<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/NCT04462445</url>
  </required_header>
  <id_info>
    <org_study_id>INT 146-14</org_study_id>
    <nct_id>NCT04462445</nct_id>
  </id_info>
  <brief_title>Prospective Translational Study Investigating Possible Molecular prEdictors of Resistance to First-Line pazopanIb</brief_title>
  <acronym>PIPELINE</acronym>
  <official_title>Prospective Translational Study Investigating Possible Molecular prEdictors of Resistance to First-Line pazopanIb in Metastatic reNal Cell Carcinoma</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>
      This is a prospective, single-arm, monocentric translational study designed to evaluate&#xD;
      possible biomarkers of resistance to the first line of therapy with pazopanib in patients&#xD;
      with metastatic renal cell carcinoma (mRCC) who have not received systemic therapy in both&#xD;
      the adjuvant and metastatic phases.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      a prospective, single-arm, monocentric translational study&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 25, 2015</start_date>
  <completion_date type="Actual">February 8, 2017</completion_date>
  <primary_completion_date type="Actual">February 8, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>A panel of possible predictive candidate biomarkers of resistance to anti-angiogenic targeted tyrosine kinase inhibitor (TKI)</measure>
    <time_frame>18 months</time_frame>
    <description>using next-generation sequencing (NGS) methods for future research. This will be done by within-patient comparison of metastatic tissue samples taken on commencement of first-line pazopanib, and secondly on development of TKI resistance</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The Overall Response Rate (ORR)</measure>
    <time_frame>18 months</time_frame>
    <description>evaluate per RECIST v.1.1 criteria in mRCC patients treated with first-line pazopanib in order to either correlate circulating angiogenic factors (CAFs) levels and gene candidate biomarkers status to clinical outcome when resistance develops</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Identification of other protein markers circulating in blood,</measure>
    <time_frame>18 months</time_frame>
    <description>To obtain serial blood samples from patients whilst they are being treated with pazopanib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>compare the frequency of previously defined promising circulating predictive biomarkers for pazopanib treatment</measure>
    <time_frame>18 months</time_frame>
    <description>between blood samples taken at commencement of therapy (baseline) and at the time of progressive disease (PD) as per RECIST 1.1 criteria as well as changes of interleukin 8 (IL-8), c-Met and hematopoietic growth factor (HGF) expression between metastatic tumour tissue samples in order to better understand changes in the tumor and in the levels of circulating angiogenic factors as resistance develops.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Collect Data</measure>
    <time_frame>18 months</time_frame>
    <description>prospective and retrospective demographic, clinical and pathological data on patients who enter the study, enabling current and future correlation of biomarkers to clinical outcomes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Perform subgroup analyses</measure>
    <time_frame>18 months</time_frame>
    <description>comparing the tissue and blood biomarkers identified in patients who developed secondary resistance with those biomarkers identified in patients who have primary resistance.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Metastatic Renal Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>pazopanib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pazopanib 800 mg (2x400mg ) taken orally daily as per clinical practice</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pazopanib</intervention_name>
    <arm_group_label>pazopanib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed Informed Consent Form&#xD;
&#xD;
          -  Unresectable advanced or metastatic renal cell carcinoma (RCC) with component of clear&#xD;
             cell histology and/or component of sarcomatoid histology that has not been previously&#xD;
             treated with any systemic agent, including treatment in the adjuvant setting&#xD;
&#xD;
          -  Availability of a representative formalin-fixed paraffin-embedded fractional&#xD;
             Fokker-Planck equation (FFPE) tumor specimen collected within 24 months of starting&#xD;
             first-line pazopanib that enables the definitive diagnosis of renal cell carcinoma&#xD;
             (RCC) (the archival specimen must contain adequate viable tumor tissue to enable&#xD;
             candidate biomarkers status; the specimen may consist of a tissue block or at least 15&#xD;
             unstained serial sections; for core needle biopsy specimens at least two cores should&#xD;
             be available for evaluation)&#xD;
&#xD;
          -  Measurable disease as defined by RECIST v1.1&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
        Hematology Absolute neutrophil count (ANC)≥1.5 X 109/L Hemoglobin ≥9 g/dL (5.6 mmol/L)&#xD;
        Platelets ≥100 X 109/L Prothrombin time (PT) or international normalized ratio (INR)b ≤1.5&#xD;
        X upper limit of normal (ULN) Activated partial thromboplastin time (aPTT) ≤1.5 X upper&#xD;
        limit of normal (ULN) Hepatic Total bilirubin ≤1.5 X upper limit of normal (ULN) Alanine&#xD;
        amino transferase (ALT) and Aspartate aminotransferase (AST)c 2.5 X upper limit of normal&#xD;
        (ULN) Patients with documented liver metastases &lt;5 X upper limit of normal (ULN) Renal&#xD;
        Serum creatinine 1.5 mg/dL (133 µmol/L) Or, if &gt;1.5 mg/dL: Calculated creatinine clearance&#xD;
        (ClCR) (reference appropriate appendix) ≥30 mL/min to ≥ 50 mL/min Urine Protein to&#xD;
        Creatinine Ratio (UPC; appropriate appendix)&lt;1 Or, 24-hour urine protein &lt;1g&#xD;
&#xD;
        - Eastern Cooperative Oncology Group (ECOG) performance Status 0-1&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Clinically significant gastrointestinal abnormalities that may increase the risk for&#xD;
             gastrointestinal bleeding including, but not limited to: active peptic ulcer disease,&#xD;
             known intraluminal metastatic lesion/s with risk of bleeding, inflammatory bowel&#xD;
             disease (e.g. ulcerative colitis, Chrohn's disease), or other gastrointestinal&#xD;
             conditions with increased risk of perforation, history of abdominal fistula,&#xD;
             gastrointestinal perforation, or intra abdominal abscess within 28 days prior to&#xD;
             beginning study treatment.&#xD;
&#xD;
          -  History of any one or more of the following cardiovascular conditions within the past&#xD;
             6 months:&#xD;
&#xD;
        cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery&#xD;
        bypass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive&#xD;
        heart failure, as defined by the New York Heart Association (NYHA) - Poorly controlled&#xD;
        hypertension [defined as systolic blood pressure (SBP) of ≥140 millimetre (s) of mercury&#xD;
        (mmHg) or diastolic blood pressure (DBP) of ≥ 90 millimetre (s) of mercury (mmHg)].&#xD;
&#xD;
        Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to&#xD;
        study entry. Following antihypertensive medication initiation or adjustment, blood pressure&#xD;
        (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours&#xD;
        must have elapsed between anti-hypertensive medication initiation or adjustment and BP&#xD;
        measurement. These three values should be averaged to obtain the mean diastolic blood&#xD;
        pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be &lt;140/90&#xD;
        millimetre (s) of mercury (mmHg) (OR 150/90 millimetre (s) of mercury (mm Hg), if this&#xD;
        criterion is approved by Safety Review Team) in order for a subject to be eligible for the&#xD;
        study&#xD;
&#xD;
        - History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary&#xD;
        embolism or untreated deep venous thrombosis (DVT) within the past 6 months.&#xD;
&#xD;
        Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating&#xD;
        agents for at least 6 weeks are eligible&#xD;
&#xD;
          -  Major surgery or trauma within 28 days prior to first dose of pazopanib and/or&#xD;
             presence of any non-healing wound, fracture, or ulcer (procedures such as catheter&#xD;
             placement not considered to be major surgery).&#xD;
&#xD;
          -  Evidence of active bleeding or bleeding diathesis.&#xD;
&#xD;
          -  Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that&#xD;
             increase the risk of pulmonary hemorrhage Note: Lesions infiltrating major pulmonary&#xD;
             vessels (contiguous tumour and vessels) are excluded; however, the presence of a tumor&#xD;
             that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with&#xD;
             contrast is strongly recommended to evaluate such lesions).&#xD;
&#xD;
          -  Large protruding endobronchial lesions in the main or lobar bronchi are excluded;&#xD;
             however, endobronchial lesions in the segmented bronchi are allowed.&#xD;
&#xD;
          -  Lesions extensively infiltrating the main or lobar bronchi are excluded; however,&#xD;
             minor infiltrations in the wall of the bronchi are allowed.&#xD;
&#xD;
          -  Recent hemoptysis (½ teaspoon of red blood within 8 weeks before first dose of study&#xD;
             drug).&#xD;
&#xD;
          -  Any serious and/or unstable pre-existing medical, psychiatric, or other condition that&#xD;
             could interfere with subject's safety, provision of informed consent, or compliance to&#xD;
             study procedures.&#xD;
&#xD;
          -  Treatment with any of the following anti-cancer therapies:&#xD;
&#xD;
          -  chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal&#xD;
             therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the&#xD;
             first dose of Pazopanib&#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_official>
    <last_name>Giuseppe Procopio, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fondazione IRCCS ISTITUTO NAZIONALE TUMORI</affiliation>
  </overall_official>
  <results_reference>
    <citation>Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29. doi: 10.3322/caac.21208. Epub 2014 Jan 7. Erratum In: CA Cancer J Clin. 2014 Sep-Oct;64(5):364.</citation>
    <PMID>24399786</PMID>
  </results_reference>
  <results_reference>
    <citation>Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996 Sep 19;335(12):865-75. doi: 10.1056/NEJM199609193351207. No abstract available.</citation>
    <PMID>8778606</PMID>
  </results_reference>
  <results_reference>
    <citation>Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317-20. doi: 10.1126/science.8493574.</citation>
    <PMID>8493574</PMID>
  </results_reference>
  <results_reference>
    <citation>George DJ, Kaelin WG Jr. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med. 2003 Jul 31;349(5):419-21. doi: 10.1056/NEJMp030061. No abstract available.</citation>
    <PMID>12890838</PMID>
  </results_reference>
  <results_reference>
    <citation>Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. Onco Targets Ther. 2009 Feb 18;2:51-61. doi: 10.2147/ott.s4052.</citation>
    <PMID>20616894</PMID>
  </results_reference>
  <results_reference>
    <citation>Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs. 2008 Feb;17(2):253-61. doi: 10.1517/13543784.17.2.253.</citation>
    <PMID>18230058</PMID>
  </results_reference>
  <results_reference>
    <citation>Kumar R, Crouthamel MC, Rominger DH, Gontarek RR, Tummino PJ, Levin RA, King AG. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer. 2009 Nov 17;101(10):1717-23. doi: 10.1038/sj.bjc.6605366. Epub 2009 Oct 20.</citation>
    <PMID>19844230</PMID>
  </results_reference>
  <results_reference>
    <citation>Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. doi: 10.1200/JCO.2009.23.9764. Epub 2010 Jan 25.</citation>
    <PMID>20100962</PMID>
  </results_reference>
  <results_reference>
    <citation>Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. doi: 10.1056/NEJMoa1303989.</citation>
    <PMID>23964934</PMID>
  </results_reference>
  <results_reference>
    <citation>Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Negrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. doi: 10.1200/JCO.2013.50.8267. Epub 2014 Mar 31.</citation>
    <PMID>24687826</PMID>
  </results_reference>
  <results_reference>
    <citation>Ravaud A, Gross-Goupil M. Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma. Cancer Treat Rev. 2012 Dec;38(8):996-1003. doi: 10.1016/j.ctrv.2012.01.003. Epub 2012 Feb 12.</citation>
    <PMID>22330762</PMID>
  </results_reference>
  <results_reference>
    <citation>Hutson TE. Targeted therapies for the treatment of metastatic renal cell carcinoma: clinical evidence. Oncologist. 2011;16 Suppl 2(Suppl 2):14-22. doi: 10.1634/theoncologist.2011-S2-14.</citation>
    <PMID>21346036</PMID>
  </results_reference>
  <results_reference>
    <citation>Hernandez-Yanez M, Heymach JV, Zurita AJ. Circulating biomarkers in advanced renal cell carcinoma: clinical applications. Curr Oncol Rep. 2012 Jun;14(3):221-9. doi: 10.1007/s11912-012-0231-2.</citation>
    <PMID>22434312</PMID>
  </results_reference>
  <results_reference>
    <citation>Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008 Aug;8(8):592-603. doi: 10.1038/nrc2442.</citation>
    <PMID>18650835</PMID>
  </results_reference>
  <results_reference>
    <citation>Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, Feng J, Stewart AE, Hu-Lowe DD, Christensen JG. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010 Dec 15;70(24):10090-100. doi: 10.1158/0008-5472.CAN-10-0489. Epub 2010 Oct 15.</citation>
    <PMID>20952508</PMID>
  </results_reference>
  <results_reference>
    <citation>Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25. doi: 10.1038/nrm1261. No abstract available.</citation>
    <PMID>14685170</PMID>
  </results_reference>
  <results_reference>
    <citation>Zhang YW, Su Y, Volpert OV, Vande Woude GF. Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12718-23. doi: 10.1073/pnas.2135113100. Epub 2003 Oct 10.</citation>
    <PMID>14555767</PMID>
  </results_reference>
  <results_reference>
    <citation>Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008 Nov 1;14(21):6735-41. doi: 10.1158/1078-0432.CCR-07-4843.</citation>
    <PMID>18980965</PMID>
  </results_reference>
  <results_reference>
    <citation>Mizukami Y, Jo WS, Duerr EM, Gala M, Li J, Zhang X, Zimmer MA, Iliopoulos O, Zukerberg LR, Kohgo Y, Lynch MP, Rueda BR, Chung DC. Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med. 2005 Sep;11(9):992-7. doi: 10.1038/nm1294. Epub 2005 Aug 28. Erratum In: Nat Med. 2006 Feb;12(2):253.</citation>
    <PMID>16127434</PMID>
  </results_reference>
  <results_reference>
    <citation>Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010 Feb 1;70(3):1063-71. doi: 10.1158/0008-5472.CAN-09-3965. Epub 2010 Jan 26.</citation>
    <PMID>20103651</PMID>
  </results_reference>
  <results_reference>
    <citation>Kapur P, Pena-Llopis S, Christie A, Zhrebker L, Pavia-Jimenez A, Rathmell WK, Xie XJ, Brugarolas J. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 2013 Feb;14(2):159-167. doi: 10.1016/S1470-2045(12)70584-3. Epub 2013 Jan 16.</citation>
    <PMID>23333114</PMID>
  </results_reference>
  <results_reference>
    <citation>Jorgensen TJ, Ruczinski I, Kessing B, Smith MW, Shugart YY, Alberg AJ. Hypothesis-driven candidate gene association studies: practical design and analytical considerations. Am J Epidemiol. 2009 Oct 15;170(8):986-93. doi: 10.1093/aje/kwp242. Epub 2009 Sep 17.</citation>
    <PMID>19762372</PMID>
  </results_reference>
  <results_reference>
    <citation>Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, Figlin RA, Hutson TE, Sternberg CN, Amado RG, Pandite LN, Heymach JV. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012 Aug;13(8):827-37. doi: 10.1016/S1470-2045(12)70241-3. Epub 2012 Jul 2.</citation>
    <PMID>22759480</PMID>
  </results_reference>
  <results_reference>
    <citation>Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015 Dec 14;28(6):690-714. doi: 10.1016/j.ccell.2015.10.012.</citation>
    <PMID>26678337</PMID>
  </results_reference>
  <results_reference>
    <citation>Donini M, Buti S, Lazzarelli S, Bozzetti R, Rivoltini L, Camisaschi C, Castelli C, Bearz A, Simonelli C, Lo Re G, Mattioli R, Caminiti C, Passalacqua R; GOIRC (Italian Oncology Group for Clinical Research). Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg). Target Oncol. 2015 Jun;10(2):277-86. doi: 10.1007/s11523-014-0337-6. Epub 2014 Sep 19.</citation>
    <PMID>25230695</PMID>
  </results_reference>
  <results_reference>
    <citation>Castelli C, Rivoltini L, Rodolfo M, Tazzari M, Belgiovine C, Allavena P. Modulation of the myeloid compartment of the immune system by angiogenic- and kinase inhibitor-targeted anti-cancer therapies. Cancer Immunol Immunother. 2015 Jan;64(1):83-9. doi: 10.1007/s00262-014-1576-1. Epub 2014 Jul 4.</citation>
    <PMID>24993564</PMID>
  </results_reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>July 2, 2020</study_first_submitted>
  <study_first_submitted_qc>July 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 8, 2020</study_first_posted>
  <last_update_submitted>July 8, 2020</last_update_submitted>
  <last_update_submitted_qc>July 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2020</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>Carcinoma, Renal Cell</mesh_term>
  </condition_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/NCT04462445
org study id: INT 146-14
nct id: NCT04462445
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a prospective, single-arm, monocentric translational study designed to evaluate
      possible biomarkers of resistance to the first line of therapy with pazopanib in patients
      with metastatic renal cell carcinoma (mRCC) who have not received systemic therapy in both
      the adjuvant and metastatic phases.
a prospective, single-arm, monocentric translational study
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: A panel of possible predictive candidate biomarkers of resistance to anti-angiogenic targeted tyrosine kinase inhibitor (TKI)
time frame: 18 months
description: using next-generation sequencing (NGS) methods for future research. This will be done by within-patient comparison of metastatic tissue samples taken on commencement of first-line pazopanib, and secondly on development of TKI resistance
measure: The Overall Response Rate (ORR)
time frame: 18 months
description: evaluate per RECIST v.1.1 criteria in mRCC patients treated with first-line pazopanib in order to either correlate circulating angiogenic factors (CAFs) levels and gene candidate biomarkers status to clinical outcome when resistance develops
measure: Identification of other protein markers circulating in blood,
time frame: 18 months
description: To obtain serial blood samples from patients whilst they are being treated with pazopanib
measure: compare the frequency of previously defined promising circulating predictive biomarkers for pazopanib treatment
time frame: 18 months
description: between blood samples taken at commencement of therapy (baseline) and at the time of progressive disease (PD) as per RECIST 1.1 criteria as well as changes of interleukin 8 (IL-8), c-Met and hematopoietic growth factor (HGF) expression between metastatic tumour tissue samples in order to better understand changes in the tumor and in the levels of circulating angiogenic factors as resistance develops.
measure: Collect Data
time frame: 18 months
description: prospective and retrospective demographic, clinical and pathological data on patients who enter the study, enabling current and future correlation of biomarkers to clinical outcomes
measure: Perform subgroup analyses
time frame: 18 months
description: comparing the tissue and blood biomarkers identified in patients who developed secondary resistance with those biomarkers identified in patients who have primary resistance.
arm group label: pazopanib
arm group type: Experimental
description: Pazopanib 800 mg (2x400mg ) taken orally daily as per clinical practice
intervention type: Drug
intervention name: Pazopanib
arm group label: pazopanib
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Giuseppe Procopio, MD
role: Principal Investigator
affiliation: Fondazione IRCCS ISTITUTO NAZIONALE TUMORI
citation: Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29. doi: 10.3322/caac.21208. Epub 2014 Jan 7. Erratum In: CA Cancer J Clin. 2014 Sep-Oct;64(5):364.
PMID: 24399786
citation: Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996 Sep 19;335(12):865-75. doi: 10.1056/NEJM199609193351207. No abstract available.
PMID: 8778606
citation: Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317-20. doi: 10.1126/science.8493574.
PMID: 8493574
citation: George DJ, Kaelin WG Jr. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med. 2003 Jul 31;349(5):419-21. doi: 10.1056/NEJMp030061. No abstract available.
PMID: 12890838
citation: Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. Onco Targets Ther. 2009 Feb 18;2:51-61. doi: 10.2147/ott.s4052.
PMID: 20616894
citation: Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs. 2008 Feb;17(2):253-61. doi: 10.1517/13543784.17.2.253.
PMID: 18230058
citation: Kumar R, Crouthamel MC, Rominger DH, Gontarek RR, Tummino PJ, Levin RA, King AG. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer. 2009 Nov 17;101(10):1717-23. doi: 10.1038/sj.bjc.6605366. Epub 2009 Oct 20.
PMID: 19844230
citation: Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. doi: 10.1200/JCO.2009.23.9764. Epub 2010 Jan 25.
PMID: 20100962
citation: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. doi: 10.1056/NEJMoa1303989.
PMID: 23964934
citation: Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Negrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. doi: 10.1200/JCO.2013.50.8267. Epub 2014 Mar 31.
PMID: 24687826
citation: Ravaud A, Gross-Goupil M. Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma. Cancer Treat Rev. 2012 Dec;38(8):996-1003. doi: 10.1016/j.ctrv.2012.01.003. Epub 2012 Feb 12.
PMID: 22330762
citation: Hutson TE. Targeted therapies for the treatment of metastatic renal cell carcinoma: clinical evidence. Oncologist. 2011;16 Suppl 2(Suppl 2):14-22. doi: 10.1634/theoncologist.2011-S2-14.
PMID: 21346036
citation: Hernandez-Yanez M, Heymach JV, Zurita AJ. Circulating biomarkers in advanced renal cell carcinoma: clinical applications. Curr Oncol Rep. 2012 Jun;14(3):221-9. doi: 10.1007/s11912-012-0231-2.
PMID: 22434312
citation: Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008 Aug;8(8):592-603. doi: 10.1038/nrc2442.
PMID: 18650835
citation: Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, Feng J, Stewart AE, Hu-Lowe DD, Christensen JG. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010 Dec 15;70(24):10090-100. doi: 10.1158/0008-5472.CAN-10-0489. Epub 2010 Oct 15.
PMID: 20952508
citation: Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25. doi: 10.1038/nrm1261. No abstract available.
PMID: 14685170
citation: Zhang YW, Su Y, Volpert OV, Vande Woude GF. Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12718-23. doi: 10.1073/pnas.2135113100. Epub 2003 Oct 10.
PMID: 14555767
citation: Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008 Nov 1;14(21):6735-41. doi: 10.1158/1078-0432.CCR-07-4843.
PMID: 18980965
citation: Mizukami Y, Jo WS, Duerr EM, Gala M, Li J, Zhang X, Zimmer MA, Iliopoulos O, Zukerberg LR, Kohgo Y, Lynch MP, Rueda BR, Chung DC. Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med. 2005 Sep;11(9):992-7. doi: 10.1038/nm1294. Epub 2005 Aug 28. Erratum In: Nat Med. 2006 Feb;12(2):253.
PMID: 16127434
citation: Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010 Feb 1;70(3):1063-71. doi: 10.1158/0008-5472.CAN-09-3965. Epub 2010 Jan 26.
PMID: 20103651
citation: Kapur P, Pena-Llopis S, Christie A, Zhrebker L, Pavia-Jimenez A, Rathmell WK, Xie XJ, Brugarolas J. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 2013 Feb;14(2):159-167. doi: 10.1016/S1470-2045(12)70584-3. Epub 2013 Jan 16.
PMID: 23333114
citation: Jorgensen TJ, Ruczinski I, Kessing B, Smith MW, Shugart YY, Alberg AJ. Hypothesis-driven candidate gene association studies: practical design and analytical considerations. Am J Epidemiol. 2009 Oct 15;170(8):986-93. doi: 10.1093/aje/kwp242. Epub 2009 Sep 17.
PMID: 19762372
citation: Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, Figlin RA, Hutson TE, Sternberg CN, Amado RG, Pandite LN, Heymach JV. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012 Aug;13(8):827-37. doi: 10.1016/S1470-2045(12)70241-3. Epub 2012 Jul 2.
PMID: 22759480
citation: Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015 Dec 14;28(6):690-714. doi: 10.1016/j.ccell.2015.10.012.
PMID: 26678337
citation: Donini M, Buti S, Lazzarelli S, Bozzetti R, Rivoltini L, Camisaschi C, Castelli C, Bearz A, Simonelli C, Lo Re G, Mattioli R, Caminiti C, Passalacqua R; GOIRC (Italian Oncology Group for Clinical Research). Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg). Target Oncol. 2015 Jun;10(2):277-86. doi: 10.1007/s11523-014-0337-6. Epub 2014 Sep 19.
PMID: 25230695
citation: Castelli C, Rivoltini L, Rodolfo M, Tazzari M, Belgiovine C, Allavena P. Modulation of the myeloid compartment of the immune system by angiogenic- and kinase inhibitor-targeted anti-cancer therapies. Cancer Immunol Immunother. 2015 Jan;64(1):83-9. doi: 10.1007/s00262-014-1576-1. Epub 2014 Jul 4.
PMID: 24993564
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Renal Cell