<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/NCT03003676</url>
  </required_header>
  <id_info>
    <org_study_id>ONCOS C824</org_study_id>
    <nct_id>NCT03003676</nct_id>
  </id_info>
  <brief_title>A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After Programmed Cell Death Protein 1 (PD1) Blockade</brief_title>
  <official_title>A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After PD1 Blockade</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Targovax Oy</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Targovax ASA</source>
  <brief_summary>
    <textblock>
      This is a multi center, phase I pilot study of sequential ONCOS-102 and pembrolizumab in&#xD;
      patients with advanced or unresectable melanoma progressing after PD1 blockade. The primary&#xD;
      objective of the study is to determine the safety of sequential treatment with ONCOS-102&#xD;
      followed by pembrolizumab. The protocol aims to enroll patients into two cohorts: Part I: up&#xD;
      to 12 patients will receive sequential treatment with ONCOS-102 followed by pembrolizumab.&#xD;
      Part II: up to 12 patients will receive an initial treatment phase with ONCOS-102 followed by&#xD;
      a treatment phase with ONCOS-102 in combination with pembrolizumab.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Actual">October 2020</completion_date>
  <primary_completion_date type="Actual">July 2020</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>Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE).</measure>
    <time_frame>6 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rates by RECIST 1.1 and irRECIST.</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab.</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab.</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR).</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST.</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease.</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease.</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Size in Individual Lesions.</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Somatic Mutational Rate and Neoepitope Burden in Tumors and Explore Relationship to Response.</measure>
    <time_frame>6 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Changes in T Cell Receptor Clonality in Infiltrating and Circulating T Cells.</measure>
    <time_frame>6 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Gene Expression Changes in the Tumor Microenvironment and Peripheral Blood.</measure>
    <time_frame>6 months</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Advanced or Unresectable Melanoma Progressing After PD1 Blockade</condition>
  <arm_group>
    <arm_group_label>Experimental: ONCOS-102+cyclophosphamide+pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part I: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24).&#xD;
Part II: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ONCOS-102</intervention_name>
    <description>Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)</description>
    <arm_group_label>Experimental: ONCOS-102+cyclophosphamide+pembrolizumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Pre-treatment</description>
    <arm_group_label>Experimental: ONCOS-102+cyclophosphamide+pembrolizumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>PD1 blockade</description>
    <arm_group_label>Experimental: ONCOS-102+cyclophosphamide+pembrolizumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults 18 years of age or older.&#xD;
&#xD;
          -  For US sites: Histopathologically confirmed melanoma with an injectable cutaneous or&#xD;
             lymph node metastasis that has progressed in the opinion of the treating investigator&#xD;
             despite administering a Food and Drug Administration (FDA) approved anti-PD1 agent,&#xD;
             with or without ipilimumab.&#xD;
&#xD;
          -  For European sites: Histopathologically confirmed melanoma with an injectable&#xD;
             cutaneous or lymph node metastasis that has progressed in the opinion of the treating&#xD;
             investigator despite administering a regulatory approved anti-PD1 agent, with or&#xD;
             without ipilimumab.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.&#xD;
&#xD;
          -  Measurable disease according to RECIST 1.1.&#xD;
&#xD;
          -  Acceptable coagulation status: international normalised ratio (INR) of blood clotting,&#xD;
             prothrombin time and activated partial thromboplastin time within ≤1.5 x upper limit&#xD;
             of normal (ULN).&#xD;
&#xD;
          -  Completion of local therapy, such as radiation, surgical resection, injectable&#xD;
             immunebased therapy, or topical pro-inflammatory agent, 21 days prior to first dose of&#xD;
             protocol therapy.&#xD;
&#xD;
          -  Adverse events from previous cancer therapies (excluding alopecia) must have recovered&#xD;
             to grade 1 (CTCAE, most recent version). Stable grade 2 AEs such as endocrine&#xD;
             conditions are allowed, and other chronic stable AEs may be considered on a case by&#xD;
             case basis by the Principal Investigator.&#xD;
&#xD;
          -  Clinical stability of brain metastases for at least 4 weeks prior to first day of&#xD;
             study therapy.&#xD;
&#xD;
          -  Acceptable liver and renal functions defined as:&#xD;
&#xD;
               -  Total bilirubin ≤1.5 x ULN (does not include patients with Gilbert's Disease)&#xD;
&#xD;
               -  Aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) ≤3.0&#xD;
                  x ULN&#xD;
&#xD;
               -  Serum creatinine ≤1.5 x ULN&#xD;
&#xD;
          -  Acceptable haematological function defined as (Patients can be transfused to meet the&#xD;
             haemoglobin entry criteria):&#xD;
&#xD;
               -  Haemoglobin ≥9 g/dL&#xD;
&#xD;
               -  Neutrophils ≥1.5 x 10^9/L&#xD;
&#xD;
               -  Platelet count ≥75 x 10^9/L&#xD;
&#xD;
          -  Able to provide valid written informed consent.&#xD;
&#xD;
          -  All women of childbearing potential must have a negative urine or serum pregnancy test&#xD;
             at screening.&#xD;
&#xD;
          -  For US sites: All patients must agree to use barrier contraception (i.e. condom)&#xD;
             during study treatment and for 2 months after the last virus treatment and 4 months&#xD;
             after the last dose of chemotherapy and pembrolizumab.&#xD;
&#xD;
          -  For European sites: All patients must agree to use highly effective contraception for&#xD;
             at least 6 months (according to the latest country specific SmPC) after administration&#xD;
             of CPO, up to 4 months after last dose of pembrolizumab, and up to 2 months after last&#xD;
             dose of ONCOS-102, whichever comes last.&#xD;
&#xD;
          -  For European sites: All women of child-bearing potential must agree to perform&#xD;
             pregnancy testing throughout the study starting at baseline, every 3 weeks from day 22&#xD;
             until last dose of study medication (ONCOS-102 and pembrolizumab) and then every month&#xD;
             for at least 6 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A concomitant medical condition requiring receipt of a therapeutic anticoagulant that&#xD;
             in the opinion of the treating physician cannot safely allow for therapeutic injection&#xD;
             of ONCOS-102 and tumor biopsies. Local clinical practice can be followed with regard&#xD;
             to holding a therapeutic anticoagulant during invasive procedures such as biopsies.&#xD;
&#xD;
          -  A concomitant medical condition that in the opinion of the treating physician would&#xD;
             pose unreasonable additional risk to therapeutic injection of ONCOS-102.&#xD;
&#xD;
          -  For US sites: Receipt of Investigational agents within 28 days prior to first dose of&#xD;
             protocol therapy.&#xD;
&#xD;
          -  For European sites: Current participation or participation in a study of an&#xD;
             investigational agent within 28 days prior to first dose of protocol therapy. Note:&#xD;
             participants who have entered the follow-up phase of an investigational study may&#xD;
             participate as long as it has been 4 weeks after the last dose of the previous&#xD;
             investigational agent.&#xD;
&#xD;
          -  Any symptomatic autoimmune disease (such as lupus, scleroderma, Crohn's disease,&#xD;
             ulcerative colitis) that requires administration of &gt;10mg of prednisone equivalent.&#xD;
             Lower dose steroids for conditions such as hypophysitis are allowed.&#xD;
&#xD;
          -  Any prior severe adverse event attributed to prior anti-PD1 therapy that, in the&#xD;
             Principal investigator's opinion, would contraindicate pembrolizumab administration&#xD;
             such as:&#xD;
&#xD;
               -  Grade 2 or higher pneumonitis&#xD;
&#xD;
               -  Grade 4 AST or ALT elevation&#xD;
&#xD;
               -  Grade 3 or higher colitis attributable to PD1 blockade; note that colitis&#xD;
                  attributable to ipilimumab is not excluded&#xD;
&#xD;
               -  Note: in the absence of clinical symptoms of pancreatitis, elevations of amylase&#xD;
                  or lipase are not contraindications to therapy on this trial&#xD;
&#xD;
          -  Known active infection with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or HIV.&#xD;
             Cleared HBV/HCV infection is not an exclusion, nor is HIV infection with cluster of&#xD;
             differentiations 4 (CD4) counts &gt;500 and an undetectable viral load.&#xD;
&#xD;
          -  Active bacterial, viral, or fungal infections, requiring systemic therapy apart from&#xD;
             anti-viral maintenance therapy for HIV.&#xD;
&#xD;
          -  History of organ transplant.&#xD;
&#xD;
          -  Patients requiring chronic systemic immunosuppressants, including steroids (prednisone&#xD;
             daily equivalent of &gt;10 mg).&#xD;
&#xD;
          -  Brain metastases that are clinically unstable (e.g. showing unequivocal growth on&#xD;
             imaging, requiring radiation therapy, or steroids &gt;10mg of prednisone equivalent)&#xD;
             within 4 weeks of first dose of study drug.&#xD;
&#xD;
          -  Known severe congenital or acquired cellular or humoral immunodeficiency such as&#xD;
             common variable immunodeficiency.&#xD;
&#xD;
          -  For US sites: Women who are pregnant or breast-feeding currently or are planning to&#xD;
             conceive during or up to 4 months after end of protocol therapy.&#xD;
&#xD;
          -  For European sites: Women who are currently pregnant or breast-feeding or are planning&#xD;
             to conceive during or up to 6 months after end of protocol therapy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of Maryland Comprehensive Cancer Center</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fox Chase Cancer Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oslo University Hospital - The Norwegian Radium Hospital</name>
      <address>
        <city>Oslo</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>December 19, 2016</study_first_submitted>
  <study_first_submitted_qc>December 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 28, 2016</study_first_posted>
  <results_first_submitted>July 16, 2021</results_first_submitted>
  <results_first_submitted_qc>July 16, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">August 9, 2021</results_first_posted>
  <last_update_submitted>October 11, 2021</last_update_submitted>
  <last_update_submitted_qc>October 11, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 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>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 12, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/76/NCT03003676/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 25, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/76/NCT03003676/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab - Part 1</title>
          <description>Part I: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will receive pembrolizumab i.v., 2mg/kg or 200 mg flat dose on day 22 (Week 3) and every three weeks thereafter until Day 169/Week 24.&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
        </group>
        <group group_id="P2">
          <title>Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab - Part 2</title>
          <description>Part II: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF) Cyclophosphamide: Pre-treatment Pembrolizumab: PD1 blockade</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Hepatitis B infection</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1</title>
          <description>Part I: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
        </group>
        <group group_id="B2">
          <title>Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2</title>
          <description>Part II: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="9"/>
            <count group_id="B2" value="12"/>
            <count group_id="B3" value="21"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="69.1" spread="13.68"/>
                    <measurement group_id="B2" value="67.3" spread="13.50"/>
                    <measurement group_id="B3" value="68.1" spread="13.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Norway</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE).</title>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1</title>
            <description>Part I1 Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
          </group>
          <group group_id="O2">
            <title>Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2</title>
            <description>Part 2: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE).</title>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Number of patients with Treatment Emergent Adverse Event (TEAE)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients with Treatment Emergent Adverse Serious Event (TESAE)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients with Grade 3 or 4 Treatment Emergent Adverse Event (TEAE)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients with Treatment Emergent Adverse Event related to any of the study treatments</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients with fatal events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients discontinuing for Adverse Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rates by RECIST 1.1 and irRECIST.</title>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Part 1</title>
            <description>Part 1: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
          </group>
          <group group_id="O2">
            <title>Part 2</title>
            <description>Part 2: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rates by RECIST 1.1 and irRECIST.</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Number of patient with Complete Response or Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Number of patients with Stable Disease or Progressive Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab.</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab.</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR).</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST.</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease.</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease.</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Size in Individual Lesions.</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Somatic Mutational Rate and Neoepitope Burden in Tumors and Explore Relationship to Response.</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Changes in T Cell Receptor Clonality in Infiltrating and Circulating T Cells.</title>
        <time_frame>6 months</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Gene Expression Changes in the Tumor Microenvironment and Peripheral Blood.</title>
        <time_frame>6 months</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>27 weeks</time_frame>
      <desc>Adverse events were reported according to NCI CTCAE vs 5.0</desc>
      <group_list>
        <group group_id="E1">
          <title>Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1</title>
          <description>Part 1: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
        </group>
        <group group_id="E2">
          <title>Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2</title>
          <description>Part 2: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).&#xD;
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)&#xD;
Cyclophosphamide: Pre-treatment&#xD;
Pembrolizumab: PD1 blockade</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA, CTCAE v5.0</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title vocab="MedDRA">Haemolytic anaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title vocab="MedDRA">Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Enterocolitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title vocab="MedDRA">Large intestine infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title vocab="MedDRA">Staphylococcal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Diabetic ketoacidosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Type 1 diabetes mellitus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA, CTCAE v5.0</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title vocab="MedDRA">Anaemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="8" subjects_affected="4" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="9" subjects_affected="4" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="9"/>
                <counts group_id="E2" events="15" subjects_affected="4" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title vocab="MedDRA">Fatigue</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Injection site pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="23" subjects_affected="7" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="9"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="8" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="6" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title vocab="MedDRA">White blood cell count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title vocab="MedDRA">Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Pollakisuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis bullous</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Embolism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="9"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title vocab="MedDRA">Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Lone H. Ottesen, Chief Development Officer</name_or_title>
      <organization>Targovax</organization>
      <phone>+44 7920567911</phone>
      <email>lone.ottesen@targovax.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03003676
org study id: ONCOS C824
nct id: NCT03003676
lead sponsor: 
This is a multi center, phase I pilot study of sequential ONCOS-102 and pembrolizumab in
      patients with advanced or unresectable melanoma progressing after PD1 blockade. The primary
      objective of the study is to determine the safety of sequential treatment with ONCOS-102
      followed by pembrolizumab. The protocol aims to enroll patients into two cohorts: Part I: up
      to 12 patients will receive sequential treatment with ONCOS-102 followed by pembrolizumab.
      Part II: up to 12 patients will receive an initial treatment phase with ONCOS-102 followed by
      a treatment phase with ONCOS-102 in combination with pembrolizumab.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE).
time frame: 6 months
measure: Objective Response Rates by RECIST 1.1 and irRECIST.
time frame: 6 months
measure: Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab.
time frame: 6 months
measure: Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab.
time frame: 6 months
measure: Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR).
time frame: 6 months
measure: Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST.
time frame: 6 months
measure: Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease.
time frame: 6 months
measure: Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease.
time frame: 6 months
measure: Change in Size in Individual Lesions.
time frame: 6 months
measure: Somatic Mutational Rate and Neoepitope Burden in Tumors and Explore Relationship to Response.
time frame: 6 months
measure: Changes in T Cell Receptor Clonality in Infiltrating and Circulating T Cells.
time frame: 6 months
measure: Gene Expression Changes in the Tumor Microenvironment and Peripheral Blood.
time frame: 6 months
arm group label: Experimental: ONCOS-102+cyclophosphamide+pembrolizumab
arm group type: Experimental
description: Part I: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24).
Part II: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).
intervention type: Biological
intervention name: ONCOS-102
description: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)
arm group label: Experimental: ONCOS-102+cyclophosphamide+pembrolizumab
intervention type: Drug
intervention name: Cyclophosphamide
description: Pre-treatment
arm group label: Experimental: ONCOS-102+cyclophosphamide+pembrolizumab
intervention type: Drug
intervention name: Pembrolizumab
description: PD1 blockade
arm group label: Experimental: ONCOS-102+cyclophosphamide+pembrolizumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
country: Norway
country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Cyclophosphamide
mesh term: Pembrolizumab
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 