<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/NCT02243605</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2014-01927</org_study_id>
    <secondary_id>NCI-2014-01927</secondary_id>
    <secondary_id>CABONE</secondary_id>
    <secondary_id>9620</secondary_id>
    <secondary_id>9620</secondary_id>
    <nct_id>NCT02243605</nct_id>
  </id_info>
  <brief_title>Cabozantinib S-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma</brief_title>
  <official_title>A Phase 2 Study of XL184 (Cabozantinib) in Treating Patients With Relapsed Osteosarcomas and Ewing Sarcomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well cabozantinib s-malate works in treating patients with&#xD;
      osteosarcoma or Ewing sarcoma that has grown or returned (come back) after a period of&#xD;
      improvement. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the&#xD;
      enzymes needed for cell growth and may also prevent the growth of new blood vessels that&#xD;
      tumors need to grow.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the antitumor activity of cabozantinib s-malate (cabozantinib) for Ewing&#xD;
      sarcomas, in terms of 6-month objectives response as per the Response Evaluation Criteria in&#xD;
      Solid Tumors, Revised (RECIST version [v]1.1).&#xD;
&#xD;
      II. To evaluate the antitumor activity of cabozantinib for osteosarcoma, in terms of 6-month&#xD;
      objective response (complete response, partial response) and 6-month non-progression&#xD;
      (complete response, partial response and stable disease), as per RECIST v1.1.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. 6-month objective response. (Ewing sarcoma only) II. Best overall response (as per the&#xD;
      revised RECIST v1.1). (Ewing sarcoma and osteosarcoma) III. 1- and 2-year progression-free&#xD;
      survival. (Ewing sarcoma and osteosarcoma) IV. 1- and 2-year overall survival. (Ewing sarcoma&#xD;
      and osteosarcoma) V. Cabozantinib safety. (Ewing sarcoma and osteosarcoma) VI. To assess the&#xD;
      ability of metabolic tumor response as measured by fludeoxyglucose (FDG)-positron emission&#xD;
      tomography (PET) at the end of one cycle of treatment to predict progression-free survival&#xD;
      (PFS). (Ewing sarcoma and osteosarcoma) VII. Translational research: to determine and compare&#xD;
      tumor expression of MET, phosphorylated (phosphor)-MET and circulating levels of HGF, soluble&#xD;
      MET (sMET), VEGF-A, and soluble VEGF receptor 2 (VEGFR2) (sVEGFR2) prior to and following&#xD;
      administration of cabozantinib. (Ewing sarcoma and osteosarcoma)&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28. Cycles&#xD;
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 6 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 19, 2014</start_date>
  <primary_completion_date type="Actual">June 30, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Non-progression at 6 Months - Osteosarcoma</measure>
    <time_frame>At 6 months</time_frame>
    <description>Non-progression defined as complete response (CR), partial response (PR), or stable disease (SD) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective Response Within 6 Months of Treatment Onset - Osteosarcoma</measure>
    <time_frame>Within 6 months of treatment onset</time_frame>
    <description>Objective response defined as complete response (CR) or partial response (PR) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, CR is defined as disappearance of all target and non-target lesions and normalization of tumour marker level of non-target lesions. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
As per revised RECIST v1.1, PR is defined as a at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and non-PD/not all evaluated non-target lesions, or, CR of target lesions and non-CR/non-PD/not evaluated non-target lesions.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective Response Within 6 Months of Treatment Onset - Ewing Sarcoma</measure>
    <time_frame>Within 6 months of treatment onset</time_frame>
    <description>Objective response defined as complete response (CR) or partial response (PR) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, CR is defined as disappearance of all target and non-target lesions and normalization of tumour marker level of non-target lesions. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
As per revised RECIST v1.1, PR is defined as a at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and non-PD/not all evaluated non-target lesions, or, CR of target lesions and non-CR/non-PD/not evaluated non-target lesions.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Best Overall Response</measure>
    <time_frame>From the start of the treatment until disease progression/recurrence, assessed up to 2 years</time_frame>
    <description>Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). Will be described using frequency, percentage, and 95% confidence interval (binomial law).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years</time_frame>
    <description>Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). PFS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox's proportional risk method and after checking the risk proportionality hypothesis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Time from start of treatment to the time of death, assessed up to 2 years</time_frame>
    <description>Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). OS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox's proportional risk method and after checking the risk proportionality hypothesis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse Events</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Quantitative variables will be described using mean and standard errors if the normality assumption is satisfied, else other descriptive statistics (median, range, quartiles) will be used. Qualitative variables will be described using frequency, percentage, and 95% confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-progression at 6 Months - Ewing Sarcoma</measure>
    <time_frame>At 6 months</time_frame>
    <description>Non-progression defined as complete response (CR), partial response (PR), or stable disease (SD) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Metastatic Ewing Sarcoma</condition>
  <condition>Metastatic Osteosarcoma</condition>
  <condition>Recurrent Ewing Sarcoma</condition>
  <condition>Recurrent Osteosarcoma</condition>
  <condition>Stage III Osteosarcoma AJCC v7</condition>
  <condition>Stage IV Osteosarcoma AJCC v7</condition>
  <condition>Stage IVA Osteosarcoma AJCC v7</condition>
  <condition>Stage IVB Osteosarcoma AJCC v7</condition>
  <condition>Unresectable Ewing Sarcoma</condition>
  <condition>Unresectable Osteosarcoma</condition>
  <arm_group>
    <arm_group_label>Treatment (cabozantinib s-malate)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive cabozantinib s-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabozantinib S-malate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (cabozantinib s-malate)</arm_group_label>
    <other_name>BMS-907351</other_name>
    <other_name>Cabometyx</other_name>
    <other_name>Cometriq</other_name>
    <other_name>XL-184</other_name>
    <other_name>XL184</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (cabozantinib s-malate)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Young patient age between 12 - 15 could be included in only 6 centers (Bordeaux, Lyon,&#xD;
             Villejuif, Lille, Marseille and Paris)&#xD;
&#xD;
          -  Patients must have histologically confirmed diagnosis of osteosarcoma or Ewing sarcoma&#xD;
             by central review, except if the diagnosis was already confirmed by the RRePS (Reseau&#xD;
             de Reference en Pathologie des Sarcomes et des Tissus Mous et des Visceres) network&#xD;
&#xD;
          -  Relapsed disease after standard chemotherapy&#xD;
&#xD;
          -  Patients must have measurable disease (lesion in previously irradiated field could be&#xD;
             considered as measurable if progressive at inclusion) defined as per RECIST v1.1 with&#xD;
             at least one lesion that can be measured in at least one dimension (longest diameter&#xD;
             to be recorded) as &gt;= 10 mm with spiral computed tomography (CT) scan&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 1&#xD;
&#xD;
          -  Life expectancy of greater than 3 months&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Lymphocyte count &gt; 1,000/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x upper limit of normal (ULN)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 3.0 x institutional upper limit of normal&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 x ULN OR creatinine clearance &gt;= 50 mL/min/1.73 m^2 for patients&#xD;
             with creatinine levels above institutional normal (Cockcroft formula)&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL&#xD;
&#xD;
          -  Serum albumin &gt;= 2.8 g/dL&#xD;
&#xD;
          -  Lipase &lt; 2.0 x ULN and no radiologic or clinical evidence of pancreatitis&#xD;
&#xD;
          -  Urine protein/creatinine ratio (UPCR) =&lt; 1&#xD;
&#xD;
          -  Serum phosphorus &gt;= lower limit of normal (LLN)&#xD;
&#xD;
          -  Serum calcium &gt;= LLN&#xD;
&#xD;
          -  Serum magnesium &gt;= LLN&#xD;
&#xD;
          -  Serum potassium &gt;= LLN&#xD;
&#xD;
          -  Female subjects of childbearing potential must not be pregnant at screening; females&#xD;
             of childbearing potential are defined as premenopausal females capable of becoming&#xD;
             pregnant (ie, females who have had any evidence of menses in the past 12 months, with&#xD;
             the exception of those who had prior hysterectomy); however, women who have been&#xD;
             amenorrheic for 12 or more months are still considered to be of childbearing potential&#xD;
             if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body&#xD;
             weight, ovarian suppression or other reasons&#xD;
&#xD;
          -  The effects of Cabozantinib on the developing human fetus are unknown; for this reason&#xD;
             and because tyrosine kinase inhibitors agents as well as other therapeutic agents used&#xD;
             in this trial are known to be teratogenic, women of child-bearing potential and men&#xD;
             must agree to use adequate contraception (see below) prior to study entry and for the&#xD;
             duration of study participation; should a woman become pregnant or suspect she is&#xD;
             pregnant while she is participating in this study, she should inform her treating&#xD;
             physician immediately; men treated or enrolled on this protocol must also agree to use&#xD;
             adequate contraception prior to the study, for the duration of study participation,&#xD;
             and 4 months after completion of cabozantinib administration&#xD;
&#xD;
               -  Sexually active subjects (men and women) must agree to use medically accepted&#xD;
                  barrier methods of contraception (e.g., male or female condom) during the course&#xD;
                  of the study and for 4 months after the last dose of study drug(s), even if oral&#xD;
                  contraceptives are also used; all subjects of reproductive potential must agree&#xD;
                  to use both a barrier method and a second method of birth control during the&#xD;
                  course of the study and for 4 months after the last dose of study drug(s)&#xD;
&#xD;
          -  Metastatic or unresectable locally advanced&#xD;
&#xD;
          -  Documented disease progression (as per RECIST v1.1) before study entry; for patients&#xD;
             with osteosarcoma, this progression will be confirmed by central review on the basis&#xD;
             of two CT scan or magnetic resonance imaging (MRI) obtained at less than 6 months in&#xD;
             the period of 12 months prior to inclusion&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
          -  In accordance with French Regulatory Authorities: Patients with French Social Security&#xD;
             in compliance with the French law relating to biomedical research (Huriet Law 88-1138&#xD;
             and related decrees)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The subject has received cytotoxic chemotherapy (including investigational cytotoxic&#xD;
             chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or&#xD;
             nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment&#xD;
&#xD;
          -  Prior treatment with cabozantinib&#xD;
&#xD;
          -  Radiation therapy for bone metastasis within 2 weeks, any other external radiation&#xD;
             therapy within 4 weeks before the first dose of study treatment; systemic treatment&#xD;
             with radionuclides within 6 weeks before the first dose of study treatment; subjects&#xD;
             with clinically relevant ongoing complications from prior radiation therapy are not&#xD;
             eligible&#xD;
&#xD;
          -  Receipt of any type of small molecule kinase inhibitor (including investigational&#xD;
             kinase inhibitor) within 14 days before the first dose of study treatment; note:&#xD;
             subjects with prostate cancer currently receiving luteinizing hormone-releasing&#xD;
             hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists may be maintained on&#xD;
             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 not recovered to baseline or Common Terminology Criteria for Adverse&#xD;
             Events (CTCAE) =&lt; grade 1 from toxicity due to all prior therapies except alopecia and&#xD;
             other non-clinically significant adverse events (AEs)&#xD;
&#xD;
          -  The subject has a primary brain tumor&#xD;
&#xD;
          -  Known brain metastases or cranial epidural disease unless adequately treated with&#xD;
             radiotherapy and/or surgery (including radiosurgery) and stable for at least 2 weeks&#xD;
             before the first dose of study treatment; eligible subjects must be neurologically&#xD;
             asymptomatic and without corticosteroid treatment at the time of the start of study&#xD;
             treatment&#xD;
&#xD;
          -  The subject has prothrombin time (PT)/international normalized ratio (INR) or partial&#xD;
             thromboplastin time (PTT) test &gt;= 1.3 x the laboratory ULN within 7 days before the&#xD;
             first dose of study treatment&#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 (=&lt; 81&#xD;
             mg/day), low-dose warfarin (=&lt; 1 mg/day), and prophylactic low molecular weight&#xD;
             heparin (LMWH) are permitted&#xD;
&#xD;
          -  The subject requires chronic concomitant treatment of strong cytochrome P450 family 3,&#xD;
             subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin,&#xD;
             carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)&#xD;
&#xD;
               -  it is important to regularly consult a frequently-updated list; medical reference&#xD;
                  texts such as the Physicians' Desk Reference may also provide this information;&#xD;
                  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&#xD;
                  medications need to be prescribed or if the patient is considering a new&#xD;
                  over-the-counter medicine or herbal product&#xD;
&#xD;
          -  The subject has experienced any of the following:&#xD;
&#xD;
               -  Clinically-significant gastrointestinal bleeding within 6 months before the first&#xD;
                  dose of study treatment&#xD;
&#xD;
               -  Hemoptysis of &gt;= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the&#xD;
                  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 radiographic evidence of cavitating pulmonary lesion(s)&#xD;
&#xD;
          -  The subject has tumor in contact with, invading or encasing any major blood vessels&#xD;
&#xD;
          -  The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus,&#xD;
             stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or&#xD;
             endobronchial tumor within 28 days before the first dose of cabozantinib&#xD;
&#xD;
          -  The subject 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 blood pressure&#xD;
                       (BP) &gt; 150 mm Hg systolic, or &gt; 90 mm Hg diastolic despite optimal&#xD;
                       antihypertensive treatment within 7 days of the first dose of study&#xD;
                       treatment&#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 transient ischemic attack [TIA], or other ischemic&#xD;
                            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 eligible&#xD;
                            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;
                         -  Any evidence of active peptic ulcer disease, patients must be&#xD;
                            completely recovered&#xD;
&#xD;
                         -  Any evidence of inflammatory bowel disease (including ulcerative&#xD;
                            colitis and Crohn's disease), diverticulitis, cholecystitis,&#xD;
                            symptomatic cholangitis or appendicitis, patients must be completely&#xD;
                            recovered from these conditions&#xD;
&#xD;
                         -  Malabsorption syndrome&#xD;
&#xD;
                    -  Any of the following within 6 months before the first dose of study&#xD;
                       treatment:&#xD;
&#xD;
                         -  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&#xD;
                            before the first dose of study treatment&#xD;
&#xD;
               -  Other disorders associated with a high risk of fistula formation including&#xD;
                  percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before&#xD;
                  the first dose of study therapy&#xD;
&#xD;
               -  Other clinically significant disorders such as:&#xD;
&#xD;
                    -  Active infection requiring systemic treatment within 28 days before the&#xD;
                       first dose of study treatment&#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 days&#xD;
                       before the first dose of study treatment&#xD;
&#xD;
                    -  History of major surgery as follows:&#xD;
&#xD;
                         -  Major surgery within 12 weeks before the first dose of study treatment;&#xD;
                            complete wound healing from major surgery must have occurred 1 month&#xD;
                            before the first dose of study treatment&#xD;
&#xD;
                         -  Minor surgery (including uncomplicated tooth extractions) within 28&#xD;
                            days before the first dose of study treatment with complete wound&#xD;
                            healing at least 10 days before the first dose of study treatment;&#xD;
                            subjects with clinically relevant ongoing complications from prior&#xD;
                            surgery are not eligible&#xD;
&#xD;
          -  The subject is unable to swallow tablets&#xD;
&#xD;
          -  The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) &gt;&#xD;
             500 ms within 28 days before treatment; note: if initial QTcF is found to be &gt; 500 ms,&#xD;
             two additional electrocardiograms (EKGs) separated by at least 3 minutes should be&#xD;
             performed; if the average of these three consecutive results for QTcF is =&lt; 500 ms,&#xD;
             the subject meets eligibility in this regard&#xD;
&#xD;
          -  The subject is unable or unwilling to abide by the study protocol or cooperate fully&#xD;
             with the investigator or designee&#xD;
&#xD;
          -  The subject has had evidence within 2 years of the start of study treatment of another&#xD;
             malignancy which required systemic treatment&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to cabozantinib&#xD;
&#xD;
          -  Pregnant women are excluded from this study because cabozantinib is a tyrosine kinase&#xD;
             inhibitor with the potential for teratogenic or abortifacient effects; because there&#xD;
             is an unknown but potential risk for adverse events in nursing infants secondary to&#xD;
             treatment of the mother with cabozantinib, breastfeeding should be discontinued if the&#xD;
             mother is treated with cabozantinib; these potential risks may also apply to other&#xD;
             agents used in this study&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             cabozantinib; in addition, these patients are at increased risk of lethal infections&#xD;
             when treated with marrow-suppressive therapy; appropriate studies will be undertaken&#xD;
             in patients receiving combination antiretroviral therapy when indicated&#xD;
&#xD;
          -  Participation to a study involving a medical or therapeutic intervention in the last&#xD;
             30 days&#xD;
&#xD;
          -  Prior participation in this study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Antoine Italiano</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut Bergonie Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut Bergonie Cancer Center</name>
      <address>
        <city>Bordeaux</city>
        <zip>33076</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Georges-Francois Leclerc</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Oscar Lambert</name>
      <address>
        <city>Lille</city>
        <zip>59020</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Leon Berard</name>
      <address>
        <city>Lyon</city>
        <zip>69373</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital De La Timone</name>
      <address>
        <city>Marseille</city>
        <zip>13385</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Antoine Lacassagne</name>
      <address>
        <city>Nice</city>
        <zip>06189</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Curie Paris</name>
      <address>
        <city>Paris</city>
        <zip>75005</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut de Cancerologie de l'Ouest-Rene Gauducheau</name>
      <address>
        <city>Saint Herblain</city>
        <zip>44805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU Strasbourg - Hospital Civil</name>
      <address>
        <city>Strasbourg</city>
        <zip>67091</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Center Claudius Regaud</name>
      <address>
        <city>Toulouse</city>
        <zip>31052</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>September 16, 2014</study_first_submitted>
  <study_first_submitted_qc>September 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2014</study_first_posted>
  <results_first_submitted>July 20, 2020</results_first_submitted>
  <results_first_submitted_qc>August 20, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">September 4, 2020</results_first_posted>
  <last_update_submitted>September 5, 2023</last_update_submitted>
  <last_update_submitted_qc>September 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sarcoma</mesh_term>
    <mesh_term>Osteosarcoma</mesh_term>
    <mesh_term>Sarcoma, Ewing</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 4, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/05/NCT02243605/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Ewing Sarcoma</title>
          <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
Single-arm phase II clinical trial based on a two-stage optimal Simon's design with 41 evaluable patients (first stage: 21 patients) used to distinguish a favorable true objective response rate within 6 months of treatment onset of 20% from a null rate of 5% (90% power and 5% type I error).&#xD;
Stage 1(21 evaluable patients): if &lt;=1 objective response within 6 months of treatment onset, the study was stopped early. Otherwise, the second group of 20 participants was recruited.&#xD;
Stage 2 (41 evaluable patients): if &gt;= 5 objective response within 6 months of treatment onset, Cabozantinib was considered promising.</description>
        </group>
        <group group_id="P2">
          <title>Osteosarcoma</title>
          <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
Single-arm phase II trial based on 2-stage dual endpoint design with 41 evaluable patients (first stage: 21 patients) used to distinguish :&#xD;
a favorable true 6-month non-progression rate of 50% from a null rate of 25% (92% power).&#xD;
a favorable true objective response rate within 6 months of treatment onset of 20% from a null rate of 5% (90% power).&#xD;
Stage 1(21 evaluable patients): if &lt;=1 objective response within 6 months of treatment onset or &lt;=6 6-month non-progression, the study was stopped early. Otherwise, the second group of 20 participants was recruited.&#xD;
Stage 2 (41 evaluable patients): if &gt;= 5 objective response within 6 months of treatment onset or &gt;=16 6-month non-progression, Cabozantinib was considered promising.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Stage 1 - Interim Analysis Population</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Stage 2 - Final Analysis Population</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="45"/>
                <participants group_id="P2" count="45"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
                <participants group_id="P2" count="42"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Progression</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Ewing Sarcoma</title>
          <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
Single-arm phase II clinical trial based on a two-stage optimal Simon's design with 41 evaluable patients (first stage: 21 patients) used to distinguish a favorable true objective response rate within 6 months of treatment onset of 20% from a null rate of 5% (90% power and 5% type I error).&#xD;
Stage 1(21 evaluable patients): if &lt;=1 objective response within 6 months of treatment onset, the study was stopped early. Otherwise, the second group of 20 participants was recruited.&#xD;
Stage 2 (41 evaluable patients): if &gt;= 5 objective response within 6 months of treatment onset, Cabozantinib was considered promising.</description>
        </group>
        <group group_id="B2">
          <title>Osteosarcoma</title>
          <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
Single-arm phase II trial based on 2-stage dual endpoint design with 41 evaluable patients (first stage: 21 patients) used to distinguish :&#xD;
a favorable true 6-month non-progression rate of 50% from a null rate of 25% (92% power).&#xD;
a favorable true objective response rate within 6 months of treatment onset of 20% from a null rate of 5% (90% power).&#xD;
Stage 1(21 evaluable patients): if &lt;=1 objective response within 6 months of treatment onset or &lt;=6 6-month non-progression, the study was stopped early. Otherwise, the second group of 20 participants was recruited.&#xD;
Stage 2 (41 evaluable patients): if &gt;= 5 objective response within 6 months of treatment onset or &gt;=16 6-month non-progression, Cabozantinib was considered promising.</description>
        </group>
        <group group_id="B3">
          <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="45"/>
            <count group_id="B2" value="45"/>
            <count group_id="B3" value="90"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="45"/>
                    <count group_id="B2" value="45"/>
                    <count group_id="B3" value="90"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="38"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="69"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="45"/>
                    <count group_id="B2" value="45"/>
                    <count group_id="B3" value="90"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33" lower_limit="24" upper_limit="45"/>
                    <measurement group_id="B2" value="34" lower_limit="20" upper_limit="53"/>
                    <measurement group_id="B3" value="34" lower_limit="21" upper_limit="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="45"/>
                    <count group_id="B2" value="45"/>
                    <count group_id="B3" value="90"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>France</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="45"/>
                    <count group_id="B2" value="45"/>
                    <count group_id="B3" value="90"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                    <measurement group_id="B2" value="45"/>
                    <measurement group_id="B3" value="90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Non-progression at 6 Months - Osteosarcoma</title>
        <description>Non-progression defined as complete response (CR), partial response (PR), or stable disease (SD) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
        <time_frame>At 6 months</time_frame>
        <population>All patients eligible and who received at least one complete or two incomplete treatment cycles.</population>
        <group_list>
          <group group_id="O1">
            <title>Osteosarcoma</title>
            <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
Single-arm phase II trial based on 2-stage dual endpoint design with 41 evaluable patients (first stage: 21 patients) used to distinguish :&#xD;
a favorable true 6-month non-progression rate of 50% from a null rate of 25% (92% power).&#xD;
a favorable true objective response rate within 6 months of treatment onset of 20% from a null rate of 5% (90% power).&#xD;
Stage 1(21 evaluable patients): if &lt;=1 objective response within 6 months of treatment onset or &lt;=6 6-month non-progression, the study was stopped early. Otherwise, the second group of 20 participants was recruited.&#xD;
Stage 2 (41 evaluable patients): if &gt;= 5 objective response within 6 months of treatment onset or &gt;=16 6-month non-progression, Cabozantinib was considered promising.</description>
          </group>
        </group_list>
        <measure>
          <title>Non-progression at 6 Months - Osteosarcoma</title>
          <description>Non-progression defined as complete response (CR), partial response (PR), or stable disease (SD) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
          <population>All patients eligible and who received at least one complete or two incomplete treatment cycles.</population>
          <units>percentage</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.3" lower_limit="19.6" upper_limit="49.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Within 6 Months of Treatment Onset - Osteosarcoma</title>
        <description>Objective response defined as complete response (CR) or partial response (PR) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, CR is defined as disappearance of all target and non-target lesions and normalization of tumour marker level of non-target lesions. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
As per revised RECIST v1.1, PR is defined as a at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and non-PD/not all evaluated non-target lesions, or, CR of target lesions and non-CR/non-PD/not evaluated non-target lesions.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
        <time_frame>Within 6 months of treatment onset</time_frame>
        <population>All patients eligible and who received at least one complete or two incomplete treatment cycles.</population>
        <group_list>
          <group group_id="O1">
            <title>Osteosarcoma</title>
            <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
Single-arm phase II trial based on 2-stage dual endpoint design with 41 evaluable patients (first stage: 21 patients) used to distinguish :&#xD;
a favorable true 6-month non-progression rate of 50% from a null rate of 25% (92% power).&#xD;
a favorable true objective response rate within 6 months of treatment onset of 20% from a null rate of 5% (90% power).&#xD;
Stage 1(21 evaluable patients): if &lt;=1 objective response within 6 months of treatment onset or &lt;=6 6-month non-progression, the study was stopped early. Otherwise, the second group of 20 participants was recruited.&#xD;
Stage 2 (41 evaluable patients): if &gt;= 5 objective response within 6 months of treatment onset or &gt;=16 6-month non-progression, Cabozantinib was considered promising.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Within 6 Months of Treatment Onset - Osteosarcoma</title>
          <description>Objective response defined as complete response (CR) or partial response (PR) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, CR is defined as disappearance of all target and non-target lesions and normalization of tumour marker level of non-target lesions. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
As per revised RECIST v1.1, PR is defined as a at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and non-PD/not all evaluated non-target lesions, or, CR of target lesions and non-CR/non-PD/not evaluated non-target lesions.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
          <population>All patients eligible and who received at least one complete or two incomplete treatment cycles.</population>
          <units>percentage</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.9" lower_limit="4.0" upper_limit="25.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Within 6 Months of Treatment Onset - Ewing Sarcoma</title>
        <description>Objective response defined as complete response (CR) or partial response (PR) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, CR is defined as disappearance of all target and non-target lesions and normalization of tumour marker level of non-target lesions. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
As per revised RECIST v1.1, PR is defined as a at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and non-PD/not all evaluated non-target lesions, or, CR of target lesions and non-CR/non-PD/not evaluated non-target lesions.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
        <time_frame>Within 6 months of treatment onset</time_frame>
        <population>All patients eligible and who received at least one complete or two incomplete treatment cycles.</population>
        <group_list>
          <group group_id="O1">
            <title>Ewing Sarcoma</title>
            <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
Single-arm phase II clinical trial based on a two-stage optimal Simon's design with 41 evaluable patients (first stage: 21 patients) used to distinguish a favorable true objective response rate within 6 months of treatment onset of 20% from a null rate of 5% (90% power and 5% type I error).&#xD;
Stage 1(21 evaluable patients): if &lt;=1 objective response within 6 months of treatment onset, the study was stopped early. Otherwise, the second group of 20 participants was recruited.&#xD;
Stage 2 (41 evaluable patients): if &gt;= 5 objective response within 6 months of treatment onset, Cabozantinib was considered promising.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Within 6 Months of Treatment Onset - Ewing Sarcoma</title>
          <description>Objective response defined as complete response (CR) or partial response (PR) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, CR is defined as disappearance of all target and non-target lesions and normalization of tumour marker level of non-target lesions. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
As per revised RECIST v1.1, PR is defined as a at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and non-PD/not all evaluated non-target lesions, or, CR of target lesions and non-CR/non-PD/not evaluated non-target lesions.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
          <population>All patients eligible and who received at least one complete or two incomplete treatment cycles.</population>
          <units>percentage</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="39"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.6" lower_limit="13.0" upper_limit="42.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Best Overall Response</title>
        <description>Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). Will be described using frequency, percentage, and 95% confidence interval (binomial law).</description>
        <time_frame>From the start of the treatment until disease progression/recurrence, assessed up to 2 years</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS)</title>
        <description>Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). PFS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox's proportional risk method and after checking the risk proportionality hypothesis.</description>
        <time_frame>Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). OS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox's proportional risk method and after checking the risk proportionality hypothesis.</description>
        <time_frame>Time from start of treatment to the time of death, assessed up to 2 years</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Adverse Events</title>
        <description>Will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Quantitative variables will be described using mean and standard errors if the normality assumption is satisfied, else other descriptive statistics (median, range, quartiles) will be used. Qualitative variables will be described using frequency, percentage, and 95% confidence interval.</description>
        <time_frame>Up to 2 years</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Non-progression at 6 Months - Ewing Sarcoma</title>
        <description>Non-progression defined as complete response (CR), partial response (PR), or stable disease (SD) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
        <time_frame>At 6 months</time_frame>
        <population>All patients eligible and who received at least one complete or two incomplete treatment cycles.</population>
        <group_list>
          <group group_id="O1">
            <title>Ewing Sarcoma</title>
            <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.&#xD;
Single-arm phase II clinical trial based on a two-stage optimal Simon's design with 41 evaluable patients (first stage: 21 patients) used to distinguish a favorable true objective response rate within 6 months of treatment onset of 20% from a null rate of 5% (90% power and 5% type I error).&#xD;
Stage 1(21 evaluable patients): if &lt;=1 objective response within 6 months of treatment onset, the study was stopped early. Otherwise, the second group of 20 participants was recruited.&#xD;
Stage 2 (41 evaluable patients): if &gt;= 5 objective response within 6 months of treatment onset, Cabozantinib was considered promising.</description>
          </group>
        </group_list>
        <measure>
          <title>Non-progression at 6 Months - Ewing Sarcoma</title>
          <description>Non-progression defined as complete response (CR), partial response (PR), or stable disease (SD) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.&#xD;
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.</description>
          <population>All patients eligible and who received at least one complete or two incomplete treatment cycles.</population>
          <units>percentage</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="39"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.6" lower_limit="13.0" upper_limit="42.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Osteosarcoma : 26 months of treatment. At the time of primary analysis, 3 were still on treatment and 42 patients discontinued treatment. Ewing sarcoma : 20 months of treatment. At the time of primary analysis, 3 were still on treatment and 42 patients discontinued treatment.</time_frame>
      <desc>Adverse event are reported for all treated patients who received at least one administration of treatment.&#xD;
All adverse events (related and unrelated to treatment) are reported. All serious adverse events (related and unrelated to treatment) are reported.</desc>
      <group_list>
        <group group_id="E1">
          <title>Osteosarcoma</title>
          <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E2">
          <title>Ewing Sarcoma</title>
          <description>Patients receive cabozantinib s-malate PO QD on days 1-28. 60 mg for patients ≥ 16 years and 40mg/m² for patients ≥ 12 years and &lt;16 years. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (5.0)</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="34" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="30" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Pericardial effusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Cardiac disorders - Other, specify</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Rectal hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death NOS</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatobiliary disorders - Other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </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="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Kidney infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Soft tissue infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Wound complication</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other, specify</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumor pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Spinal cord compression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Psychiatric disorders - Other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" events="11" subjects_affected="11" subjects_at_risk="45"/>
                <counts group_id="E2" events="14" subjects_affected="14" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other, specify</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (5.0)</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="45" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="45" subjects_at_risk="45"/>
              </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="7" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="10" subjects_affected="8" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="25" subjects_affected="23" subjects_at_risk="45"/>
                <counts group_id="E2" events="23" subjects_affected="21" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="12" subjects_affected="12" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="20" subjects_affected="14" subjects_at_risk="45"/>
                <counts group_id="E2" events="19" subjects_affected="14" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="45" subjects_affected="30" subjects_at_risk="45"/>
                <counts group_id="E2" events="46" subjects_affected="33" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="45"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Gastrointestinal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="30" subjects_affected="25" subjects_at_risk="45"/>
                <counts group_id="E2" events="29" subjects_affected="24" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="22" subjects_affected="19" subjects_at_risk="45"/>
                <counts group_id="E2" events="18" subjects_affected="15" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="45"/>
                <counts group_id="E2" events="12" subjects_affected="10" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <counts group_id="E1" events="13" subjects_affected="12" subjects_at_risk="45"/>
                <counts group_id="E2" events="11" subjects_affected="9" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="41" subjects_affected="34" subjects_at_risk="45"/>
                <counts group_id="E2" events="36" subjects_affected="32" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="11" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="11" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="9" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Rhinitis infective</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="45"/>
              </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="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="25" subjects_affected="21" subjects_at_risk="45"/>
                <counts group_id="E2" events="27" subjects_affected="22" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="9" subjects_affected="7" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="28" subjects_affected="23" subjects_at_risk="45"/>
                <counts group_id="E2" events="27" subjects_affected="22" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>CPK increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="6" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT corrected interval prolonged</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="16" subjects_affected="9" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="45"/>
                <counts group_id="E2" events="11" subjects_affected="10" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="13" subjects_affected="13" subjects_at_risk="45"/>
                <counts group_id="E2" events="21" subjects_affected="19" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="14" subjects_affected="14" subjects_at_risk="45"/>
                <counts group_id="E2" events="14" subjects_affected="14" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="7" subjects_affected="5" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Blood lactate dehydrogenase increased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="45"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Thyroid stimulating hormone increased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="27" subjects_affected="23" subjects_at_risk="45"/>
                <counts group_id="E2" events="13" subjects_affected="11" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="14" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="18" subjects_affected="12" subjects_at_risk="45"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="11" subjects_at_risk="45"/>
                <counts group_id="E2" events="21" subjects_affected="15" subjects_at_risk="45"/>
              </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="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="15" subjects_affected="12" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="8" subjects_affected="6" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="45"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Muscle cramp</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumor pain</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="9" subjects_at_risk="45"/>
                <counts group_id="E2" events="14" subjects_affected="14" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="45"/>
                <counts group_id="E2" events="12" subjects_affected="10" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Spinal cord compression</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders - Other, specify</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="14" subjects_affected="11" subjects_at_risk="45"/>
                <counts group_id="E2" events="12" subjects_affected="10" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="12" subjects_affected="12" subjects_at_risk="45"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="10" subjects_affected="9" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" events="11" subjects_affected="10" subjects_at_risk="45"/>
                <counts group_id="E2" events="15" subjects_affected="10" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="11" subjects_affected="10" subjects_at_risk="45"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other, specify</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="45"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="45"/>
              </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="6" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="14" subjects_affected="13" subjects_at_risk="45"/>
                <counts group_id="E2" events="18" subjects_affected="16" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="14" subjects_affected="14" subjects_at_risk="45"/>
                <counts group_id="E2" events="21" subjects_affected="18" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="45"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Skin hypopigmentation</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="45"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="45"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, specify</sub_title>
                <counts group_id="E1" events="34" subjects_affected="22" subjects_at_risk="45"/>
                <counts group_id="E2" events="14" subjects_affected="9" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Hair color changes</sub_title>
                <counts group_id="E1" events="15" subjects_affected="15" subjects_at_risk="45"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="45"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="45"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </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>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Pr Italiano Antoine, Department of Medical Oncology</name_or_title>
      <organization>Institut Bergonie</organization>
      <phone>0524071947</phone>
      <email>a.italiano@bordeaux.unicancer.fr</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/NCT02243605
org study id: NCI-2014-01927
secondary id: NCI-2014-01927
secondary id: CABONE
secondary id: 9620
secondary id: 9620
nct id: NCT02243605
lead sponsor: 
has dmc: No
This phase II trial studies how well cabozantinib s-malate works in treating patients with
      osteosarcoma or Ewing sarcoma that has grown or returned (come back) after a period of
      improvement. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the
      enzymes needed for cell growth and may also prevent the growth of new blood vessels that
      tumors need to grow.
PRIMARY OBJECTIVES:

      I. To evaluate the antitumor activity of cabozantinib s-malate (cabozantinib) for Ewing
      sarcomas, in terms of 6-month objectives response as per the Response Evaluation Criteria in
      Solid Tumors, Revised (RECIST version [v]1.1).

      II. To evaluate the antitumor activity of cabozantinib for osteosarcoma, in terms of 6-month
      objective response (complete response, partial response) and 6-month non-progression
      (complete response, partial response and stable disease), as per RECIST v1.1.

      SECONDARY OBJECTIVES:

      I. 6-month objective response. (Ewing sarcoma only) II. Best overall response (as per the
      revised RECIST v1.1). (Ewing sarcoma and osteosarcoma) III. 1- and 2-year progression-free
      survival. (Ewing sarcoma and osteosarcoma) IV. 1- and 2-year overall survival. (Ewing sarcoma
      and osteosarcoma) V. Cabozantinib safety. (Ewing sarcoma and osteosarcoma) VI. To assess the
      ability of metabolic tumor response as measured by fludeoxyglucose (FDG)-positron emission
      tomography (PET) at the end of one cycle of treatment to predict progression-free survival
      (PFS). (Ewing sarcoma and osteosarcoma) VII. Translational research: to determine and compare
      tumor expression of MET, phosphorylated (phosphor)-MET and circulating levels of HGF, soluble
      MET (sMET), VEGF-A, and soluble VEGF receptor 2 (VEGFR2) (sVEGFR2) prior to and following
      administration of cabozantinib. (Ewing sarcoma and osteosarcoma)

      OUTLINE:

      Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28. Cycles
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Non-progression at 6 Months - Osteosarcoma
time frame: At 6 months
description: Non-progression defined as complete response (CR), partial response (PR), or stable disease (SD) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.
measure: Objective Response Within 6 Months of Treatment Onset - Osteosarcoma
time frame: Within 6 months of treatment onset
description: Objective response defined as complete response (CR) or partial response (PR) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.
As per revised RECIST v1.1, CR is defined as disappearance of all target and non-target lesions and normalization of tumour marker level of non-target lesions. All lymph nodes must be non-pathological in size (<10 mm short axis).
As per revised RECIST v1.1, PR is defined as a at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and non-PD/not all evaluated non-target lesions, or, CR of target lesions and non-CR/non-PD/not evaluated non-target lesions.
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.
measure: Objective Response Within 6 Months of Treatment Onset - Ewing Sarcoma
time frame: Within 6 months of treatment onset
description: Objective response defined as complete response (CR) or partial response (PR) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.
As per revised RECIST v1.1, CR is defined as disappearance of all target and non-target lesions and normalization of tumour marker level of non-target lesions. All lymph nodes must be non-pathological in size (<10 mm short axis).
As per revised RECIST v1.1, PR is defined as a at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and non-PD/not all evaluated non-target lesions, or, CR of target lesions and non-CR/non-PD/not evaluated non-target lesions.
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.
measure: Best Overall Response
time frame: From the start of the treatment until disease progression/recurrence, assessed up to 2 years
description: Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). Will be described using frequency, percentage, and 95% confidence interval (binomial law).
measure: Progression Free Survival (PFS)
time frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
description: Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). PFS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox's proportional risk method and after checking the risk proportionality hypothesis.
measure: Overall Survival (OS)
time frame: Time from start of treatment to the time of death, assessed up to 2 years
description: Will be analyzed independently for each stratum (osteosarcoma and Ewing sarcoma). OS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based on Cox's proportional risk method and after checking the risk proportionality hypothesis.
measure: Incidence of Adverse Events
time frame: Up to 2 years
description: Will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Quantitative variables will be described using mean and standard errors if the normality assumption is satisfied, else other descriptive statistics (median, range, quartiles) will be used. Qualitative variables will be described using frequency, percentage, and 95% confidence interval.
measure: Non-progression at 6 Months - Ewing Sarcoma
time frame: At 6 months
description: Non-progression defined as complete response (CR), partial response (PR), or stable disease (SD) as per the Response Evaluation Criteria In Solid Tumors Criteria, revised RECIST v1.1.
As per revised RECIST v1.1, progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or a measurable increase in a non-target lesion, or the appearance of one or more new lesions.
arm group label: Treatment (cabozantinib s-malate)
arm group type: Experimental
description: Patients receive cabozantinib s-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Cabozantinib S-malate
description: Given PO
arm group label: Treatment (cabozantinib s-malate)
other name: BMS-907351
other name: Cabometyx
other name: Cometriq
other name: XL-184
other name: XL184
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (cabozantinib s-malate)
criteria: 
gender: All
minimum age: 12 Years
maximum age: N/A
healthy volunteers: No
last name: Antoine Italiano
role: Principal Investigator
affiliation: Institut Bergonie Cancer Center
facility: 
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country: France
responsible party type: Sponsor
mesh term: Sarcoma
mesh term: Osteosarcoma
mesh term: Sarcoma, Ewing
mesh term: Recurrence
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 