<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/NCT04400474</url>
  </required_header>
  <id_info>
    <org_study_id>GETNE-T1914</org_study_id>
    <secondary_id>2019-002279-32</secondary_id>
    <nct_id>NCT04400474</nct_id>
  </id_info>
  <brief_title>Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System. The CABATEN Study</brief_title>
  <acronym>CABATEN</acronym>
  <official_title>Exploratory Basket Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System. CABATEN Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Grupo Espanol de Tumores Neuroendocrinos</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ipsen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Roche Pharma AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Grupo Espanol de Tumores Neuroendocrinos</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and&#xD;
      progressive tumors from endocrine system.&#xD;
&#xD;
      The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination&#xD;
      by means of radiological objective response rate (ORR) evaluated following RECIST v1.1&#xD;
      criteria in advanced endocrine tumors.&#xD;
&#xD;
      Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal&#xD;
      gland and paraganglia) are characterized by being remarkably vascular and expressing several&#xD;
      growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth&#xD;
      factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF),&#xD;
      and transforming growth factor (TGF)-α and -β. The (over) expression of some of these factors&#xD;
      has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with&#xD;
      atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the&#xD;
      resistance to prior antiangiogenic drugs.&#xD;
&#xD;
      The trial will include patients with advanced and refractory tumors of endocrine system and&#xD;
      patients would be allocated to six different cohorts according to the following tumor types.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and&#xD;
      progressive tumors from endocrine system.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      The main hypothesis is that the administration of cabozantinib plus atezolizumab will improve&#xD;
      the probability of expected objective response rate in advanced and refractory tumors of the&#xD;
      endocrine system.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination&#xD;
      by means of radiological objective response rate (ORR) evaluated following RECIST v1.1&#xD;
      criteria in advanced endocrine tumors. Secondary objectives include:&#xD;
&#xD;
        -  To evaluate the safety profile of cabozantinib and atezolizumab combination, according&#xD;
           to NCI-CTCAE V5.0.&#xD;
&#xD;
        -  Duration of response (DoR) as per RECIST V1.1.&#xD;
&#xD;
        -  Progression-free survival (PFS): median PFS as per RECIST V1.1.&#xD;
&#xD;
        -  Overall Survival (OS): median OS as per RECIST V1.1.&#xD;
&#xD;
        -  Tumor biomarkers: translational sub-study (optional).&#xD;
&#xD;
      Treatment:&#xD;
&#xD;
      All the subjects will be treated with the combination until disease progression, unacceptable&#xD;
      toxicity, or patient consent withdrawal (whichever occurs first):&#xD;
&#xD;
        -  Cabozantinib 40 mg or 20 mg tablets, oral administration once daily continuously.&#xD;
&#xD;
        -  Atezolizumab 1200 mg administered intravenously (IV) every three weeks (cycle).&#xD;
&#xD;
      Rationale:&#xD;
&#xD;
      Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal&#xD;
      gland and paraganglia) are characterized by being remarkably vascular and expressing several&#xD;
      growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth&#xD;
      factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF),&#xD;
      and transforming growth factor (TGF)-α and -β. The (over) expression of some of these factors&#xD;
      has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with&#xD;
      atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the&#xD;
      resistance to prior antiangiogenic drugs.&#xD;
&#xD;
      Patients allocation:&#xD;
&#xD;
      The trial will include patients with advanced and refractory tumors of endocrine system and&#xD;
      patients would be allocated to six different cohorts according to the following tumor types:&#xD;
&#xD;
      Cohort 1: Well-differentiated neuroendocrine tumors of the lung and thymus (grades 1 and 2)&#xD;
      after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.&#xD;
&#xD;
      Cohort 2: Anaplastic thyroid cancer in first-line or after progression to chemotherapy or&#xD;
      investigational drugs.&#xD;
&#xD;
      Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane.&#xD;
&#xD;
      Cohort 4: Pheochromocytoma and paraganglioma after progression to peptide receptor&#xD;
      radionuclide therapy (PRRT) if indicated, prior chemotherapy and biological therapy, such as&#xD;
      somatostatin analogs, are allowed.&#xD;
&#xD;
      Cohort 5: Well-differentiated neuroendocrine tumors of digestive system after progression to&#xD;
      somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.&#xD;
&#xD;
      Cohort 6: Grade 3 neuroendocrine neoplasm of any origin, excluding small cell lung cancer,&#xD;
      after progression to chemotherapy or targeted agents/PRRT.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 7, 2020</start_date>
  <completion_date type="Anticipated">March 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</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>Objective response rate (ORR)</measure>
    <time_frame>Through study completion, average 1 year</time_frame>
    <description>To assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological objective response rate (ORR) in advanced endocrine tumors. Includes patients with confirmed partial (PR) and complete response (CR) as best response according to RECIST v 1.1.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety Profile ( number/severity of Serious Adverse Events, SAEs)</measure>
    <time_frame>SAEs will be reported through clinical study till 6 months after study end.</time_frame>
    <description>Number of serious adverse events classified by severity as assessed by CTCAE v4.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety Profile ( number/severity of treatment related Serious Adverse Events, SAEs)</measure>
    <time_frame>SAEs will be reported through clinical study till 6 months after study end.</time_frame>
    <description>Number of serious adverse events related to the investigational drug classified by severity as assessed by CTCAE v4.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR)</measure>
    <time_frame>From date of first documented clinical response (PR, CR) until the date of first documented progression, date of death from any cause or patient withdrawal, whichever came first, assessed up to 36 months</time_frame>
    <description>the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer. DoR will be determined based on tumour assessment (RECIST version 1.1 criteria).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>From date of randomization until the date of first documented progression, date of death from any cause or patient withdrawal, whichever came first, assessed up to 36 months</time_frame>
    <description>Median Progression free survival (mPFS) is defined as the time from the date of inclusion to the date of the first documented disease progression or death due to any cause, whichever occurs first. PFS will be determined based on tumour assessment (RECIST version 1.1 criteria). The local Investigator's assessments will be used for analyses.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>From date of randomization until the date of death from any cause or patient withdrawal, whichever came first, assessed up to 36 months</time_frame>
    <description>Median Overall Survival (mOS) is calculated as the time from date of inclusion to date of death due to any cause.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">93</enrollment>
  <condition>Neuroendocrine Tumor</condition>
  <condition>Anaplastic Thyroid Cancer</condition>
  <condition>Adenocarcinoma</condition>
  <condition>Pheochromocytoma</condition>
  <condition>Paraganglioma</condition>
  <arm_group>
    <arm_group_label>Cabozantinib 40 mg + Atezolizumab 1200 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cabozantinib 40 mg tablets, oral administration, once daily, continuously.&#xD;
Atezolizumab 1200 mg administered intravenously, every three weeks (cycle).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabozantinib 40 mg</intervention_name>
    <description>All the subjects will be treated with the combination of cabozantinib and atezolizumab until disease progression, unacceptable toxicity or patient consent withdrawal (whichever occurs first).</description>
    <arm_group_label>Cabozantinib 40 mg + Atezolizumab 1200 mg</arm_group_label>
    <other_name>Atezolizumab 1200 mg</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female subjects ≥ 18 years old.&#xD;
&#xD;
          2. Willingness to participate in the study by signing informed consent form (ICF)&#xD;
             approved by the trial Central Ethic Committee (CEIm).&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.&#xD;
&#xD;
          4. Measurable disease per RECIST 1.1 as determined by the investigator.&#xD;
&#xD;
          5. Patients with an histopathologically confirmed disease (as per local pathology&#xD;
             report), meeting one of the following (according to WHO 2010 classification):&#xD;
&#xD;
               1. Cohort 1: Well-differentiated neuroendocrine tumours of the lung and thymus (WHO&#xD;
                  grade 1 and 2, typical and atypical carcinoids) after progression to somatostatin&#xD;
                  analogs, targeted agents, PRRT, and/or chemotherapy.&#xD;
&#xD;
               2. Cohort 2: Anaplastic thyroid cancer in first-line or after progression to&#xD;
                  chemotherapy or investigational drugs. Primary tumour can be resected or not but&#xD;
                  risk of aerodigestive compression or bleeding should be ruled out.&#xD;
&#xD;
               3. Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or&#xD;
                  mitotane.&#xD;
&#xD;
               4. Cohort 4: Pheochromocytoma and paraganglioma after progression to peptide&#xD;
                  receptor radionuclide therapy (PRRT) if indicated. Prior chemotherapy and&#xD;
                  biological therapy, such as somatostatin analogs, are allowed.&#xD;
&#xD;
               5. Cohort 5: Well-differentiated neuroendocrine tumours of digestive system (WHO&#xD;
                  grade 1 and 2) after progression to somatostatin analogs, targeted agents, PRRT,&#xD;
                  and/or chemotherapy.&#xD;
&#xD;
               6. Cohort 6: Grade 3 neuroendocrine neoplasm (WHO grade 3, including neuroendocrine&#xD;
                  (NET) and neuroendocrine carcinomas (NEC) G3) of any origin, excluding small cell&#xD;
                  lung cancer, after progression to chemotherapy or targeted agents/PRRT.&#xD;
&#xD;
          6. Recovery from toxicity related to any prior treatments to ≤ Grade 1, unless the&#xD;
             adverse events (AEs) are clinically non-significant and/or stable on supportive&#xD;
             therapy.&#xD;
&#xD;
          7. Ability to swallow tablets.&#xD;
&#xD;
          8. Adequate normal organ and marrow function as defined below:&#xD;
&#xD;
               1. Haemoglobin ≥ 9.0 g/dL.&#xD;
&#xD;
               2. Absolute neutrophil count (ANC) &gt; 1500 per mm.&#xD;
&#xD;
               3. Platelet count ≥ 100,000 per mm.&#xD;
&#xD;
               4. Serum bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless liver&#xD;
                  metastases are present, in which case it must be ≤ 2X ULN. This will not apply to&#xD;
                  patients with confirmed Gilbert's syndrome (persistent or recurrent&#xD;
                  hyperbilirubinemia that is predominantly unconjugated in the absence of&#xD;
                  haemolysis or hepatic pathology); however, they will be allowed only in&#xD;
                  consultation with their physician.&#xD;
&#xD;
               5. Aspartate Transaminase (AST) (SGOT)/Alanine aminotransferase (ALT) (SGPT) ≤ 2.5x&#xD;
                  institutional upper limit of normal unless liver metastases are present, in which&#xD;
                  case it must be ≤ 3x ULN.&#xD;
&#xD;
               6. Measured creatinine clearance (CL) &gt; 40 mL/min or Calculated creatinine CL &gt; 40&#xD;
                  mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour&#xD;
                  urine collection for the determination of creatinine clearance.&#xD;
&#xD;
          9. Female subjects of childbearing potential (not surgically sterile or at least 2 years&#xD;
             postmenopausal) must provide a negative urine pregnancy test at Screening, and use a&#xD;
             medically accepted double barrier method of contraception (i.e condom with spermicide&#xD;
             + IUD or cervical caps). In addition, they must agree to continue the use of this&#xD;
             double barrier method for the duration of the study and for 4 months after&#xD;
             participation in the study.&#xD;
&#xD;
         10. Males should agree to abstain from sexual intercourse with a female partner or agree&#xD;
             to use a double barrier method of contraception (i.e.condom with spermicide, in&#xD;
             addition to having their female partner use some contraceptive measures such as,&#xD;
             intrauterine device (IUD) or cervical caps), for the duration of the study and for 4&#xD;
             months after participation in the study.&#xD;
&#xD;
         11. Willingness and ability of patients to comply with the protocol for the duration of&#xD;
             the study including undergoing treatment as well as availability for scheduled visits&#xD;
             and examinations including follow up.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior treatment with cabozantinib or any immune checkpoint inhibitor therapy (e.g,&#xD;
             CTLA4, PD-1, or PD-L1 targeting agent).&#xD;
&#xD;
          2. Receipt of any type of small molecule kinase inhibitor (including investigational&#xD;
             kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer.&#xD;
             Patients should have been out of mitotane for at least 4 weeks.&#xD;
&#xD;
          3. Receipt of any type of anticancer antibody (including investigational antibody) or&#xD;
             systemic chemotherapy within 2 weeks before starting treatment.&#xD;
&#xD;
          4. Current or prior use of immunosuppressive medication within 2 weeks before the first&#xD;
             dose of cabozantinib and atezolizumab, with the exceptions of intranasal and inhaled&#xD;
             corticosteroids or systemic corticosteroids at physiological doses, which are not to&#xD;
             exceed 10 mg/day of prednisone, or an equivalent corticosteroid.&#xD;
&#xD;
          5. Active or prior documented autoimmune disease within the past 2 years. Note: Subjects&#xD;
             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within&#xD;
             the past 2 years) are not excluded.&#xD;
&#xD;
          6. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease and&#xD;
             ulcerative colitis).&#xD;
&#xD;
          7. History of allogeneic organ transplant.&#xD;
&#xD;
          8. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid&#xD;
             therapy or any other form of immunosuppressive therapy within 28 days prior to the&#xD;
             first dose of trial treatment.&#xD;
&#xD;
          9. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation&#xD;
             therapy within 4 weeks before inclusion. Subjects with clinically relevant ongoing&#xD;
             complications from prior radiation therapy that have not completely resolved are not&#xD;
             eligible (e.g, radiation esophagitis or other inflammation of the viscera).&#xD;
&#xD;
         10. Known brain metastases or cranial epidural disease unless adequately treated with&#xD;
             radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks&#xD;
             before inclusion. Eligible subjects must be neurologically asymptomatic and without&#xD;
             corticosteroid treatment at the time of study treatment.&#xD;
&#xD;
         11. Concomitant anticoagulation with oral anticoagulants (e.g, warfarin, direct thrombin&#xD;
             and factor Xa inhibitors) or platelet inhibitors (e.g, clopidogrel), except for the&#xD;
             following allowed anticoagulants:&#xD;
&#xD;
               -  Low-dose aspirin for cardioprotection (per local applicable guidelines) and&#xD;
                  low-dose low molecular weight heparins (LMWH).&#xD;
&#xD;
               -  Anticoagulation with therapeutic doses of LMWH in subjects without known brain&#xD;
                  metastases and who are on a stable dose of LMWH for at least 6 weeks before&#xD;
                  inclusion and who have had no clinically significant hemorrhagic complications&#xD;
                  from the anticoagulation regimen or the tumour.&#xD;
&#xD;
         12. The subject has uncontrolled, significant intercurrent or recent illness including,&#xD;
             but not limited to, the following conditions:&#xD;
&#xD;
             a. Cardiovascular disorders: i. Class 3 or 4 congestive heart failure as defined by&#xD;
             the New York Heart Association, unstable angina pectoris, and serious cardiac&#xD;
             arrhythmias.&#xD;
&#xD;
             ii. Uncontrolled hypertension defined as sustained blood press &gt; 150 mm hg systolic or&#xD;
             &gt; 100 mm hg diastolic despite optimal antihypertensive treatment.&#xD;
&#xD;
             iii. Stroke, including transient ischemic attack (TIA), myocardial infarction, other&#xD;
             ischemic event, or thromboembolic event, e.g, deep venous thrombosis (DVT) and&#xD;
             pulmonary embolism) within 6 months before inclusion. Subjects with a more recent&#xD;
             diagnosis of DVT are allowed if stable, asymptomatic, and treated with LMWH for at&#xD;
             least 6 weeks before study treatment.&#xD;
&#xD;
             b. Gastrointestinal disorders (e.g, malabsorption syndrome or gastric outlet&#xD;
             obstruction) including those associated with a high risk of perforation or fistula&#xD;
             formulation: i. Tumours invading the GI tract, active peptic ulcer disease,&#xD;
             inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis,&#xD;
             symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of&#xD;
             the pancreatic or biliary duct, or gastric outlet obstruction. ii. Abdominal fistula,&#xD;
             GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before&#xD;
             inclusion. Note: complete healing of an intra-abdominal abscess must be confirmed&#xD;
             prior to start of the treatment.&#xD;
&#xD;
             c. Clinically significant hematemesis or hemoptysis of &gt; 0.5 teaspoon (&gt; 2.5 ml) of&#xD;
             red blood or history of other significant bleeding within 3 months before treatment.&#xD;
&#xD;
             d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. e.&#xD;
             Lesions invading major pulmonary blood vessels. f. Other clinically significant&#xD;
             disorders such as: i. Active infection requiring systemic treatment, infection with&#xD;
             human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or&#xD;
             chronic hepatitis B or C infection.&#xD;
&#xD;
             ii. Serious non-healing wound/ulcer/bone fracture. iii. Moderate to severe hepatic&#xD;
             impairment (child-pugh B or C). iv. Requirement for hemodialysis or peritoneal&#xD;
             dialysis. v. Uncontrolled diabetes mellitus. vi. History of solid organ&#xD;
             transplantation.&#xD;
&#xD;
         13. Major surgery (e.g, GI surgery and removal or biopsy of brain metastasis) within 8&#xD;
             weeks before inclusion. Complete wound healing from major surgery must have occurred 4&#xD;
             weeks before study treatment and from minor surgery (e.g, simple excision, tooth&#xD;
             extraction) at least 10 days before study treatment. Subjects with clinically relevant&#xD;
             ongoing complications from prior surgery are not eligible.&#xD;
&#xD;
         14. Corrected QT interval calculated by the Fridericia formula (QTcf) &gt; 500 ms within 28&#xD;
             days before study treatment.&#xD;
&#xD;
             Note: if a single ECG shows a QTCf with an absolute value &gt; 500 ms, two additional&#xD;
             ECGs at intervals of approximately 3 min must be performed within 30 min after the&#xD;
             initial ECG, and the average of these 3 consecutive results for qtcf will be used to&#xD;
             determine eligibility.&#xD;
&#xD;
         15. Pregnant or lactating females.&#xD;
&#xD;
         16. Inability to swallow tablets.&#xD;
&#xD;
         17. Previously identified allergy or hypersensitivity to components of the study treatment&#xD;
             formulations.&#xD;
&#xD;
         18. Diagnosis of another malignancy within 3 years before study treatment, except for&#xD;
             superficial skin cancers, or localized, low grade tumors deemed cured and not treated&#xD;
             with systemic therapy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jaume Capdevila, M.D, Ph.D</last_name>
    <role>Study Chair</role>
    <affiliation>Hospital Universitari Vall d'Hebron, Barcelona</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Germans Trias i Pujol - ICO Badalona</name>
      <address>
        <city>Badalona</city>
        <state>Barcelona</state>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Duran i Reynals - ICO L'Hospitalet</name>
      <address>
        <city>L'Hospitalet de Llobregat</city>
        <state>Barcelona</state>
        <zip>08908</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital General Universitario Elche</name>
      <address>
        <city>Alicante</city>
        <zip>03010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari Vall d'Hebron</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD Anderson Cancer Center</name>
      <address>
        <city>Madrid</city>
        <zip>28033</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Ramón y Cajal</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario La Paz</name>
      <address>
        <city>Madrid</city>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital General Universitario Morales Meseguer</name>
      <address>
        <city>Murcia</city>
        <zip>30008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen de la Victoria</name>
      <address>
        <city>Málaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Central de Asturias</name>
      <address>
        <city>Oviedo</city>
        <zip>33011</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Marqués de Valdecilla</name>
      <address>
        <city>Santander</city>
        <zip>39008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen del Rocío</name>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Canarias</name>
      <address>
        <city>Tenerife</city>
        <zip>38320</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Miguel Servet</name>
      <address>
        <city>Zaragoza</city>
        <zip>50009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>May 12, 2020</study_first_submitted>
  <study_first_submitted_qc>May 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 22, 2020</study_first_posted>
  <last_update_submitted>May 26, 2023</last_update_submitted>
  <last_update_submitted_qc>May 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cabozantinib</keyword>
  <keyword>Atezolizumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Neuroendocrine Tumors</mesh_term>
    <mesh_term>Pheochromocytoma</mesh_term>
    <mesh_term>Paraganglioma</mesh_term>
    <mesh_term>Thyroid Carcinoma, Anaplastic</mesh_term>
    <mesh_term>Endocrine Gland Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atezolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT04400474
org study id: GETNE-T1914
secondary id: 2019-002279-32
nct id: NCT04400474
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and
      progressive tumors from endocrine system.

      The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination
      by means of radiological objective response rate (ORR) evaluated following RECIST v1.1
      criteria in advanced endocrine tumors.

      Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal
      gland and paraganglia) are characterized by being remarkably vascular and expressing several
      growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth
      factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF),
      and transforming growth factor (TGF)-α and -β. The (over) expression of some of these factors
      has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with
      atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the
      resistance to prior antiangiogenic drugs.

      The trial will include patients with advanced and refractory tumors of endocrine system and
      patients would be allocated to six different cohorts according to the following tumor types.
CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and
      progressive tumors from endocrine system.

      Hypothesis:

      The main hypothesis is that the administration of cabozantinib plus atezolizumab will improve
      the probability of expected objective response rate in advanced and refractory tumors of the
      endocrine system.

      Objectives:

      The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination
      by means of radiological objective response rate (ORR) evaluated following RECIST v1.1
      criteria in advanced endocrine tumors. Secondary objectives include:

        -  To evaluate the safety profile of cabozantinib and atezolizumab combination, according
           to NCI-CTCAE V5.0.

        -  Duration of response (DoR) as per RECIST V1.1.

        -  Progression-free survival (PFS): median PFS as per RECIST V1.1.

        -  Overall Survival (OS): median OS as per RECIST V1.1.

        -  Tumor biomarkers: translational sub-study (optional).

      Treatment:

      All the subjects will be treated with the combination until disease progression, unacceptable
      toxicity, or patient consent withdrawal (whichever occurs first):

        -  Cabozantinib 40 mg or 20 mg tablets, oral administration once daily continuously.

        -  Atezolizumab 1200 mg administered intravenously (IV) every three weeks (cycle).

      Rationale:

      Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal
      gland and paraganglia) are characterized by being remarkably vascular and expressing several
      growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth
      factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF),
      and transforming growth factor (TGF)-α and -β. The (over) expression of some of these factors
      has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with
      atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the
      resistance to prior antiangiogenic drugs.

      Patients allocation:

      The trial will include patients with advanced and refractory tumors of endocrine system and
      patients would be allocated to six different cohorts according to the following tumor types:

      Cohort 1: Well-differentiated neuroendocrine tumors of the lung and thymus (grades 1 and 2)
      after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.

      Cohort 2: Anaplastic thyroid cancer in first-line or after progression to chemotherapy or
      investigational drugs.

      Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane.

      Cohort 4: Pheochromocytoma and paraganglioma after progression to peptide receptor
      radionuclide therapy (PRRT) if indicated, prior chemotherapy and biological therapy, such as
      somatostatin analogs, are allowed.

      Cohort 5: Well-differentiated neuroendocrine tumors of digestive system after progression to
      somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.

      Cohort 6: Grade 3 neuroendocrine neoplasm of any origin, excluding small cell lung cancer,
      after progression to chemotherapy or targeted agents/PRRT.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective response rate (ORR)
time frame: Through study completion, average 1 year
description: To assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological objective response rate (ORR) in advanced endocrine tumors. Includes patients with confirmed partial (PR) and complete response (CR) as best response according to RECIST v 1.1.
measure: Safety Profile ( number/severity of Serious Adverse Events, SAEs)
time frame: SAEs will be reported through clinical study till 6 months after study end.
description: Number of serious adverse events classified by severity as assessed by CTCAE v4.0
measure: Safety Profile ( number/severity of treatment related Serious Adverse Events, SAEs)
time frame: SAEs will be reported through clinical study till 6 months after study end.
description: Number of serious adverse events related to the investigational drug classified by severity as assessed by CTCAE v4.0
measure: Duration of Response (DoR)
time frame: From date of first documented clinical response (PR, CR) until the date of first documented progression, date of death from any cause or patient withdrawal, whichever came first, assessed up to 36 months
description: the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer. DoR will be determined based on tumour assessment (RECIST version 1.1 criteria).
measure: Progression-free Survival (PFS)
time frame: From date of randomization until the date of first documented progression, date of death from any cause or patient withdrawal, whichever came first, assessed up to 36 months
description: Median Progression free survival (mPFS) is defined as the time from the date of inclusion to the date of the first documented disease progression or death due to any cause, whichever occurs first. PFS will be determined based on tumour assessment (RECIST version 1.1 criteria). The local Investigator's assessments will be used for analyses.
measure: Overall Survival (OS)
time frame: From date of randomization until the date of death from any cause or patient withdrawal, whichever came first, assessed up to 36 months
description: Median Overall Survival (mOS) is calculated as the time from date of inclusion to date of death due to any cause.
arm group label: Cabozantinib 40 mg + Atezolizumab 1200 mg
arm group type: Experimental
description: Cabozantinib 40 mg tablets, oral administration, once daily, continuously.
Atezolizumab 1200 mg administered intravenously, every three weeks (cycle).
intervention type: Drug
intervention name: Cabozantinib 40 mg
description: All the subjects will be treated with the combination of cabozantinib and atezolizumab until disease progression, unacceptable toxicity or patient consent withdrawal (whichever occurs first).
arm group label: Cabozantinib 40 mg + Atezolizumab 1200 mg
other name: Atezolizumab 1200 mg
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jaume Capdevila, M.D, Ph.D
role: Study Chair
affiliation: Hospital Universitari Vall d'Hebron, Barcelona
facility: 
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country: Spain
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Neuroendocrine Tumors
mesh term: Pheochromocytoma
mesh term: Paraganglioma
mesh term: Thyroid Carcinoma, Anaplastic
mesh term: Endocrine Gland Neoplasms
mesh term: Atezolizumab
sharing ipd: No