<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/NCT04429321</url>
  </required_header>
  <id_info>
    <org_study_id>UPCC 06820</org_study_id>
    <secondary_id>843082</secondary_id>
    <nct_id>NCT04429321</nct_id>
  </id_info>
  <brief_title>Nivolumab + Ipilimumab With Immunostimulatory Embolization for Stage 4 Renal Cell Carcinoma With Unresected Primary</brief_title>
  <official_title>UPCC06820 Phase 1 Trial of Nivolumab + Ipilimumab With Immunostimulatory Embolization for Stage 4 Renal Cell Carcinoma With Unresected Primary</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Abramson Cancer Center at Penn Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Abramson Cancer Center at Penn Medicine</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This single center phase 1 trial will study the combination of nivolumab+ipilimumab with&#xD;
      embolization in participants with renal cell carcinoma. The study will evaluate the safety of&#xD;
      embolotherapy in patients with metastatic RCC receiving nivolumab+ipilimumab. The hypothesis&#xD;
      is that the number of serious adverse events will be no greater than the number of serious&#xD;
      adverse events for both therapies combined.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Previously untreated subjects with stage 4 RCC and unresected primary tumor or metastasis&#xD;
      amenable to embolization will undergo two cycles of combination immune checkpoint inhibition&#xD;
      (ICI) therapy, embolization of the target tumor, then resume ICI therapy. Study ends with&#xD;
      safety and efficacy assessment at 6 months. Correlative blood and tissue specimens will be&#xD;
      obtained.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 26, 2020</start_date>
  <completion_date type="Anticipated">August 2023</completion_date>
  <primary_completion_date type="Anticipated">August 2023</primary_completion_date>
  <phase>Phase 1</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>Rate of serious adverse events</measure>
    <time_frame>Serious adverse events will be recorded from time of informed to consent to 100 days after the end of study intervention</time_frame>
    <description>SAE rate following embolization in patients</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate</measure>
    <time_frame>Measured from baseline to 6 months post initiation</time_frame>
    <description>Objective response rate by RECIST 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Characterization of immune cells</measure>
    <time_frame>From baseline to 12 weeks post initiation of therapy</time_frame>
    <description>Characterization of tumor-infiltrating leukocytes in primary and metastatic lesions before and after embolotherapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PD-L1</measure>
    <time_frame>From baseline to 12 weeks post initiation of therapy</time_frame>
    <description>Percentage of PD-L1 stain positivity in the primary tumor biopsy of participants</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">22</enrollment>
  <condition>Renal Cell Carcinoma</condition>
  <condition>Renal Cell Carcinoma Stage IV</condition>
  <arm_group>
    <arm_group_label>Ipilimumab +Nivolumab with Embolization</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients initiate ICI therapy with Nivolumab 3 mg/kg + ipilimumab 1/mg/kg IV every 3 weeks x 4 cycles, followed by nivolumab 480mg flat dose IV every four weeks for a total of 6 months of therapy unless stopped for confirmed progression or intolerable toxicities.&#xD;
Patients will receive 2 cycles of systemic therapy followed by embolization of their primary tumor or metastatic lesion(s) and continue systemic therapy subsequently.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab 3 mg/kg IV every four weeks, first in combination with capecitabine then alone</description>
    <arm_group_label>Ipilimumab +Nivolumab with Embolization</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>ipilimumab 1/mg/kg IV every 3 weeks x 4 cycles, in combination with Nivolumab</description>
    <arm_group_label>Ipilimumab +Nivolumab with Embolization</arm_group_label>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>bland embolization</intervention_name>
    <description>Lipiodol:ethanol embolization of their primary or target tumor</description>
    <arm_group_label>Ipilimumab +Nivolumab with Embolization</arm_group_label>
    <other_name>trans-arterial embolization</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Metastatic renal cell carcinoma with unresected primary tumor or with metastasis&#xD;
             amenable to embolization.&#xD;
&#xD;
          2. No prior immune checkpoint therapy&#xD;
&#xD;
          3. Primary tumor or metastasis amenable to percutaneous embolization per review by the&#xD;
             treating interventional oncologist&#xD;
&#xD;
             · Patent feeding artery to tumor &gt; 2 mm diameter without macroscopic arteriovenous&#xD;
             fistula/shunt&#xD;
&#xD;
          4. Additional metastatic site &gt; 1 cm assessable for response by RECIST 1.1&#xD;
&#xD;
          5. Adequate organ function by screening laboratory studies within 30 days of embolization&#xD;
&#xD;
               -  platelets &gt; 50K, correctable by transfusion&#xD;
&#xD;
               -  INR &lt; 1.5, correctable by transfusion&#xD;
&#xD;
               -  creatinine &lt; 2.0&#xD;
&#xD;
          6. ECOG performance status 0-2&#xD;
&#xD;
          7. Age ≥ 18 years&#xD;
&#xD;
          8. Have signed the current approved informed consent form and be willing and able to&#xD;
             comply with this protocol&#xD;
&#xD;
          9. Women of childbearing potential (WOCBP) must use appropriate method(s) of&#xD;
             contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months&#xD;
             after the last dose of study drug&#xD;
&#xD;
         10. Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
&#xD;
         11. Men who are sexually active with WOCBP must use any contraceptive method with a&#xD;
             failure rate of less than 1% per year Men receiving nivolumab and who are sexually&#xD;
             active with WOCBP will be instructed to adhere to contraception for a period of 7&#xD;
             months after the last dose&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Untreated CNS metastasis&#xD;
&#xD;
          2. Autoimmune disorder; subjects are permitted to enroll if they have vitiligo, type I&#xD;
             diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring&#xD;
             hormone replacement, psoriasis not requiring systemic treatment&#xD;
&#xD;
          3. Immunodeficiency syndrome&#xD;
&#xD;
          4. Glucocorticoid (&gt; 10 mg daily prednisone equivalents) or immunosuppressant therapy&#xD;
&#xD;
          5. Active infection requiring systemic therapy&#xD;
&#xD;
          6. Any other medical or personal condition that, in the opinion of the site investigator,&#xD;
             may potentially compromise the safety or compliance of the patient, or may preclude&#xD;
             the patient's successful completion of the clinical trial.&#xD;
&#xD;
          7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus&#xD;
             ribonucleic acid (HCV antibody) indicating acute or chronic infection&#xD;
&#xD;
          8. Contrast allergy not mitigated by usual prophylaxis&#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>Michale Soulen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pennsylvania</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Michael Soulen, MD</last_name>
    <phone>855-216-0098</phone>
    <email>michael.soulen@pennmedicine.upenn.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Hospital of the University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael C Soulen, MD, FSIR</last_name>
      <phone>855-216-0098</phone>
      <email>michael.soulen@uphs.upenn.edu</email>
    </contact>
    <investigator>
      <last_name>Michael C Soulen, MD, FSIR</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthelemy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.</citation>
    <PMID>29562145</PMID>
  </reference>
  <reference>
    <citation>Zielinski H, Szmigielski S, Petrovich Z. Comparison of preoperative embolization followed by radical nephrectomy with radical nephrectomy alone for renal cell carcinoma. Am J Clin Oncol. 2000 Feb;23(1):6-12. doi: 10.1097/00000421-200002000-00002.</citation>
    <PMID>10683065</PMID>
  </reference>
  <reference>
    <citation>Swanson DA, Wallace S. Surgery of metastatic renal cell carcinoma and use of renal infarction. Semin Surg Oncol. 1988;4(2):124-8.</citation>
    <PMID>3293153</PMID>
  </reference>
  <reference>
    <citation>Sabel MS. Cryo-immunology: a review of the literature and proposed mechanisms for stimulatory versus suppressive immune responses. Cryobiology. 2009 Feb;58(1):1-11. doi: 10.1016/j.cryobiol.2008.10.126. Epub 2008 Oct 17.</citation>
    <PMID>19007768</PMID>
  </reference>
  <reference>
    <citation>den Brok MH, Sutmuller RP, Nierkens S, Bennink EJ, Frielink C, Toonen LW, Boerman OC, Figdor CG, Ruers TJ, Adema GJ. Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity. Br J Cancer. 2006 Oct 9;95(7):896-905. doi: 10.1038/sj.bjc.6603341. Epub 2006 Sep 5.</citation>
    <PMID>16953240</PMID>
  </reference>
  <reference>
    <citation>Mehta A, Oklu R, Sheth RA. Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response? Gastroenterol Res Pract. 2016;2016:9251375. doi: 10.1155/2016/9251375. Epub 2016 Mar 8.</citation>
    <PMID>27051417</PMID>
  </reference>
  <reference>
    <citation>Kato T, Iwasaki T, Uemura M, Nagahara A, Higashihara H, Osuga K, Ikeda Y, Kiyotani K, Park JH, Nonomura N, Nakamura Y. Characterization of the cryoablation-induced immune response in kidney cancer patients. Oncoimmunology. 2017 May 16;6(7):e1326441. doi: 10.1080/2162402X.2017.1326441. eCollection 2017.</citation>
    <PMID>28811963</PMID>
  </reference>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>June 9, 2020</study_first_submitted>
  <study_first_submitted_qc>June 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 12, 2020</study_first_posted>
  <last_update_submitted>March 14, 2022</last_update_submitted>
  <last_update_submitted_qc>March 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 15, 2022</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</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/NCT04429321
org study id: UPCC 06820
secondary id: 843082
nct id: NCT04429321
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: Yes
is us export: No
This single center phase 1 trial will study the combination of nivolumab+ipilimumab with
      embolization in participants with renal cell carcinoma. The study will evaluate the safety of
      embolotherapy in patients with metastatic RCC receiving nivolumab+ipilimumab. The hypothesis
      is that the number of serious adverse events will be no greater than the number of serious
      adverse events for both therapies combined.
Previously untreated subjects with stage 4 RCC and unresected primary tumor or metastasis
      amenable to embolization will undergo two cycles of combination immune checkpoint inhibition
      (ICI) therapy, embolization of the target tumor, then resume ICI therapy. Study ends with
      safety and efficacy assessment at 6 months. Correlative blood and tissue specimens will be
      obtained.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of serious adverse events
time frame: Serious adverse events will be recorded from time of informed to consent to 100 days after the end of study intervention
description: SAE rate following embolization in patients
measure: Objective response rate
time frame: Measured from baseline to 6 months post initiation
description: Objective response rate by RECIST 1.1
measure: Characterization of immune cells
time frame: From baseline to 12 weeks post initiation of therapy
description: Characterization of tumor-infiltrating leukocytes in primary and metastatic lesions before and after embolotherapy
measure: PD-L1
time frame: From baseline to 12 weeks post initiation of therapy
description: Percentage of PD-L1 stain positivity in the primary tumor biopsy of participants
arm group label: Ipilimumab +Nivolumab with Embolization
arm group type: Experimental
description: Patients initiate ICI therapy with Nivolumab 3 mg/kg + ipilimumab 1/mg/kg IV every 3 weeks x 4 cycles, followed by nivolumab 480mg flat dose IV every four weeks for a total of 6 months of therapy unless stopped for confirmed progression or intolerable toxicities.
Patients will receive 2 cycles of systemic therapy followed by embolization of their primary tumor or metastatic lesion(s) and continue systemic therapy subsequently.
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab 3 mg/kg IV every four weeks, first in combination with capecitabine then alone
arm group label: Ipilimumab +Nivolumab with Embolization
other name: Opdivo
intervention type: Drug
intervention name: Ipilimumab
description: ipilimumab 1/mg/kg IV every 3 weeks x 4 cycles, in combination with Nivolumab
arm group label: Ipilimumab +Nivolumab with Embolization
other name: Yervoy
intervention type: Device
intervention name: bland embolization
description: Lipiodol:ethanol embolization of their primary or target tumor
arm group label: Ipilimumab +Nivolumab with Embolization
other name: trans-arterial embolization
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michale Soulen, MD
role: Principal Investigator
affiliation: University of Pennsylvania
last name: Michael Soulen, MD
phone: 855-216-0098
email: michael.soulen@pennmedicine.upenn.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
citation: Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthelemy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.
PMID: 29562145
citation: Zielinski H, Szmigielski S, Petrovich Z. Comparison of preoperative embolization followed by radical nephrectomy with radical nephrectomy alone for renal cell carcinoma. Am J Clin Oncol. 2000 Feb;23(1):6-12. doi: 10.1097/00000421-200002000-00002.
PMID: 10683065
citation: Swanson DA, Wallace S. Surgery of metastatic renal cell carcinoma and use of renal infarction. Semin Surg Oncol. 1988;4(2):124-8.
PMID: 3293153
citation: Sabel MS. Cryo-immunology: a review of the literature and proposed mechanisms for stimulatory versus suppressive immune responses. Cryobiology. 2009 Feb;58(1):1-11. doi: 10.1016/j.cryobiol.2008.10.126. Epub 2008 Oct 17.
PMID: 19007768
citation: den Brok MH, Sutmuller RP, Nierkens S, Bennink EJ, Frielink C, Toonen LW, Boerman OC, Figdor CG, Ruers TJ, Adema GJ. Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity. Br J Cancer. 2006 Oct 9;95(7):896-905. doi: 10.1038/sj.bjc.6603341. Epub 2006 Sep 5.
PMID: 16953240
citation: Mehta A, Oklu R, Sheth RA. Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response? Gastroenterol Res Pract. 2016;2016:9251375. doi: 10.1155/2016/9251375. Epub 2016 Mar 8.
PMID: 27051417
citation: Kato T, Iwasaki T, Uemura M, Nagahara A, Higashihara H, Osuga K, Ikeda Y, Kiyotani K, Park JH, Nonomura N, Nakamura Y. Characterization of the cryoablation-induced immune response in kidney cancer patients. Oncoimmunology. 2017 May 16;6(7):e1326441. doi: 10.1080/2162402X.2017.1326441. eCollection 2017.
PMID: 28811963
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Renal Cell
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: No