metastatic, progressive urothelial cancer. The remainder will be enrolled on
           exploratory cohorts 2 & 3, bone only metastatic urothelial disease and non transitional
           cell carcinoma (TCC) bladder cancer respectively, during the time the study is accruing
           patients for cohort 1. Note: Patients who tolerate cabozantinib at 60 mg daily during
           the first 2 cycles (first restaging time period) without (Bullet) grade 2 toxicity may
           undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator.

        -  A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error
           probabilities. Initially 21 subjects will be enrolled and followed for progression. If 2
           or more of cohort 1 subjects experiences a response, enrollment will continue until a
           total of 41 evaluable subjects with progressive urothelial cancer have been entered. 2-3
           patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the
           accrual period.

        -  Each patient will undergo response evaluation assessments with chest abdomen pelvis
           computed tomography (CAP CT) (or magnetic resonance imaging (MRI)) with or without
           18F-Sodium Fluoride (Na18F) positron emission tomography (PET CT) every 8 weeks while on
           active protocol therapy starting at baseline. Patients will undergo investigational
           Fludeoxyglucose, (FDG) PET/CT and PET/MRI (optional) at baseline, week 4 and week 8.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Participants With Overall Response
time frame: Median follow-up was 61.2 months
description: Complete Response (CR) or Partial Response (PR) to Cabozantinib (XL184) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
measure: Overall Survival
time frame: Median follow-up was 61.2 months
description: Measure the timing from the study start until death.
measure: Progression Free Survival
time frame: Median follow-up was 61.2 months
description: Measure the timing of maintaining stable disease or partial response until disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest um diameters while on study.
measure: Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib
time frame: Median follow-up was 61.2 months
description: Grade 4 toxicity hypomagnesium experienced by participants related to Cabozantinib. Grade 4 toxicity is life-threatening consequences; urgent intervention indicated.
measure: Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution
time frame: Median follow-up was 61.2 months
description: Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
arm group label: Cabozantinib
arm group type: Experimental
description: Administered orally at a dose of 60 mg once daily on each day of a 28-day cycle.
intervention type: Drug
intervention name: Cabozantinib
description: 60 mg by mouth (PO) daily each 28 day cycle. Treatment continues until toxicity or disease progression.
arm group label: Cabozantinib
other name: Cometriq
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Andrea B Apolo, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2012-C-0205.html
description: NIH Clinical Center Detailed Web Page
url: http://medicine.iupui.edu/clinpharm/ddis/
description: http://medicine.iupui.edu/clinpharm/ddis/
citation: Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49. doi: 10.3322/caac.20006. Epub 2009 May 27.
PMID: 19474385
citation: McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. doi: 10.1200/JCO.1997.15.5.1853.
PMID: 9164195
citation: Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. doi: 10.1200/JCO.2002.20.4.937.
PMID: 11844814
citation: Apolo AB, Nadal R, Tomita Y, Davarpanah NN, Cordes LM, Steinberg SM, Cao L, Parnes HL, Costello R, Merino MJ, Folio LR, Lindenberg L, Raffeld M, Lin J, Lee MJ, Lee S, Alarcon SV, Yuno A, Dawson NA, Allette K, Roy A, De Silva D, Lee MM, Sissung TM, Figg WD, Agarwal PK, Wright JJ, Ning YM, Gulley JL, Dahut WL, Bottaro DP, Trepel JB. Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial. Lancet Oncol. 2020 Aug;21(8):1099-1109. doi: 10.1016/S1470-2045(20)30202-3. Epub 2020 Jul 6.
PMID: 32645282
responsible party type: Principal Investigator
investigator affiliation: National Cancer Institute (NCI)
investigator full name: Andrea Apolo, M.D.
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Neoplasms
mesh term: Carcinoma, Transitional Cell
mesh term: Urinary Bladder Neoplasms
mesh term: Kidney Neoplasms
mesh term: Urethral Neoplasms
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 