<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/NCT03824691</url>
  </required_header>
  <id_info>
    <org_study_id>INT 180/18</org_study_id>
    <nct_id>NCT03824691</nct_id>
  </id_info>
  <brief_title>hARnessing CAbozantinib and Durvalumab Immuno-oncology Association: ARCADIA Study&quot;</brief_title>
  <acronym>ARCADIA</acronym>
  <official_title>Cabozantinib Plus Durvalumab in Patients With Advanced and Chemotherapy-treated Bladder Carcinoma, of Urothelial and Non-urothelial Histology: an Open-label, Single-centre, Phase 2, Single-arm Proof-of-concept Trial: ARCADIA Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</source>
  <oversight_info>
    <has_dmc>No</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>
      Cabozantinib plus Durvalumab in patients with advanced and chemotherapy-treated bladder&#xD;
      carcinoma, of urothelial and non-urothelial histology: an open-label, single-centre, phase 2,&#xD;
      single-arm proof-of-concept trial: ARCADIA study&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      an open-label, single-centre, phase 2,&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 25, 2019</start_date>
  <completion_date type="Anticipated">February 2023</completion_date>
  <primary_completion_date type="Anticipated">February 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>The primary endpoint of the study will be overall survival (OS).</measure>
    <time_frame>48 months</time_frame>
    <description>to evaluate whether the combination of durvalumab and cabozantinib will be active and will result in an increased efficacy compared to the available results with the use of both single-agents</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).</measure>
    <time_frame>48 months</time_frame>
    <description>incidence, nature and severity of all-cause and treatment-related adverse events (AE), graded with the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>progression-free survival (PFS)</measure>
    <time_frame>48 months</time_frame>
    <description>RECIST 1.1 criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>responses to treatment</measure>
    <time_frame>48 months</time_frame>
    <description>Assessment of RR (investigator-assessed) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. RR (%) = complete (CR) + partial responses (PR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>response duration</measure>
    <time_frame>48 months</time_frame>
    <description>PET-responses according to the EORTC criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomarkers of activity and efficacy of either agents and their combination.</measure>
    <time_frame>48 months</time_frame>
    <description>determination of a patient's PD-L1 status. Biomarkers Blood Collection will be performend at baseline, every 2 cycles and progression disease</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">122</enrollment>
  <condition>Bladder Carcinoma</condition>
  <arm_group>
    <arm_group_label>Cabozantinib + Durvalumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive 1500 mg durvalumab (MEDI4736) IV infusion every 28 days + Cabozantinib 40 mg orally once daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabozantinib</intervention_name>
    <description>cabozantinib 40 mg orally once daily</description>
    <arm_group_label>Cabozantinib + Durvalumab</arm_group_label>
    <other_name>CABOMETYX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>1500 mg durvalumab (MEDI4736) IV infusion every 28 days</description>
    <arm_group_label>Cabozantinib + Durvalumab</arm_group_label>
    <other_name>Imfinzi</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent.&#xD;
&#xD;
          -  Age ≥18 years.&#xD;
&#xD;
          -  Body weight &gt;30kg&#xD;
&#xD;
          -  Histologically-confirmed diagnosis of UC or variant histologies (e.g. squamous cell&#xD;
             carcinoma, adenocarcinoma, micropapillary tumors, BUT excluding pure small cell&#xD;
             carcinoma) of the bladder or the urothelium.&#xD;
&#xD;
          -  Either bladder, urethral, or upper tract primary tumor will be allowed.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.&#xD;
&#xD;
          -  Life expectancy of at ≥ 12 weeks.&#xD;
&#xD;
          -  Availability of tumor tissue for PD-L1 IHC assay.&#xD;
&#xD;
          -  Measurable and non-measurable disease will be included (e.g. patients with bone&#xD;
             metastases only will be allowed for inclusion).&#xD;
&#xD;
          -  Failure of 1 or 2 cisplatin-based conventional chemotherapy regimens for metastatic&#xD;
             disease (2nd-to-3rd line only).&#xD;
&#xD;
          -  Neoadjuvant/adjuvant regimens will be counted provided that a relapse occurred with 6&#xD;
             months of the last cycle of chemotherapy.&#xD;
&#xD;
          -  Adequate function of the organs:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) ≥ 1500/mm3&#xD;
&#xD;
               2. Platelets ≥ 100,000/mm3&#xD;
&#xD;
               3. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).&#xD;
&#xD;
               4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &lt; 3.0 × upper&#xD;
                  limit of normal.&#xD;
&#xD;
               5. Total bilirubin ≤ 1.5 × the upper limit of normal. For subjects with Gilbert's&#xD;
                  disease ≤ 3 mg/dL&#xD;
&#xD;
             g. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥&#xD;
             30 mL/min using the Cockroft-Gault equation h. Lipase &lt; 2.0 times the upper limit of&#xD;
             normal (ULN)&#xD;
&#xD;
          -  Recovery to baseline or ≤ Grade 1 Common Terminology Criteria for Adverse Events&#xD;
             (CTCAE) v5.0 from toxicities related to any prior treatments, unless AE(s) are&#xD;
             clinically nonsignificant and/or stable on supportive therapy&#xD;
&#xD;
          -  Ability to swallow tablets&#xD;
&#xD;
          -  Contraception for sexually active fertile patients and their partners. Of note, a&#xD;
             barrier method is recommended in addition to the use of steroid hormonal&#xD;
             contraceptives, because the effects of cabozantinib on the pharmacokinetics of the&#xD;
             latter are unknown.&#xD;
&#xD;
          -  Evidence of post menopausal status or serum pregnancy test for female pre-menopausal&#xD;
             subject&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients taking regular oral steroids, above the allowed limit of 10mg/day&#xD;
             methylprednisolone or analogues, for any reason. Patients must not have had steroids&#xD;
             for 28 days prior to study entry.&#xD;
&#xD;
          -  Malignancies other than bladder carcinoma within 5 years prior to Cycle 1, Day 1, with&#xD;
             the exception of those with a negligible risk of metastasis or death and treated with&#xD;
             expected curative outcome (such as adequately treated carcinoma in situ of the cervix,&#xD;
             basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically&#xD;
             with curative intent) or localized prostate cancer treated with curative intent and&#xD;
             absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer&#xD;
             (Gleason score ≤ 3 + 4 and PSA &lt; 10 ng/mL undergoing active surveillance and treatment&#xD;
             naive).&#xD;
&#xD;
          -  Evidence of significant uncontrolled concomitant disease that could affect compliance&#xD;
             with the protocol or interpretation of results.&#xD;
&#xD;
          -  Active or untreated CNS metastases as determined by computed tomography (CT) or&#xD;
             magnetic resonance imaging evaluation during screening and prior radiographic&#xD;
             assessments.&#xD;
&#xD;
          -  Patients with treated asymptomatic CNS metastases are eligible, provided they meet all&#xD;
             of the following criteria:&#xD;
&#xD;
               1. Evaluable or measurable disease outside the CNS&#xD;
&#xD;
               2. No metastases to midbrain, pons, medulla, or within 10 mm of the optic apparatus&#xD;
                  (optic nerves and chiasm)&#xD;
&#xD;
               3. No history of intracranial or spinal cord hemorrhage&#xD;
&#xD;
               4. No ongoing requirement for corticosteroid as therapy for CNS disease;&#xD;
                  anti-convulsants at a stable dose are allowed&#xD;
&#xD;
               5. No evidence of significant vasogenic edema&#xD;
&#xD;
               6. No stereotactic radiation, whole-brain radiation or neurosurgical resection&#xD;
                  within 4 weeks prior to Cycle 1, Day 1&#xD;
&#xD;
               7. Radiographic demonstration of interim stability (i.e., no progression) between&#xD;
                  the completion of CNS-directed therapy and the screening radiographic study&#xD;
&#xD;
               8. Screening CNS radiographic study ≥ 4 weeks since completion of radiotherapy or&#xD;
                  surgical resection and ≥ 2 weeks since discontinuation of corticosteroids&#xD;
&#xD;
          -  Pregnant female patients. All female patients of childbearing potential with a&#xD;
             positive pregnancy test within 2 weeks prior to the first dose of study treatment will&#xD;
             be excluded from the study.&#xD;
&#xD;
          -  Clinically significant cardiovascular disease, for example, myocardial infarction&#xD;
             (within 3months prior to enrolment), unstable angina, New York Heart Association&#xD;
             (NYHA) grade II or greater congestive heart failure or serious cardiac arrhythmia&#xD;
             requiring medication (beta-blockers and digoxin are allowed)&#xD;
&#xD;
          -  Uncontrolled hypertension, stroke or other ischemic or thromboembolic event (DVT, PE)&#xD;
             within 6 months before first dose of cabozantinib.&#xD;
&#xD;
          -  Severe infections within 4 weeks prior to enrolment in the study including but not&#xD;
             limited to hospitalization for complications of infection, bacteraemia, or severe&#xD;
             pneumonia.&#xD;
&#xD;
          -  Major surgical procedure within 4 weeks prior to enrolmentor anticipation of need for&#xD;
             a major surgical procedure during the course of the study other than for diagnosis.&#xD;
             Complete wound healing from major surgery must have occurred 1 month before inclusion&#xD;
             and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before&#xD;
             inclusion. Subjects with clinically relevant ongoing complications from prior surgery&#xD;
             are not eligible.&#xD;
&#xD;
          -  Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to&#xD;
             enrolment (patients receiving prophylactic antibiotics, e.g., for prevention of a&#xD;
             urinary tract infection or chronic obstructive pulmonary disease, are eligible).&#xD;
&#xD;
          -  Concomitant anticoagulation with oral anticoagulants or platelet inhibitors.&#xD;
&#xD;
          -  History of autoimmune disease including, but not limited to, myasthenia gravis,&#xD;
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,&#xD;
             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid&#xD;
             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,&#xD;
             multiple sclerosis, vasculitis, or glomerulonephritis.&#xD;
&#xD;
          -  Patients with a history of autoimmune-related hypothyroidism, unless on a stable dose&#xD;
             of thyroid-replacement hormone.&#xD;
&#xD;
          -  Patients with uncontrolled Type 1 diabetes mellitus&#xD;
&#xD;
          -  Uncontrolled hypercalcemia (&gt; 1.5 mmol/L ionized calcium or Ca &gt; 12 mg/dL or corrected&#xD;
             serum calcium &gt; ULN) or symptomatic hypercalcemia requiring continued use of&#xD;
             bisphosphonate therapy or denosumab. Patients who are receiving bisphosphonate therapy&#xD;
             or denosumab specifically to prevent skeletal events and who do not have a history of&#xD;
             clinically significant hypercalcemia are eligible. Patients who are receiving&#xD;
             denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate&#xD;
             instead while on study.&#xD;
&#xD;
          -  radiation therapy for bone within 2 weeks or other radiation therapy within 4 weeks&#xD;
             before first dose of study treatment. patients with clinically relevant ongoing&#xD;
             complications from prior radiation therapy&#xD;
&#xD;
          -  serious non healing wound/ulcer/bone fracture, moderate to severe hepatic impairment&#xD;
             (Child Pugh B or C)&#xD;
&#xD;
          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced&#xD;
             pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic&#xD;
             organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan&#xD;
             (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).&#xD;
&#xD;
          -  Patients with tumors invading major pulmonary vessels and/or with cavitating pulmonary&#xD;
             lesions.&#xD;
&#xD;
          -  Positive test for HIV.&#xD;
&#xD;
          -  Patients with active hepatitis infection (defined as having a positive hepatitis B&#xD;
             surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past&#xD;
             hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a&#xD;
             negative HBs Ag test and a positive antibody to hepatitis B core antigen [anti-HBc]&#xD;
             antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody&#xD;
             are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.&#xD;
&#xD;
          -  Patients with active tuberculosis.&#xD;
&#xD;
          -  Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g.&#xD;
             partial bowel obstruction or malabsorption).&#xD;
&#xD;
          -  Subjects with gastrointestinal disorders associated with a high risk of perforation or&#xD;
             fistula formation&#xD;
&#xD;
          -  Subjects with active peptic ulcer or with a history of clinically significant GI&#xD;
             bleeding within 12 weeks before the first dose of study treatment&#xD;
&#xD;
          -  Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or&#xD;
             pathway-targeting agents.&#xD;
&#xD;
          -  Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or&#xD;
             anticipation that such a live, attenuated vaccine will be required during the study.&#xD;
&#xD;
          -  Treatment with any other investigational agent or participation in another clinical&#xD;
             trial with therapeutic intent within 28 days prior to enrolment.&#xD;
&#xD;
          -  Treatment with systemic immunostimulatory agents (including but not limited to&#xD;
             interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug,&#xD;
             whichever is shorter, prior to enrolment.&#xD;
&#xD;
          -  Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or&#xD;
             glucose-galactose malabsorption&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Patrizia Giannatempo, MD</last_name>
    <phone>+390223902402</phone>
    <email>patrizia.giannatempo@istitutotumori.mi.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Rosanna Montone, Dr.ssa</last_name>
    <phone>+390223903817</phone>
    <email>rosanna.montone@istitutotumori.mi.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Fondazione IRCCS Istituto Nazionale Tumori</name>
      <address>
        <city>Milano</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Patrizia Giannatempo, MD</last_name>
      <phone>+390223902402</phone>
      <email>patrizia.giannatempo@istitutotumori.mi.it</email>
    </contact>
    <contact_backup>
      <last_name>Rosanna Montone, Dr.ssa</last_name>
      <phone>+390223903817</phone>
      <email>rosanna.montone@istitutotumori.mi.it</email>
    </contact_backup>
    <investigator>
      <last_name>Patrizia Giannatempo, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <results_reference>
    <citation>Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, Guo CC, Lotan Y, Kassouf W. Bladder cancer. Lancet. 2016 Dec 3;388(10061):2796-2810. doi: 10.1016/S0140-6736(16)30512-8. Epub 2016 Jun 23. Erratum In: Lancet. 2016 Dec 3;388(10061):2742.</citation>
    <PMID>27345655</PMID>
  </results_reference>
  <results_reference>
    <citation>Necchi A, Sonpavde G, Lo Vullo S, Giardiello D, Bamias A, Crabb SJ, Harshman LC, Bellmunt J, De Giorgi U, Sternberg CN, Cerbone L, Ladoire S, Wong YN, Yu EY, Chowdhury S, Niegisch G, Srinivas S, Vaishampayan UN, Pal SK, Agarwal N, Alva A, Baniel J, Golshayan AR, Morales-Barrera R, Bowles DW, Milowsky MI, Theodore C, Berthold DR, Daugaard G, Sridhar SS, Powles T, Rosenberg JE, Galsky MD, Mariani L; RISC Investigators. Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC). Eur Urol. 2017 Feb;71(2):281-289. doi: 10.1016/j.eururo.2016.09.042. Epub 2016 Oct 8.</citation>
    <PMID>27726966</PMID>
  </results_reference>
  <results_reference>
    <citation>Raggi D, Miceli R, Sonpavde G, Giannatempo P, Mariani L, Galsky MD, Bellmunt J, Necchi A. Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis. Ann Oncol. 2016 Jan;27(1):49-61. doi: 10.1093/annonc/mdv509. Epub 2015 Oct 20.</citation>
    <PMID>26487582</PMID>
  </results_reference>
  <results_reference>
    <citation>Necchi A, Pond GR, Raggi D, Giannatempo P, Vogelzang NJ, Grivas P, Galsky MD, Bellmunt J, Sonpavde G. Efficacy and Safety of Gemcitabine Plus Either Taxane or Carboplatin in the First-Line Setting of Metastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis. Clin Genitourin Cancer. 2017 Feb;15(1):23-30.e2. doi: 10.1016/j.clgc.2016.05.003. Epub 2016 May 27.</citation>
    <PMID>27324051</PMID>
  </results_reference>
  <results_reference>
    <citation>Dash A, Galsky MD, Vickers AJ, Serio AM, Koppie TM, Dalbagni G, Bochner BH. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer. 2006 Aug 1;107(3):506-13. doi: 10.1002/cncr.22031.</citation>
    <PMID>16773629</PMID>
  </results_reference>
  <results_reference>
    <citation>Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, Dreicer R, Vogelzang N, Sternberg CN, Bajorin DF, Bellmunt J. Treatment of patients with metastatic urothelial cancer &quot;unfit&quot; for Cisplatin-based chemotherapy. J Clin Oncol. 2011 Jun 10;29(17):2432-8. doi: 10.1200/JCO.2011.34.8433. Epub 2011 May 9.</citation>
    <PMID>21555688</PMID>
  </results_reference>
  <results_reference>
    <citation>Reardon ZD, Patel SG, Zaid HB, Stimson CJ, Resnick MJ, Keegan KA, Barocas DA, Chang SS, Cookson MS. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol. 2015 Jan;67(1):165-170. doi: 10.1016/j.eururo.2014.01.009. Epub 2014 Jan 23.</citation>
    <PMID>24472710</PMID>
  </results_reference>
  <results_reference>
    <citation>Gentzler R, Hall R, Kunk PR, Gaughan E, Dillon P, Slingluff CL Jr, Rahma OE. Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors. Immunotherapy. 2016 May;8(5):583-600. doi: 10.2217/imt-2015-0029.</citation>
    <PMID>27140411</PMID>
  </results_reference>
  <results_reference>
    <citation>Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. doi: 10.1038/nature13904.</citation>
    <PMID>25428503</PMID>
  </results_reference>
  <results_reference>
    <citation>Herr HW, Morales A. History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story. J Urol. 2008 Jan;179(1):53-6. doi: 10.1016/j.juro.2007.08.122. Epub 2007 Nov 13.</citation>
    <PMID>17997439</PMID>
  </results_reference>
  <results_reference>
    <citation>Rink M, Shariat SF, Soave A. Liquid biopsies in bladder cancer-did we find the Holy Grail for biomarker analyses? Transl Androl Urol. 2016 Dec;5(6):980-983. doi: 10.21037/tau.2016.09.03. No abstract available.</citation>
    <PMID>28078238</PMID>
  </results_reference>
  <results_reference>
    <citation>Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014 Mar 20;507(7492):315-22. doi: 10.1038/nature12965. Epub 2014 Jan 29.</citation>
    <PMID>24476821</PMID>
  </results_reference>
  <results_reference>
    <citation>Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013 Jul 11;499(7457):214-218. doi: 10.1038/nature12213. Epub 2013 Jun 16.</citation>
    <PMID>23770567</PMID>
  </results_reference>
  <results_reference>
    <citation>Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, Curiel TJ, Colon-Otero G, Hamid O, Sanborn RE, O'Donnell PH, Drakaki A, Tan W, Kurland JF, Rebelatto MC, Jin X, Blake-Haskins JA, Gupta A, Segal NH. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol. 2016 Sep 10;34(26):3119-25. doi: 10.1200/JCO.2016.67.9761. Epub 2016 Jun 6.</citation>
    <PMID>27269937</PMID>
  </results_reference>
  <results_reference>
    <citation>Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, Lee JL, Ong M, Sridhar SS, Vogelzang NJ, Fishman MN, Zhang J, Srinivas S, Parikh J, Antal J, Jin X, Gupta AK, Ben Y, Hahn NM. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 2017 Sep 14;3(9):e172411. doi: 10.1001/jamaoncol.2017.2411. Epub 2017 Sep 14.</citation>
    <PMID>28817753</PMID>
  </results_reference>
  <results_reference>
    <citation>Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.</citation>
    <PMID>19097774</PMID>
  </results_reference>
  <results_reference>
    <citation>Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. doi: 10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2. Erratum In: Lancet Oncol. 2019 May;20(5):e242.</citation>
    <PMID>28271869</PMID>
  </results_reference>
  <results_reference>
    <citation>Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999 Dec;35(13):1773-82. doi: 10.1016/s0959-8049(99)00229-4.</citation>
    <PMID>10673991</PMID>
  </results_reference>
  <results_reference>
    <citation>Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, Srinivasan P, Gao J, Chakravarty D, Devlin SM, Hellmann MD, Barron DA, Schram AM, Hameed M, Dogan S, Ross DS, Hechtman JF, DeLair DF, Yao J, Mandelker DL, Cheng DT, Chandramohan R, Mohanty AS, Ptashkin RN, Jayakumaran G, Prasad M, Syed MH, Rema AB, Liu ZY, Nafa K, Borsu L, Sadowska J, Casanova J, Bacares R, Kiecka IJ, Razumova A, Son JB, Stewart L, Baldi T, Mullaney KA, Al-Ahmadie H, Vakiani E, Abeshouse AA, Penson AV, Jonsson P, Camacho N, Chang MT, Won HH, Gross BE, Kundra R, Heins ZJ, Chen HW, Phillips S, Zhang H, Wang J, Ochoa A, Wills J, Eubank M, Thomas SB, Gardos SM, Reales DN, Galle J, Durany R, Cambria R, Abida W, Cercek A, Feldman DR, Gounder MM, Hakimi AA, Harding JJ, Iyer G, Janjigian YY, Jordan EJ, Kelly CM, Lowery MA, Morris LGT, Omuro AM, Raj N, Razavi P, Shoushtari AN, Shukla N, Soumerai TE, Varghese AM, Yaeger R, Coleman J, Bochner B, Riely GJ, Saltz LB, Scher HI, Sabbatini PJ, Robson ME, Klimstra DS, Taylor BS, Baselga J, Schultz N, Hyman DM, Arcila ME, Solit DB, Ladanyi M, Berger MF. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017 Jun;23(6):703-713. doi: 10.1038/nm.4333. Epub 2017 May 8. Erratum In: Nat Med. 2017 Aug 4;23 (8):1004.</citation>
    <PMID>28481359</PMID>
  </results_reference>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>January 8, 2019</study_first_submitted>
  <study_first_submitted_qc>January 29, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>February 24, 2021</last_update_submitted>
  <last_update_submitted_qc>February 24, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 25, 2021</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>Carcinoma</mesh_term>
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03824691
org study id: INT 180/18
nct id: NCT03824691
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Cabozantinib plus Durvalumab in patients with advanced and chemotherapy-treated bladder
      carcinoma, of urothelial and non-urothelial histology: an open-label, single-centre, phase 2,
      single-arm proof-of-concept trial: ARCADIA study
an open-label, single-centre, phase 2,
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The primary endpoint of the study will be overall survival (OS).
time frame: 48 months
description: to evaluate whether the combination of durvalumab and cabozantinib will be active and will result in an increased efficacy compared to the available results with the use of both single-agents
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).
time frame: 48 months
description: incidence, nature and severity of all-cause and treatment-related adverse events (AE), graded with the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
measure: progression-free survival (PFS)
time frame: 48 months
description: RECIST 1.1 criteria
measure: responses to treatment
time frame: 48 months
description: Assessment of RR (investigator-assessed) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. RR (%) = complete (CR) + partial responses (PR)
measure: response duration
time frame: 48 months
description: PET-responses according to the EORTC criteria
measure: Biomarkers of activity and efficacy of either agents and their combination.
time frame: 48 months
description: determination of a patient's PD-L1 status. Biomarkers Blood Collection will be performend at baseline, every 2 cycles and progression disease
arm group label: Cabozantinib + Durvalumab
arm group type: Experimental
description: Subjects will receive 1500 mg durvalumab (MEDI4736) IV infusion every 28 days + Cabozantinib 40 mg orally once daily
intervention type: Drug
intervention name: Cabozantinib
description: cabozantinib 40 mg orally once daily
arm group label: Cabozantinib + Durvalumab
other name: CABOMETYX
intervention type: Drug
intervention name: Durvalumab
description: 1500 mg durvalumab (MEDI4736) IV infusion every 28 days
arm group label: Cabozantinib + Durvalumab
other name: Imfinzi
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Patrizia Giannatempo, MD
phone: +390223902402
email: patrizia.giannatempo@istitutotumori.mi.it
last name: Rosanna Montone, Dr.ssa
phone: +390223903817
email: rosanna.montone@istitutotumori.mi.it
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Italy
citation: Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, Guo CC, Lotan Y, Kassouf W. Bladder cancer. Lancet. 2016 Dec 3;388(10061):2796-2810. doi: 10.1016/S0140-6736(16)30512-8. Epub 2016 Jun 23. Erratum In: Lancet. 2016 Dec 3;388(10061):2742.
PMID: 27345655
citation: Necchi A, Sonpavde G, Lo Vullo S, Giardiello D, Bamias A, Crabb SJ, Harshman LC, Bellmunt J, De Giorgi U, Sternberg CN, Cerbone L, Ladoire S, Wong YN, Yu EY, Chowdhury S, Niegisch G, Srinivas S, Vaishampayan UN, Pal SK, Agarwal N, Alva A, Baniel J, Golshayan AR, Morales-Barrera R, Bowles DW, Milowsky MI, Theodore C, Berthold DR, Daugaard G, Sridhar SS, Powles T, Rosenberg JE, Galsky MD, Mariani L; RISC Investigators. Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC). Eur Urol. 2017 Feb;71(2):281-289. doi: 10.1016/j.eururo.2016.09.042. Epub 2016 Oct 8.
PMID: 27726966
citation: Raggi D, Miceli R, Sonpavde G, Giannatempo P, Mariani L, Galsky MD, Bellmunt J, Necchi A. Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis. Ann Oncol. 2016 Jan;27(1):49-61. doi: 10.1093/annonc/mdv509. Epub 2015 Oct 20.
PMID: 26487582
citation: Necchi A, Pond GR, Raggi D, Giannatempo P, Vogelzang NJ, Grivas P, Galsky MD, Bellmunt J, Sonpavde G. Efficacy and Safety of Gemcitabine Plus Either Taxane or Carboplatin in the First-Line Setting of Metastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis. Clin Genitourin Cancer. 2017 Feb;15(1):23-30.e2. doi: 10.1016/j.clgc.2016.05.003. Epub 2016 May 27.
PMID: 27324051
citation: Dash A, Galsky MD, Vickers AJ, Serio AM, Koppie TM, Dalbagni G, Bochner BH. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer. 2006 Aug 1;107(3):506-13. doi: 10.1002/cncr.22031.
PMID: 16773629
citation: Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, Dreicer R, Vogelzang N, Sternberg CN, Bajorin DF, Bellmunt J. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011 Jun 10;29(17):2432-8. doi: 10.1200/JCO.2011.34.8433. Epub 2011 May 9.
PMID: 21555688
citation: Reardon ZD, Patel SG, Zaid HB, Stimson CJ, Resnick MJ, Keegan KA, Barocas DA, Chang SS, Cookson MS. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol. 2015 Jan;67(1):165-170. doi: 10.1016/j.eururo.2014.01.009. Epub 2014 Jan 23.
PMID: 24472710
citation: Gentzler R, Hall R, Kunk PR, Gaughan E, Dillon P, Slingluff CL Jr, Rahma OE. Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors. Immunotherapy. 2016 May;8(5):583-600. doi: 10.2217/imt-2015-0029.
PMID: 27140411
citation: Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. doi: 10.1038/nature13904.
PMID: 25428503
citation: Herr HW, Morales A. History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story. J Urol. 2008 Jan;179(1):53-6. doi: 10.1016/j.juro.2007.08.122. Epub 2007 Nov 13.
PMID: 17997439
citation: Rink M, Shariat SF, Soave A. Liquid biopsies in bladder cancer-did we find the Holy Grail for biomarker analyses? Transl Androl Urol. 2016 Dec;5(6):980-983. doi: 10.21037/tau.2016.09.03. No abstract available.
PMID: 28078238
citation: Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014 Mar 20;507(7492):315-22. doi: 10.1038/nature12965. Epub 2014 Jan 29.
PMID: 24476821
citation: Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013 Jul 11;499(7457):214-218. doi: 10.1038/nature12213. Epub 2013 Jun 16.
PMID: 23770567
citation: Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, Curiel TJ, Colon-Otero G, Hamid O, Sanborn RE, O'Donnell PH, Drakaki A, Tan W, Kurland JF, Rebelatto MC, Jin X, Blake-Haskins JA, Gupta A, Segal NH. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol. 2016 Sep 10;34(26):3119-25. doi: 10.1200/JCO.2016.67.9761. Epub 2016 Jun 6.
PMID: 27269937
citation: Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, Lee JL, Ong M, Sridhar SS, Vogelzang NJ, Fishman MN, Zhang J, Srinivas S, Parikh J, Antal J, Jin X, Gupta AK, Ben Y, Hahn NM. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 2017 Sep 14;3(9):e172411. doi: 10.1001/jamaoncol.2017.2411. Epub 2017 Sep 14.
PMID: 28817753
citation: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
PMID: 19097774
citation: Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. doi: 10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2. Erratum In: Lancet Oncol. 2019 May;20(5):e242.
PMID: 28271869
citation: Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999 Dec;35(13):1773-82. doi: 10.1016/s0959-8049(99)00229-4.
PMID: 10673991
citation: Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, Srinivasan P, Gao J, Chakravarty D, Devlin SM, Hellmann MD, Barron DA, Schram AM, Hameed M, Dogan S, Ross DS, Hechtman JF, DeLair DF, Yao J, Mandelker DL, Cheng DT, Chandramohan R, Mohanty AS, Ptashkin RN, Jayakumaran G, Prasad M, Syed MH, Rema AB, Liu ZY, Nafa K, Borsu L, Sadowska J, Casanova J, Bacares R, Kiecka IJ, Razumova A, Son JB, Stewart L, Baldi T, Mullaney KA, Al-Ahmadie H, Vakiani E, Abeshouse AA, Penson AV, Jonsson P, Camacho N, Chang MT, Won HH, Gross BE, Kundra R, Heins ZJ, Chen HW, Phillips S, Zhang H, Wang J, Ochoa A, Wills J, Eubank M, Thomas SB, Gardos SM, Reales DN, Galle J, Durany R, Cambria R, Abida W, Cercek A, Feldman DR, Gounder MM, Hakimi AA, Harding JJ, Iyer G, Janjigian YY, Jordan EJ, Kelly CM, Lowery MA, Morris LGT, Omuro AM, Raj N, Razavi P, Shoushtari AN, Shukla N, Soumerai TE, Varghese AM, Yaeger R, Coleman J, Bochner B, Riely GJ, Saltz LB, Scher HI, Sabbatini PJ, Robson ME, Klimstra DS, Taylor BS, Baselga J, Schultz N, Hyman DM, Arcila ME, Solit DB, Ladanyi M, Berger MF. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017 Jun;23(6):703-713. doi: 10.1038/nm.4333. Epub 2017 May 8. Erratum In: Nat Med. 2017 Aug 4;23 (8):1004.
PMID: 28481359
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Urinary Bladder Neoplasms
mesh term: Durvalumab