<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/NCT01683994</url>
  </required_header>
  <id_info>
    <org_study_id>120204</org_study_id>
    <secondary_id>12-C-0204</secondary_id>
    <nct_id>NCT01683994</nct_id>
  </id_info>
  <brief_title>Cabozantinib Plus Docetaxel and Prednisone for Advanced Prostate Cancer</brief_title>
  <official_title>A Phase I and Randomized Phase II Multicenter Study of Cabozantinib (XL184) Plus Docetaxel and Prednisone in Metastatic Castrate Resistant Prostate Cancer</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 tumors&#xD;
      respond to it. Docetaxel and prednisone are standard treatments for advanced prostate cancer.&#xD;
      Researchers want to see if adding cabozantinib to these two drugs can be a safe and effective&#xD;
      treatment for this type of cancer.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To test the safety and effectiveness of cabozantinib with standard treatments for advanced&#xD;
      prostate cancer.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Individuals at least 18 years of age who have advanced prostate 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. Imaging studies will also be performed.&#xD;
&#xD;
        -  Participants will receive the cancer drugs over 21-day cycles of treatment. They will&#xD;
           take docetaxel and cabozantinib on day 1 of each cycle. Each docetaxel infusion will&#xD;
           take about 1 hour. They will also take prednisone by mouth twice each day.&#xD;
&#xD;
        -  Treatment will be monitored with frequent blood tests and imaging studies.&#xD;
&#xD;
        -  Participants will continue to take the study drugs 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;
        -  Docetaxel is established as first-line chemotherapy in patients with metastatic castrate&#xD;
           resistant prostate cancer (CRPC). However; it is increasingly recognized that combining&#xD;
           docetaxel with other agents of clinical activities without overlapping toxicities could&#xD;
           simultaneously target different cellular signaling pathways vital for tumor survival,&#xD;
           producing either additive or synergistic activities.&#xD;
&#xD;
        -  Inhibition of angiogenesis, either as a stand-alone approach or in combination with&#xD;
           chemotherapy, has demonstrable antitumor efficacy against CRPC and there are several&#xD;
           antiangiogenic agents that are now in clinical trials in this population of patients.&#xD;
&#xD;
        -  Cabozantinib (XL184) was developed as an inhibitor of both angiogenesis and of its&#xD;
           resistance mechanism. It is an inhibitor of multiple receptor tyrosine kinases including&#xD;
           tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor receptor 2&#xD;
           (VEGFR2) and rearranged during transfection (RET).&#xD;
&#xD;
        -  In single agent clinical studies, cabozantinib demonstrated, broad anti-tumor activities&#xD;
           across many solid tumor types.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
        -  To determine the safety profile of cabozantinib in combination with docetaxel and&#xD;
           prednisone, and to determine the maximal tolerated dose (MTD) as recommended phase II&#xD;
           dose in combination with docetaxel&#xD;
&#xD;
        -  To determine the relative efficacy (in terms of progression free survival (PFS)) of&#xD;
           docetaxel and cabozantinib compared to docetaxel alone&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Patients must have progressive metastatic CRPC. There must be radiographic evidence of&#xD;
           disease after primary treatment with surgery or radiotherapy. If patients had been on&#xD;
           flutamide, they must have disease progression at least 4 weeks after withdrawal.&#xD;
           Patients on bicalutamide or nilutamide must have progression at least 6 weeks after&#xD;
           withdrawal. Withdrawal criteria apply only to patients on the above anti-androgens for&#xD;
           at least the prior 6 months.&#xD;
&#xD;
        -  Patients must be at least 18 years of age and able to give informed consent.&#xD;
&#xD;
        -  Patients in the Phase II portion of the study must have progressed on abiraterone or&#xD;
           enzalutamide&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  The initial phase I portion of this study will test fixed dose docetaxel and prednisone&#xD;
           in combination with cabozantinib at three escalating doses. Using a standard 3 + 3&#xD;
           design, three patients will initially be treated at each dose level until MTD has been&#xD;
           defined.&#xD;
&#xD;
        -  An expansion cohort will then be enrolled at the MTD to further characterize safety,&#xD;
           toxicity and pharmacokinetic data and to obtain preliminary information on the efficacy&#xD;
           of the combination treatment.&#xD;
&#xD;
        -  In Phase II, patients will be enrolled to a randomized two-arm cohort comparing&#xD;
           docetaxel in combination with cabozantinib to docetaxel alone with a primary endpoint of&#xD;
           PFS.&#xD;
&#xD;
        -  The accrual ceiling for the study, including the Phase I dose escalation and the&#xD;
           expansion phases as well as the Phase II randomized phase, is set at 81.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 7, 2012</start_date>
  <completion_date type="Actual">January 16, 2019</completion_date>
  <primary_completion_date type="Actual">July 1, 2018</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival (PFS) of Cabozantinib + Docetaxel + Prednisone Compared to Docetaxel + Prednisone Alone</measure>
    <time_frame>From start date of treatment until the date of first documented progression, date of death from any cause and up to 40 months, whichever occurred first.</time_frame>
    <description>PFS is the time interval from start of treatment to documented evidence of disease progression or death. Disease progression was assessed by the Response Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions as referenced by the smallest sum on study. Appearance of one or more new lesions on bone scan and/or two consecutive rising prostatic-specific antigen values above the baseline at a minimum of one week intervals. A normal PSA value is 4.0 ng/ml and lower.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD)</measure>
    <time_frame>First two cycles of treatment (each cycle is 21 days), approximately 42 days.</time_frame>
    <description>MTD is defined as the dose level at which no more than 1 of 6 patients experiences a dose limiting toxicity (DLT) at the level below that which had two instances of DLT. A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of &gt; 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count &lt;500/µL lasting &gt; 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia &lt; 50K/µL requiring platelet transfusion for bleeding.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)</measure>
    <time_frame>Adverse events were assessed from the date treatment consent signed to date off study, approximately 45 months and 14 days for Arm A; 43 months and 14 days for Arm B; 9 months and 11 days for DL1; 27 months and 1 day for DL2; &amp; 11 months &amp; 25 days for DL3</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>
  <other_outcome>
    <measure>Number of Participants With a Dose Limiting Toxicities (DLTs)</measure>
    <time_frame>First two cycles of treatment (each cycle is 21 days), approximately 42 days.</time_frame>
    <description>A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of &gt; 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count &lt;500/µL lasting &gt; 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia &lt; 50K/µL requiring platelet transfusion for bleeding.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Participants Achieving Prostatic-Specific Antigen (PSA) Decline of 30% or 50% From Baseline</measure>
    <time_frame>up to 38 months</time_frame>
    <description>PSA normal range is 4 ng/ml or lower. Participants with PSA decline of 30% or 50% is the measures for prostate cancer based on conventional reporting metrics.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">49</enrollment>
  <condition>Prostatic Neoplasms</condition>
  <arm_group>
    <arm_group_label>combination of cabozantinib, docetaxel and prednisone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>combination of cabozantinib, docetaxel and prednisone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PII/ Arm 1-docetaxel + prednisone only</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>docetaxel + prednisone only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PII/Arm 2 -docetaxel+ prednisone + cabozantinib</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>docetaxel+ prednisone + cabozantinib</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabozantinib</intervention_name>
    <description>Assigned dose given daily during each 21 day cycle. Treatment may continue until disease progression or intolerable toxicity.</description>
    <arm_group_label>PII/Arm 2 -docetaxel+ prednisone + cabozantinib</arm_group_label>
    <arm_group_label>combination of cabozantinib, docetaxel and prednisone</arm_group_label>
    <other_name>Cometriq</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Docetaxel</intervention_name>
    <description>75mg/m^2 intravenous (IV) over approximately 60 minutes on cycle 1 day 1 and repeated every 21 days until disease progression or intolerable toxicity.</description>
    <arm_group_label>PII/ Arm 1-docetaxel + prednisone only</arm_group_label>
    <arm_group_label>PII/Arm 2 -docetaxel+ prednisone + cabozantinib</arm_group_label>
    <arm_group_label>combination of cabozantinib, docetaxel and prednisone</arm_group_label>
    <other_name>Taxotere</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>5 mg by mouth (PO) twice a day during each 21 day cycle until disease progression or intolerable toxicity.</description>
    <arm_group_label>PII/ Arm 1-docetaxel + prednisone only</arm_group_label>
    <arm_group_label>PII/Arm 2 -docetaxel+ prednisone + cabozantinib</arm_group_label>
    <arm_group_label>combination of cabozantinib, docetaxel and prednisone</arm_group_label>
    <other_name>Deltasone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Must have metastatic, progressive, castrate resistant prostate cancer (CRPC). There&#xD;
             must be radiographic evidence of disease after primary treatment with surgery or&#xD;
             radiotherapy that has continued to progress radiographically or biochemically (rising&#xD;
             PSA levels on successive measurements) despite adequate androgen-deprivation therapy,&#xD;
             which is defined as having undergone bilateral surgical castration or continued&#xD;
             treatment on GnRH agonists or antagonists.&#xD;
&#xD;
        Progression must be evidenced and documented by any of the following parameters:&#xD;
&#xD;
          -  Two consecutively rising PSA values, above the baseline, at a minimum of 1- week&#xD;
             intervals&#xD;
&#xD;
          -  Appearance of one or more new lesions on bone scan&#xD;
&#xD;
          -  Progressive measurable disease by RECIST 1.1&#xD;
&#xD;
        The use of androgen receptor inhibitors is not required prior to study entry. For those&#xD;
        patients receiving an anti-androgen agent (flutamide, bicalutamide, or nilutamide), for at&#xD;
        least 6 consecutive months immediately prior to study entry, and are entering the trial due&#xD;
        to a rise in PSA, they must demonstrate a continued rise in PSA within 4 weeks after&#xD;
        stopping flutamide and within 6 weeks after stopping bicalutamide or nilutamide. Flutamide,&#xD;
        nilutamide and bicalutamide disease progression requirements only apply to patients who&#xD;
        have been on these drugs for at least the prior 6 months.&#xD;
&#xD;
          -  Histopathological confirmation of prostate cancer by the Laboratory of Pathology of&#xD;
             the National Cancer Institute (NCI) Pathology Department of the Walter Reed National&#xD;
             Military Medical Center or YALE is required prior to entering this study. Patients&#xD;
             whose pathology specimens are no longer available may be enrolled if the patient has a&#xD;
             clinical course that is consistent with prostate cancer and available documentation&#xD;
             from an outside pathology laboratory of the diagnosis. All efforts should be made to&#xD;
             have the material forwarded to the research team for use in correlative studies in&#xD;
             cases where original tissue blocks or archival biopsy material is available.&#xD;
&#xD;
          -  Patients must have metastatic disease, defined as at least one lesion on bone scan or&#xD;
             at least one lesion that can be accurately measured in at least one dimension (longest&#xD;
             diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as&#xD;
             greater than or equal to 20 mm with conventional techniques or as greater than or&#xD;
             equal to 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging&#xD;
             (MRI), or calipers by clinical exam.&#xD;
&#xD;
          -  Patients must have a performance status of 0 to 2 according to the ECOG criteria.&#xD;
&#xD;
          -  Patients must have adequate bone marrow, hepatic, and renal function with:&#xD;
&#xD;
               -  Hemoglobin greater than or equal to 9 grams per deciliter&#xD;
&#xD;
               -  Leukocytes greater than or equal to 3000 per microliters&#xD;
&#xD;
               -  ANC greater than or equal to 1500 per microliters, without CSF support&#xD;
&#xD;
               -  Platelets greater than or equal to 100,000 per microliters&#xD;
&#xD;
               -  AST (SGOT) less than or equal to 2.5 times upper limit of normal (ULN)&#xD;
&#xD;
               -  ALT (SGPT) less than or equal to 2.5 times upper limit of normal (ULN)&#xD;
&#xD;
               -  Total serum bilirubin less than or equal to the upper limit of normal (ULN)&#xD;
&#xD;
               -  Serum albumin greater than or equal to 2.8 grams per deciliters&#xD;
&#xD;
               -  Serum phosphorus, calcium, magnesium, and potassium greater than or equal to LLN&#xD;
&#xD;
               -  Lipase less than 2.0 times the upper limit of normal and no radiologic or&#xD;
                  clinical evidence of pancreatitis&#xD;
&#xD;
               -  Creatinine less than or equal to 1.5 times institutional upper limits of normal&#xD;
&#xD;
        OR&#xD;
&#xD;
          -  creatinine clearance of greater than or equal to 50 ml/min/1.73 m^2 for patients with&#xD;
             creatinine levels above institutional normal by 24 hour urine.&#xD;
&#xD;
          -  urine protein/urine creatinine ratio (UPCR) less than or equal to 1&#xD;
&#xD;
               -  Patients must be at least 18 years of age. Because no dosing or adverse event&#xD;
                  data are currently available on the use of cabozantinib in combination with&#xD;
                  docetaxel and prednisone in patients less than 18 years of age, children are&#xD;
                  excluded from this study, but may be eligible for future pediatric trials&#xD;
&#xD;
               -  Patient must be capable of understanding and complying with protocol requirements&#xD;
                  and is willing to give informed consent&#xD;
&#xD;
               -  Men treated or enrolled on this protocol must also agree to use adequate&#xD;
                  contraception prior to the study, for the duration of study participation, and 4&#xD;
                  months after completion of XL184 administration. Sexually active subjects and&#xD;
                  their female partners must agree to use medically accepted barrier methods of&#xD;
                  contraception (eg, male or female condom) during the course of the study and for&#xD;
                  4 months after the last dose of study drug(s), even if oral contraceptives are&#xD;
                  also used. All subjects of reproductive potential must also agree to use both a&#xD;
                  barrier method and a second method of birth control during the course of the&#xD;
                  study and for 4 months after the last dose of study drug(s). Should a woman&#xD;
                  become pregnant or suspect she is pregnant while her partner is participating in&#xD;
                  this study, she should inform her treating physician immediately.&#xD;
&#xD;
               -  Patients enrolled on the randomized portion of the study must have had disease&#xD;
                  progression on arbiraterone or enzalutamide.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  The subject has had evidence within 2 years of the start of study treatment of another&#xD;
             malignancy which required systemic treatment&#xD;
&#xD;
          -  The subject is unable to swallow tablets&#xD;
&#xD;
          -  The subject has tumor invading (or there is concern for invasion of) major blood&#xD;
             vessel&#xD;
&#xD;
          -  The subject has active brain metastases or epidural disease Subjects with brain&#xD;
             metastases previously treated with whole brain radiation or radiosurgery or subjects&#xD;
             with epidural disease previously treated with radiation or surgery who are&#xD;
             asymptomatic and do not require steroid treatment for at least 2 weeks before starting&#xD;
             study treatment are eligible. Neurosurgical resection of brain metastases or brain&#xD;
             biopsy is permitted if completed at least 3 months before starting study treatment.&#xD;
             Baseline brain scans are not required to confirm eligibility.&#xD;
&#xD;
          -  The subject requires concomitant treatment, in therapeutic doses, with anticoagulants&#xD;
             such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa&#xD;
             inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (less than or&#xD;
             equal to 81 milligrams per day), low-dose warfarin (less than or equal to1 milligrams&#xD;
             per day), and prophylactic low molecular weight heparin (LMWH) are permitted.&#xD;
&#xD;
          -  The subject has a corrected QT interval calculated by the Fridericia formula (QTcF)&#xD;
             greater than 500 milliseconds within 28 days before initiation of protocol therapy.&#xD;
             Note: if initial QTcF is found to be greater than 500 milliseconds, two additional&#xD;
             EKGs separated by at least 3 minutes should be performed. If the average of these&#xD;
             three consecutive results for QTcF is less than or equal to 500 milliseconds, the&#xD;
             subject meets eligibility in this regard.&#xD;
&#xD;
          -  Patients with contraindication to steroid use&#xD;
&#xD;
          -  Prior treatment with cabozantinib&#xD;
&#xD;
          -  The patient has received cytotoxic chemotherapy (including investigational cytotoxic&#xD;
             chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or&#xD;
             nitrosoureas or mitomycin within 6 weeks before the first dose 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 with the exception of patients receiving&#xD;
             prior abiraterone or ketoconazole. For patients receiving prior abiraterone or&#xD;
             ketoconazole, they must discontinue the medication within 5 half lives of the compound&#xD;
             before the first dose of study treatment in order to participate in this study. Note:&#xD;
             Subjects with prostate cancer currently receiving LHRH or GnRH agonists must be&#xD;
             maintained on these agents.&#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 received radiation therapy:&#xD;
&#xD;
               -  to the thoracic cavity or gastrointestinal tract within 3 months before the first&#xD;
                  dose of study treatment&#xD;
&#xD;
               -  to bone or brain metastasis within 14 days before the first dose of study&#xD;
                  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 prior to the first dose&#xD;
             of the study treatment&#xD;
&#xD;
          -  The subject has not recovered to baseline or CTCAE less than or equal to Grade 1 from&#xD;
             toxicity due to all prior therapies, including surgery, except alopecia and other&#xD;
             non-clinically significant AEs.&#xD;
&#xD;
          -  The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial&#xD;
             thromboplastin time (PTT) test results at screening greater than or equal 1.3 times&#xD;
             the laboratory ULN within 7 days before the first dose of study treatment&#xD;
&#xD;
          -  The subject has experienced any of the following:&#xD;
&#xD;
               -  clinically-significant hematemesis or gastrointestinal bleeding within 6 months&#xD;
                  before the first dose of study treatment&#xD;
&#xD;
               -  hemoptysis of greater than or equal to 0.5 teaspoon (2.5 mL) of red blood within&#xD;
                  3 months before the first dose of study treatment&#xD;
&#xD;
               -  any other signs indicative of pulmonary hemorrhage within 3 months before the&#xD;
                  first dose of study treatment&#xD;
&#xD;
          -  The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or&#xD;
             large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor&#xD;
             within 28 days before the first dose of cabozantinib&#xD;
&#xD;
          -  The subject has uncontrolled, significant intercurrent or recent illness including,&#xD;
             but not limited to, the following conditions:&#xD;
&#xD;
               -  Cardiovascular disorders including&#xD;
&#xD;
                    -  Congestive heart failure (CHF): New York Heart Association (NYHA) Class III&#xD;
                       (moderate) or Class IV (severe) at the time of screening&#xD;
&#xD;
                    -  Concurrent uncontrolled hypertension defined as sustained BP greater than&#xD;
                       140 millimeters of mercury systolic, or greater than 90 millimeters of&#xD;
                       mercury diastolic despite optimal antihypertensive treatment (BP must be&#xD;
                       controlled at screening)&#xD;
&#xD;
                    -  Any history of congenital long QT syndrome&#xD;
&#xD;
                    -  Any of the following within 6 months before the first dose of study&#xD;
                       treatment:&#xD;
&#xD;
                         -  unstable angina pectoris&#xD;
&#xD;
                         -  clinically-significant cardiac arrhythmias&#xD;
&#xD;
                         -  stroke (including TIA, or other ischemic event)&#xD;
&#xD;
                         -  myocardial infarction&#xD;
&#xD;
                              -  thromboembolic event requiring therapeutic anticoagulation (Note:&#xD;
                                 subjects with a venous filter (e.g. vena cava filter) are not&#xD;
                                 eligible for this study)&#xD;
&#xD;
               -  Gastrointestinal disorders particularly those associated with a high risk of&#xD;
                  perforation or fistula formation including:&#xD;
&#xD;
                    -  Any of the following within 28 days before the first dose of study treatment&#xD;
&#xD;
                         -  intra-abdominal tumor/metastases invading GI mucosa&#xD;
&#xD;
                         -  active peptic ulcer disease&#xD;
&#xD;
                         -  inflammatory bowel disease (including ulcerative colitis and Crohns&#xD;
                            disease), diverticulitis, cholecystitis, symptomatic cholangitis or&#xD;
                            appendicitis&#xD;
&#xD;
                              -  malabsorption syndrome&#xD;
&#xD;
                    -  Any of the following within 6 months before the first dose of study&#xD;
                       treatment:&#xD;
&#xD;
                         -  history of abdominal fistula&#xD;
&#xD;
                         -  gastrointestinal perforation&#xD;
&#xD;
                         -  bowel obstruction or gastric outlet obstruction&#xD;
&#xD;
                         -  intra-abdominal abscess. Note: Complete resolution of an&#xD;
                            intra-abdominal abscess must be confirmed prior to initiating treatment&#xD;
                            with cabozantinib even if the abscess occurred more than 6 months ago.&#xD;
&#xD;
               -  Other disorders associated with a high risk of fistula formation including PEG&#xD;
                  tube placement within 3 months before the first dose of study therapy or&#xD;
                  concurrent evidence of intraluminal tumor involving the trachea and esophagus.&#xD;
&#xD;
                    -  Other clinically significant disorders such as:&#xD;
&#xD;
                         -  active infection requiring intravenous treatment within 10 days of&#xD;
                            starting protocol&#xD;
&#xD;
                         -  serious non-healing wound/ulcer/bone fracture within 28 days before the&#xD;
                            first dose of study treatment&#xD;
&#xD;
                         -  history of organ transplant&#xD;
&#xD;
                         -  concurrent uncompensated hypothyroidism or thyroid dysfunction within 7&#xD;
                            days before the first dose of study treatment&#xD;
&#xD;
                         -  history of major surgery as follows:&#xD;
&#xD;
                              -  Major surgery within 3 months of the first dose of cabozantinib if&#xD;
                                 there were no wound healing complications or within 6 months of&#xD;
                                 the first dose of cabozantinib if there were wound complications&#xD;
&#xD;
                              -  Minor surgery within 1 months of the first dose of cabozantinib if&#xD;
                                 therewere no wound healing complications or within 3 months of the&#xD;
                                 first dose of cabozantinib if there were wound complications.&#xD;
&#xD;
        In addition, complete wound healing from prior surgery must be confirmed at least 28 days&#xD;
        before the first dose of cabozantinib irrespective of the time from surgery&#xD;
&#xD;
          -  HIV-positive patients on combination antiretroviral therapy are ineligible because of&#xD;
             the potential for pharmacokinetic interactions with the study agents. In addition,&#xD;
             these patients are at increased risk of lethal infections when treated with&#xD;
             marrow-suppressive therapy. Appropriate studies will be undertaken in patients&#xD;
             receiving combination antiretroviral therapy when indicated.&#xD;
&#xD;
          -  Patients who require taking drugs that are strong inhibitors/inducers of CYP3A4 and&#xD;
             cannot be switched to an alternative medication.&#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-thecounter medicine or&#xD;
        herbal product.&#xD;
&#xD;
          -  Patients with greater than or equal to grade 2 peripheral neuropathy at baseline.&#xD;
&#xD;
          -  The subject has had treatment with docetaxel for the treatment of metastatic&#xD;
             castratesensitive prostate cancer within 6 months before the first dose of study&#xD;
             treatment.&#xD;
&#xD;
          -  The subject has had progression of prostate cancer during 6 cycles of prior docetaxel&#xD;
             treatment for castrate sensitive disease.&#xD;
&#xD;
          -  The subject has received chemotherapy for castration-resistant prostate cancer.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>William L Dahut, 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-0204.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26(7):1148-59. doi: 10.1200/JCO.2007.12.4487.</citation>
    <PMID>18309951</PMID>
  </reference>
  <reference>
    <citation>Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300. doi: 10.3322/caac.20073. Epub 2010 Jul 7. Erratum In: CA Cancer J Clin. 2011 Mar-Apr;61(2):133-4.</citation>
    <PMID>20610543</PMID>
  </reference>
  <reference>
    <citation>Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. doi: 10.1056/NEJMoa041318.</citation>
    <PMID>15470214</PMID>
  </reference>
  <results_reference>
    <citation>A phase I and randomized phase II study of cabozantinib plus docetaxel and prednisone (C+DP) versus docetaxel and prednisone (DP) alone in metastatic castrate-resistant prostate cancer (mCRPC). Munjid Al Harthy, Ravi Amrit Madan, Fatima Karzai, Daniel Peter Petrylak, Joseph W. Kim, Philip M. Arlen, Marc Robert Theoret, Jenn Marte, Marijo Bilusic, Anna Couvillon, Guinevere Chun, Helen Owens, Amy Hankin, Lisa M. Cordes, William Douglas Figg, James L. Gulley, and William L. Dahut Journal of Clinical Oncology 2019 37:7_suppl, 173-173</citation>
  </results_reference>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>September 8, 2012</study_first_submitted>
  <study_first_submitted_qc>September 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2012</study_first_posted>
  <results_first_submitted>August 27, 2019</results_first_submitted>
  <results_first_submitted_qc>October 15, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">November 8, 2019</results_first_posted>
  <last_update_submitted>October 15, 2019</last_update_submitted>
  <last_update_submitted_qc>October 15, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cancer Institute (NCI)</investigator_affiliation>
    <investigator_full_name>William Dahut Jr., M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Angiogenesis Inhibitors</keyword>
  <keyword>Small Molecules</keyword>
  <keyword>Tyrosine Kinase Inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Docetaxel</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 27, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT01683994/Prot_SAP_000.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>May 25, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT01683994/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>49 participants were enrolled on this study. 4 participants were screen failures and were not assigned to any treatment groups. Data is shown for 45/49 participants. 13 participants were assigned to Ph II Arm A Docetaxel &amp; Prednisone but only 12 started treatment; one participant declined to start treatment. Data is shown for 45/49 participants.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Ph I Dose Level 1:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 20 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="P2">
          <title>Ph I Dose Level 2:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 40 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="P3">
          <title>Ph I Dose Level 3:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 60 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="P4">
          <title>Ph II Arm A: Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg by mouth (PO) twice a day (BID)</description>
        </group>
        <group group_id="P5">
          <title>Ph II Arm B: Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID); Cabozantinib: 40 mg by mouth (PO) everyday (QD)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="13"/>
                <participants group_id="P5" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title># of Patients Who Received Treatment</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="12"/>
                <participants group_id="P5" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="10"/>
                <participants group_id="P5" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="3"/>
                <participants group_id="P5" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Intercurrent illness</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Ph I Dose Level 1:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 20 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="B2">
          <title>Ph I Dose Level 2:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 40 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="B3">
          <title>Ph I Dose Level 3:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 60 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="B4">
          <title>Ph II Arm A: Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg by mouth (PO) twice a day (BID)</description>
        </group>
        <group group_id="B5">
          <title>Ph II Arm B: Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID); Cabozantinib: 40 mg by mouth (PO) everyday (QD)</description>
        </group>
        <group group_id="B6">
          <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="4"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="7"/>
            <count group_id="B4" value="13"/>
            <count group_id="B5" value="13"/>
            <count group_id="B6" value="45"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="5"/>
                    <measurement group_id="B6" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="10"/>
                    <measurement group_id="B5" value="8"/>
                    <measurement group_id="B6" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.45" spread="11.67"/>
                    <measurement group_id="B2" value="66.16" spread="9.51"/>
                    <measurement group_id="B3" value="70.15" spread="12.03"/>
                    <measurement group_id="B4" value="67.72" spread="8.34"/>
                    <measurement group_id="B5" value="68.89" spread="8.46"/>
                    <measurement group_id="B6" value="67.34" spread="9.41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="13"/>
                    <measurement group_id="B5" value="13"/>
                    <measurement group_id="B6" value="45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="10"/>
                    <measurement group_id="B6" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="5"/>
                    <measurement group_id="B5" value="6"/>
                    <measurement group_id="B6" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="6"/>
                    <measurement group_id="B6" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="13"/>
                    <measurement group_id="B5" value="13"/>
                    <measurement group_id="B6" value="45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Baseline Prostatic-Specific Antigen (PSA)</title>
          <description>PSA normal range is 4 ng/ml or lower.</description>
          <units>ng/ml</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="182.38" lower_limit="0.01" upper_limit="508.5"/>
                    <measurement group_id="B2" value="73.71" lower_limit="8.39" upper_limit="225"/>
                    <measurement group_id="B3" value="166.3" lower_limit="2.06" upper_limit="897.9"/>
                    <measurement group_id="B4" value="346.9" lower_limit="94.62" upper_limit="2649"/>
                    <measurement group_id="B5" value="65.6" lower_limit="4.5" upper_limit="3940.38"/>
                    <measurement group_id="B6" value="118.4" lower_limit="0.01" upper_limit="3940.38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior Treatment with Enzalutamide or Abiraterone</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="5"/>
                    <measurement group_id="B6" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression Free Survival (PFS) of Cabozantinib + Docetaxel + Prednisone Compared to Docetaxel + Prednisone Alone</title>
        <description>PFS is the time interval from start of treatment to documented evidence of disease progression or death. Disease progression was assessed by the Response Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions as referenced by the smallest sum on study. Appearance of one or more new lesions on bone scan and/or two consecutive rising prostatic-specific antigen values above the baseline at a minimum of one week intervals. A normal PSA value is 4.0 ng/ml and lower.</description>
        <time_frame>From start date of treatment until the date of first documented progression, date of death from any cause and up to 40 months, whichever occurred first.</time_frame>
        <population>Four participants came off study before restaging. One participant did not start treatment. Forty participants are evaluable for PFS. No participants received carbozantinib after progression from Docetaxel and Prednisone alone.</population>
        <group_list>
          <group group_id="O1">
            <title>Ph I Dose Level 1:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 20 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O2">
            <title>Ph I Dose Level 2:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 40 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O3">
            <title>Ph I Dose Level 3:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 60 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O4">
            <title>Ph II Arm A: Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg by mouth (PO) twice a day (BID)</description>
          </group>
          <group group_id="O5">
            <title>Ph II Arm B: Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID); Cabozantinib: 40 mg by mouth (PO) everyday (QD)</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) of Cabozantinib + Docetaxel + Prednisone Compared to Docetaxel + Prednisone Alone</title>
          <description>PFS is the time interval from start of treatment to documented evidence of disease progression or death. Disease progression was assessed by the Response Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions as referenced by the smallest sum on study. Appearance of one or more new lesions on bone scan and/or two consecutive rising prostatic-specific antigen values above the baseline at a minimum of one week intervals. A normal PSA value is 4.0 ng/ml and lower.</description>
          <population>Four participants came off study before restaging. One participant did not start treatment. Forty participants are evaluable for PFS. No participants received carbozantinib after progression from Docetaxel and Prednisone alone.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="7"/>
                <count group_id="O4" value="10"/>
                <count group_id="O5" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8" lower_limit="2" upper_limit="39"/>
                    <measurement group_id="O2" value="13" lower_limit="8" upper_limit="21"/>
                    <measurement group_id="O3" value="6" lower_limit="2" upper_limit="13"/>
                    <measurement group_id="O4" value="10" lower_limit="1" upper_limit="10"/>
                    <measurement group_id="O5" value="6.5" lower_limit="2" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD)</title>
        <description>MTD is defined as the dose level at which no more than 1 of 6 patients experiences a dose limiting toxicity (DLT) at the level below that which had two instances of DLT. A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of &gt; 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count &lt;500/µL lasting &gt; 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia &lt; 50K/µL requiring platelet transfusion for bleeding.</description>
        <time_frame>First two cycles of treatment (each cycle is 21 days), approximately 42 days.</time_frame>
        <population>Maximum tolerated dose was assessed only on phase 1 cohort participants. All 19 patients (e.g. 4 participants on dose level 1, 8 participants on dose level 2, and 7 participants on dose level 3) were included in the safety assessment to determine maximum tolerated dose.</population>
        <group_list>
          <group group_id="O1">
            <title>Ph I Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 20 mg, 40mg, and 60 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD)</title>
          <description>MTD is defined as the dose level at which no more than 1 of 6 patients experiences a dose limiting toxicity (DLT) at the level below that which had two instances of DLT. A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of &gt; 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count &lt;500/µL lasting &gt; 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia &lt; 50K/µL requiring platelet transfusion for bleeding.</description>
          <population>Maximum tolerated dose was assessed only on phase 1 cohort participants. All 19 patients (e.g. 4 participants on dose level 1, 8 participants on dose level 2, and 7 participants on dose level 3) were included in the safety assessment to determine maximum tolerated dose.</population>
          <units>mg</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40"/>
                  </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 Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)</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>Adverse events were assessed from the date treatment consent signed to date off study, approximately 45 months and 14 days for Arm A; 43 months and 14 days for Arm B; 9 months and 11 days for DL1; 27 months and 1 day for DL2; &amp; 11 months &amp; 25 days for DL3</time_frame>
        <population>One participant in Arm A declined to participate before treatment started.</population>
        <group_list>
          <group group_id="O1">
            <title>Ph I Dose Level 1:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 20 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O2">
            <title>Ph I Dose Level 2:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 40 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O3">
            <title>Ph I Dose Level 3:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 60 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O4">
            <title>Ph II Arm A: Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg by mouth (PO) twice a day (BID)</description>
          </group>
          <group group_id="O5">
            <title>Ph II Arm B: Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID); Cabozantinib: 40 mg by mouth (PO) everyday (QD)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)</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>One participant in Arm A declined to participate before treatment started.</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="4"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="7"/>
                <count group_id="O4" value="12"/>
                <count group_id="O5" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="8"/>
                    <measurement group_id="O3" value="7"/>
                    <measurement group_id="O4" value="12"/>
                    <measurement group_id="O5" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With a Dose Limiting Toxicities (DLTs)</title>
        <description>A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of &gt; 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count &lt;500/µL lasting &gt; 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia &lt; 50K/µL requiring platelet transfusion for bleeding.</description>
        <time_frame>First two cycles of treatment (each cycle is 21 days), approximately 42 days.</time_frame>
        <population>DLT only pertains to DL1, 2 and 3. Arms A and B did not evaluate for DLT.</population>
        <group_list>
          <group group_id="O1">
            <title>Ph I Dose Level 1: Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 20mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O2">
            <title>Ph I Dose Level 2: Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 40mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O3">
            <title>Ph I Dose Level 3: Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 60mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With a Dose Limiting Toxicities (DLTs)</title>
          <description>A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of &gt; 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count &lt;500/µL lasting &gt; 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia &lt; 50K/µL requiring platelet transfusion for bleeding.</description>
          <population>DLT only pertains to DL1, 2 and 3. Arms A and B did not evaluate for DLT.</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="4"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Neutropenic fever</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Palmar plantar erythroderma</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants Achieving Prostatic-Specific Antigen (PSA) Decline of 30% or 50% From Baseline</title>
        <description>PSA normal range is 4 ng/ml or lower. Participants with PSA decline of 30% or 50% is the measures for prostate cancer based on conventional reporting metrics.</description>
        <time_frame>up to 38 months</time_frame>
        <population>One participant randomized to Arm A declined to participate before treatment started.</population>
        <group_list>
          <group group_id="O1">
            <title>Ph I Dose Level 1:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 20 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O2">
            <title>Ph I Dose Level 2:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 40 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O3">
            <title>Ph I Dose Level 3:Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Cabozantinib: 60 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
          </group>
          <group group_id="O4">
            <title>Ph II Arm A Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg by mouth (PO) twice a day (BID)</description>
          </group>
          <group group_id="O5">
            <title>Ph II Arm B: Cabozantinib + Docetaxel + Prednisone</title>
            <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg by mouth (PO) twice a day (BID); Cabozantinib: 40mg by mouth (PO) everyday (QD)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Achieving Prostatic-Specific Antigen (PSA) Decline of 30% or 50% From Baseline</title>
          <description>PSA normal range is 4 ng/ml or lower. Participants with PSA decline of 30% or 50% is the measures for prostate cancer based on conventional reporting metrics.</description>
          <population>One participant randomized to Arm A declined to participate before treatment started.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="7"/>
                <count group_id="O4" value="12"/>
                <count group_id="O5" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Decline in PSA&gt;30% from baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="5"/>
                    <measurement group_id="O4" value="5"/>
                    <measurement group_id="O5" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Decline in PSA&gt;50% from baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="3"/>
                    <measurement group_id="O5" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were assessed from the date treatment consent signed to date off study, approximately 45 months and 14 days for Arm A; 43 months and 14 days for Arm B; 9 months and 11 days for Dose Level 1; 27 months and 1 day for Dose Level 2; and 11 months and 25 days for Dose Level 3.</time_frame>
      <desc>One participant in Arm/Group A declined to participate before treatment started.</desc>
      <group_list>
        <group group_id="E1">
          <title>Ph I Dose Level 1:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 20 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="E2">
          <title>Ph I Dose Level 2:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 40 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="E3">
          <title>Ph I Dose Level 3:Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Cabozantinib: 60 mg by mouth (PO) everyday (QD); Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID)</description>
        </group>
        <group group_id="E4">
          <title>Ph II Arm A: Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg by mouth (PO) twice a day (BID)</description>
        </group>
        <group group_id="E5">
          <title>Ph II Arm B: Cabozantinib + Docetaxel + Prednisone</title>
          <description>Cycle=21 days; Docetaxel: 75 mg/m^2 intravenous (IV) over 60 min on day 1; Prednisone: 5 mg PO twice a day (BID); Cabozantinib: 40 mg by mouth (PO) everyday (QD)</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="13"/>
              </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="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Heart failure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lower gastrointestinal hemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gastric ulcer</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rectal ulcer</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Sudden death NOS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Death NOS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Anorectal infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Transient ischemic attacks</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </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="4" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="7"/>
                <counts group_id="E4" subjects_affected="12" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="13" subjects_at_risk="13"/>
              </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="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="11" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="5" subjects_affected="4" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Watering eyes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Periorbital edema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="9" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E5" events="7" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Duodenal ulcer</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gastroparesis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="8" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Proctitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rectal hemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="6" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="3" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="11" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E3" events="5" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Oral dysesthesia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="5" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rectal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rectal perforation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rectal ulcer</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fecal incontinence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gingival pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="8" subjects_affected="6" subjects_at_risk="12"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Infusion site extravasation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="3" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="8" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nail infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gum infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Burn</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Infusion site extravasation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="6" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="3" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="10" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="5" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="10" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="3" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" events="16" subjects_affected="7" subjects_at_risk="8"/>
                <counts group_id="E3" events="6" subjects_affected="4" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="8" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E5" events="5" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E3" events="9" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>Burning sensation in legs/bones</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Neck edema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Osteonecrosis of jaw</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </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>Extraosseous extension</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="7" subjects_affected="7" subjects_at_risk="12"/>
                <counts group_id="E5" events="8" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E3" events="6" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="4" subjects_affected="4" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, neuropathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Movements involuntary</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urinary tract obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urinary tract pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Testicular pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Genital edema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gynecomastia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Postnasal drip</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Bronchial obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="8" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pleuritic pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </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="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E5" events="7" subjects_affected="7" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nail discoloration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nail loss</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nail ridging</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="26" subjects_affected="7" subjects_at_risk="8"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="8" subjects_affected="6" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, skin discoloration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin hypopigmentation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="6" subjects_affected="4" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="14" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Scalp pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, dermatitis-eye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Purpura</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, petechiae</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin atrophy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pain of skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="4" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, R. thigh lesion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, dermatitis-hand</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vascular disorders - Other, peripheral vascular disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vascular disorders - Other, vasculopathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </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. William Dahut</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>240-760-6070</phone>
      <email>william_dahut@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/NCT01683994
org study id: 120204
secondary id: 12-C-0204
nct id: NCT01683994
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 tumors
      respond to it. Docetaxel and prednisone are standard treatments for advanced prostate cancer.
      Researchers want to see if adding cabozantinib to these two drugs can be a safe and effective
      treatment for this type of cancer.

      Objectives:

      - To test the safety and effectiveness of cabozantinib with standard treatments for advanced
      prostate cancer.

      Eligibility:

      - Individuals at least 18 years of age who have advanced prostate 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. Imaging studies will also be performed.

        -  Participants will receive the cancer drugs over 21-day cycles of treatment. They will
           take docetaxel and cabozantinib on day 1 of each cycle. Each docetaxel infusion will
           take about 1 hour. They will also take prednisone by mouth twice each day.

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

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

        -  Docetaxel is established as first-line chemotherapy in patients with metastatic castrate
           resistant prostate cancer (CRPC). However; it is increasingly recognized that combining
           docetaxel with other agents of clinical activities without overlapping toxicities could
           simultaneously target different cellular signaling pathways vital for tumor survival,
           producing either additive or synergistic activities.

        -  Inhibition of angiogenesis, either as a stand-alone approach or in combination with
           chemotherapy, has demonstrable antitumor efficacy against CRPC and there are several
           antiangiogenic agents that are now in clinical trials in this population of patients.

        -  Cabozantinib (XL184) was developed as an inhibitor of both angiogenesis and of its
           resistance mechanism. It is an inhibitor of multiple receptor tyrosine kinases including
           tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor receptor 2
           (VEGFR2) and rearranged during transfection (RET).

        -  In single agent clinical studies, cabozantinib demonstrated, broad anti-tumor activities
           across many solid tumor types.

      Objectives:

        -  To determine the safety profile of cabozantinib in combination with docetaxel and
           prednisone, and to determine the maximal tolerated dose (MTD) as recommended phase II
           dose in combination with docetaxel

        -  To determine the relative efficacy (in terms of progression free survival (PFS)) of
           docetaxel and cabozantinib compared to docetaxel alone

      Eligibility:

        -  Patients must have progressive metastatic CRPC. There must be radiographic evidence of
           disease after primary treatment with surgery or radiotherapy. If patients had been on
           flutamide, they must have disease progression at least 4 weeks after withdrawal.
           Patients on bicalutamide or nilutamide must have progression at least 6 weeks after
           withdrawal. Withdrawal criteria apply only to patients on the above anti-androgens for
           at least the prior 6 months.

        -  Patients must be at least 18 years of age and able to give informed consent.

        -  Patients in the Phase II portion of the study must have progressed on abiraterone or
           enzalutamide

      Design:

        -  The initial phase I portion of this study will test fixed dose docetaxel and prednisone
           in combination with cabozantinib at three escalating doses. Using a standard 3 + 3
           design, three patients will initially be treated at each dose level until MTD has been
           defined.

        -  An expansion cohort will then be enrolled at the MTD to further characterize safety,
           toxicity and pharmacokinetic data and to obtain preliminary information on the efficacy
           of the combination treatment.

        -  In Phase II, patients will be enrolled to a randomized two-arm cohort comparing
           docetaxel in combination with cabozantinib to docetaxel alone with a primary endpoint of
           PFS.

        -  The accrual ceiling for the study, including the Phase I dose escalation and the
           expansion phases as well as the Phase II randomized phase, is set at 81.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival (PFS) of Cabozantinib + Docetaxel + Prednisone Compared to Docetaxel + Prednisone Alone
time frame: From start date of treatment until the date of first documented progression, date of death from any cause and up to 40 months, whichever occurred first.
description: PFS is the time interval from start of treatment to documented evidence of disease progression or death. Disease progression was assessed by the Response Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions as referenced by the smallest sum on study. Appearance of one or more new lesions on bone scan and/or two consecutive rising prostatic-specific antigen values above the baseline at a minimum of one week intervals. A normal PSA value is 4.0 ng/ml and lower.
measure: Maximum Tolerated Dose (MTD)
time frame: First two cycles of treatment (each cycle is 21 days), approximately 42 days.
description: MTD is defined as the dose level at which no more than 1 of 6 patients experiences a dose limiting toxicity (DLT) at the level below that which had two instances of DLT. A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of > 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count <500/µL lasting > 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia < 50K/µL requiring platelet transfusion for bleeding.
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
time frame: Adverse events were assessed from the date treatment consent signed to date off study, approximately 45 months and 14 days for Arm A; 43 months and 14 days for Arm B; 9 months and 11 days for DL1; 27 months and 1 day for DL2; & 11 months & 25 days for DL3
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.
measure: Number of Participants With a Dose Limiting Toxicities (DLTs)
time frame: First two cycles of treatment (each cycle is 21 days), approximately 42 days.
description: A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of > 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count <500/µL lasting > 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia < 50K/µL requiring platelet transfusion for bleeding.
measure: Number of Participants Achieving Prostatic-Specific Antigen (PSA) Decline of 30% or 50% From Baseline
time frame: up to 38 months
description: PSA normal range is 4 ng/ml or lower. Participants with PSA decline of 30% or 50% is the measures for prostate cancer based on conventional reporting metrics.
arm group label: combination of cabozantinib, docetaxel and prednisone
arm group type: Experimental
description: combination of cabozantinib, docetaxel and prednisone
arm group label: PII/ Arm 1-docetaxel + prednisone only
arm group type: Active Comparator
description: docetaxel + prednisone only
arm group label: PII/Arm 2 -docetaxel+ prednisone + cabozantinib
arm group type: Active Comparator
description: docetaxel+ prednisone + cabozantinib
intervention type: Drug
intervention name: Cabozantinib
description: Assigned dose given daily during each 21 day cycle. Treatment may continue until disease progression or intolerable toxicity.
arm group label: PII/Arm 2 -docetaxel+ prednisone + cabozantinib
arm group label: combination of cabozantinib, docetaxel and prednisone
other name: Cometriq
intervention type: Drug
intervention name: Docetaxel
description: 75mg/m^2 intravenous (IV) over approximately 60 minutes on cycle 1 day 1 and repeated every 21 days until disease progression or intolerable toxicity.
arm group label: PII/ Arm 1-docetaxel + prednisone only
arm group label: PII/Arm 2 -docetaxel+ prednisone + cabozantinib
arm group label: combination of cabozantinib, docetaxel and prednisone
other name: Taxotere
intervention type: Drug
intervention name: Prednisone
description: 5 mg by mouth (PO) twice a day during each 21 day cycle until disease progression or intolerable toxicity.
arm group label: PII/ Arm 1-docetaxel + prednisone only
arm group label: PII/Arm 2 -docetaxel+ prednisone + cabozantinib
arm group label: combination of cabozantinib, docetaxel and prednisone
other name: Deltasone
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: William L Dahut, 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-0204.html
description: NIH Clinical Center Detailed Web Page
citation: Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26(7):1148-59. doi: 10.1200/JCO.2007.12.4487.
PMID: 18309951
citation: Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300. doi: 10.3322/caac.20073. Epub 2010 Jul 7. Erratum In: CA Cancer J Clin. 2011 Mar-Apr;61(2):133-4.
PMID: 20610543
citation: Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. doi: 10.1056/NEJMoa041318.
PMID: 15470214
citation: A phase I and randomized phase II study of cabozantinib plus docetaxel and prednisone (C+DP) versus docetaxel and prednisone (DP) alone in metastatic castrate-resistant prostate cancer (mCRPC). Munjid Al Harthy, Ravi Amrit Madan, Fatima Karzai, Daniel Peter Petrylak, Joseph W. Kim, Philip M. Arlen, Marc Robert Theoret, Jenn Marte, Marijo Bilusic, Anna Couvillon, Guinevere Chun, Helen Owens, Amy Hankin, Lisa M. Cordes, William Douglas Figg, James L. Gulley, and William L. Dahut Journal of Clinical Oncology 2019 37:7_suppl, 173-173
responsible party type: Principal Investigator
investigator affiliation: National Cancer Institute (NCI)
investigator full name: William Dahut Jr., M.D.
investigator title: Principal Investigator
mesh term: Prostatic Neoplasms
mesh term: Prednisone
mesh term: Docetaxel
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 