<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/NCT03799744</url>
  </required_header>
  <id_info>
    <org_study_id>ICO-VCN-H&amp;N-2018</org_study_id>
    <secondary_id>2018-001095-38</secondary_id>
    <nct_id>NCT03799744</nct_id>
  </id_info>
  <brief_title>Safety,Tolerability,and Efficacy of VCN-01 With Durvalumab in R/M Head and Neck Squamous Cell Carcinoma</brief_title>
  <official_title>A Phase I Study to Evaluate the Safety, Tolerability, and Efficacy of VCN-01 in Combination With Durvalumab (MEDI4736) in Subjects With Recurrent/ Metastatic Squamous Cell Carcinoma of the Head and Neck</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Català d'Oncologia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Theriva Biologics SL</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>BioClever 2005 S.L.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut Català d'Oncologia</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 Phase I Study to Evaluate the Safety, Tolerability, and Efficacy of VCN-01 in&#xD;
      Combination With Durvalumab (MEDI4736) in Subjects With Recurrent/Metastatic Squamous Cell&#xD;
      Carcinoma of the Head and Neck.&#xD;
&#xD;
      VCN-01 is a genetically modified oncolytic adenovirus characterized by the presence of four&#xD;
      independent genetic modifications on the backbone of the wild-type HAd5 adenovirus genome,&#xD;
      encoding human PH20, that confer tumor selectivity and anti-tumor activity.&#xD;
&#xD;
      Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa&#xD;
      subclass that inhibits binding of PD-L1.&#xD;
&#xD;
      The proposed mechanism of action (MOA) for durvalumab is interference in the interaction of&#xD;
      PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases&#xD;
      the inhibition of immune responses, including those that may result in tumor elimination.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      -  Research Hypothesis The presence of VCN-01 into the tumor after systemic administration&#xD;
           will help to overcome the observed resistance to durvalumab and other PD1/PD-L1&#xD;
           checkpoint inhibitors.&#xD;
&#xD;
        -  Primary objectives To evaluate the safety and tolerability of a single intravenous&#xD;
           injection of VCN-01 combined with durvalumab in two administration regimens (concomitant&#xD;
           or durvalumab starting two weeks later &quot;sequential schedule&quot;), and to determine the&#xD;
           recommended phase II dose (RP2D) of the combination.&#xD;
&#xD;
        -  Study design This is a phase I trial, multicenter, open label, and dose escalation&#xD;
           study. Patients will be entered at each dose level, according to a planned dose&#xD;
           escalation schedule. Absence of unacceptable toxicity at the previous dose is required&#xD;
           for entering a patient in the subsequent level.&#xD;
&#xD;
        -  Number of Centers: up to 3&#xD;
&#xD;
        -  Number of Patients: 15-20 patients&#xD;
&#xD;
        -  Study Population: Patients with metastatic squamous cell carcinoma of the head and neck&#xD;
           who have progressed during or after treatment with immune-checkpoint inhibitors.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 20, 2019</start_date>
  <completion_date type="Anticipated">January 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This is a phase I trial, multicenter, open label, and dose escalation study. Patients will be entered at each dose level, according to a planned dose escalation schedule. Absence of unacceptable toxicity at the previous dose is required for entering a patient in the subsequent level.&#xD;
The investigational treatment will be a single i.v. VCN-01 dose combined with concomitant i.v. durvalumab (MEDI4736) 1500 mg Q4W (Arm I) or durvalumab starting two weeks after VCN-01 administration, &quot;sequential schedule&quot; (Arm II). Patient recruitment in Arm I and Arm II will be performed in parallel based on slot availability. Only one single dose of VCN-01 will be administered to each patient during the trial. Durvalumab will be administered Q4W until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety by means of Adverse Events (AEs)</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Incidence of Adverse Events as assessed by CTCAE v4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>On Cycle 3 (+/- 3 days, each cycle is 28 days), and then every 2 cycles (± 7 days) until disease progression or withdrawal (an average of 2 years)</time_frame>
    <description>Proportion of patients with reduction in tumor burden of a predefined amount assessed by CT or MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>On Cycle 3 (+/- 3 days, each cycle is 28 days), and then every 2 cycles (± 7 days) until disease progression or withdrawal (an average of 2 years)</time_frame>
    <description>Time from study enrollment until disease progression or death assessed by CT or MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Plasma Concentration (Cmax ) of VCN-01</measure>
    <time_frame>For both arms: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1, 2, 4, 6, 24 and 48 hours post VCN-01 administration.</time_frame>
    <description>The maximum (or peak) concentration that VCN-01 achieves in plasma after its administration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax of VCN-01</measure>
    <time_frame>VCN-01 and Durvalumab concomitant arm: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, 24 hours and 48 hours post VCN-01 administration. VCN-01 and Durvalumab sequential: On day 1</time_frame>
    <description>Time to Maximum Plasma Concentration of VCN-01</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC of VCN-01</measure>
    <time_frame>VCN-01 and Durvalumab concomitant arm: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, 24 hours and 48 hours post VCN-01 administration. VCN-01 and Durvalumab sequential: On day 1</time_frame>
    <description>The definite integral in a plot of drug concentration in blood plasma vs. time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Half-Life (t1/2) of VCN-01</measure>
    <time_frame>VCN-01 and Durvalumab concomitant arm: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, 24 hours and 48 hours post VCN-01 administration. VCN-01 and Durvalumab sequential: On day 1</time_frame>
    <description>The time it takes for half to be removed</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Elimination rate constant of VCN-01</measure>
    <time_frame>VCN-01 and Durvalumab concomitant arm: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, 24 hours and 48 hours post VCN-01 administration. VCN-01 and Durvalumab sequential: On day 1</time_frame>
    <description>The rate at which VCN-01 is removed from the body.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VCN-01 viral shedding in blood</measure>
    <time_frame>VCN-01 and Durvalumab concomitant arm: On day 1: pre-dose and then, 4 hours, 24 hours and 48 hours post dose, on day 8, day 15, day 22 of cycle 1 (each cycle is 28 days), then on day1 of subsequent durvalumab cycles and at the final visit. Arm II: On day</time_frame>
    <description>Determination of VCN-01 levels in peripheral blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>anti-VCN-01 antibodies</measure>
    <time_frame>At screening, on day 1 pre-dose (within 15 minutes prior to VCN-01 ) in both arms. In concomitant arm: at day1 of subsequent durvalumab cycles (each cycle is 28 days), and at the final visit. In sequential arm: at day15 on cycle 1, at day1 of subsequent</time_frame>
    <description>Assessment of Blood levels of neutralizing anti-VCN-01 antibodies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VCN-01 viral shedding in stool and sputum</measure>
    <time_frame>VCN-01 and Durvalumab concomitant arm: at day 1, 8, 15 and 22 on cycle 1 (each cycle is 28 days) And at day1 of subsequent durvalumab cycles. VCN-01 and Durvalumab sequential: at day -14, -7, 1, 8, 15 on cycle 1 and at day 1 of subsequent durvalumab</time_frame>
    <description>Determination of VCN-01 levels in stool and sputum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological changes induced by the combination of VCN-01 and durvalumab.</measure>
    <time_frame>VCN-01 and Durvalumab concomitant arm: On day 1: pre-dose, at 30 minutes, 6 hours, 24 hours, 48 hours, at day 8 on cycle 1 (each cycle is 28 days), at day 1of cycle 2 and at the final visit. VCN-01 and Durvalumab sequential: On day 1, 15 minutes before</time_frame>
    <description>Study of the Immunological changes induced by the combination of VCN-01 and durvalumab by assessment of blood levels of circulating Interleukin 6 and Interleukin 10</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Microbiome in stool (VCN-01 and Durvalumab concomitant arm)</measure>
    <time_frame>On day 1: pre-dose and 1st deposition after-dose (the first deposition occurred from day 1 to day 7), day 8, day 15, day 22 on cycle 1 (each cycle is 28 days).</time_frame>
    <description>Analyse the microbiome in stool, prior and after VCN-01 administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Microbiome in stool (VCN-01 and Durvalumab sequential)</measure>
    <time_frame>On day -14 (pre-dose and 1st deposition after-dose), day -7, Day 1, day 8 and day15 on cycle 1 (each cycle is 28 days).</time_frame>
    <description>Analyse the microbiome in stool, prior and after VCN-01 administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Circulating free DNA (cfDNA) in plasma analysis (VCN-01 and Durvalumab concomitant arm)</measure>
    <time_frame>Pre-dose on day 1 (within 15min prior to VCN-01 infusion) and at day 8 on cycle 1, at day 1 on cycle 2, at day 1 on cycle 3 and at day 1 on cycle 4 (within 15min prior durvalumab administration) (each cycle is 28 days).</time_frame>
    <description>To analyse the circulating free DNA (cfDNA) in plasma obtained from samples collected prior and post VCN-01 treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Circulating free DNA (cfDNA) in plasma analysis (VCN-01 and Durvalumab sequential)</measure>
    <time_frame>On day -14 pre-dose and 1st deposition after-dose(the first deposition occurred from day -14 to day -8), day -7, day 1, day 8 and day15 on cycle 1 (each cycle is 28 days).</time_frame>
    <description>To analyse the circulating free DNA (cfDNA) in plasma obtained from samples collected prior and post VCN-01 treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Head and Neck Neoplasms</condition>
  <condition>Carcinoma, Squamous Cell of Head and Neck</condition>
  <condition>Metastasis</condition>
  <condition>Recurrence</condition>
  <arm_group>
    <arm_group_label>VCN-01 and Durvalumab; concomitant.</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Combination VCN-01 (single iv dose) with Durvalumab, Concomitant schedule; Dose Escalation of VCN-01</description>
  </arm_group>
  <arm_group>
    <arm_group_label>VCN-01 and Durvalumab; sequential</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Combination VCN-01 (single iv dose) with Durvalumab, Delayed schedule (14 days); Dose Escalation of VCN-01</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>VCN-01</intervention_name>
    <description>Dose level 1: 3.3x10^12 viral particles/patient and Dose level 2: 1x10^13 viral particles/patient</description>
    <arm_group_label>VCN-01 and Durvalumab; concomitant.</arm_group_label>
    <arm_group_label>VCN-01 and Durvalumab; sequential</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Dose: 1500 mg Q4W</description>
    <arm_group_label>VCN-01 and Durvalumab; concomitant.</arm_group_label>
    <arm_group_label>VCN-01 and Durvalumab; sequential</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent and any locally-required authorization (e.g., Data Privacy&#xD;
             Directive in the EU) obtained from the patient prior to performing any&#xD;
             protocol-related procedures; including screening evaluations must be obtained.&#xD;
&#xD;
          2. Adult subjects; age ≥ 18 years at time of study entry&#xD;
&#xD;
          3. ECOG Performance status 0 or 1&#xD;
&#xD;
          4. Life expectancy above 3 months&#xD;
&#xD;
          5. Body weight &gt;30kg&#xD;
&#xD;
          6. Adequate normal organ and marrow function as defined below (transfusions intended to&#xD;
             elevate any parameters below solely for the intent of meeting study eligibility are&#xD;
             not permitted):&#xD;
&#xD;
               -  Leukocytes ≥3000 mcL&#xD;
&#xD;
               -  Absolute neutrophil count ≥1500 mcL (or 1.0) x (≥ 1500 per mm3)&#xD;
&#xD;
               -  Platelets ≥100 000 mcL&#xD;
&#xD;
               -  Haemoglobin ≥9 g/dL&#xD;
&#xD;
               -  Total bilirubin ≤1.5 x ULN; total bilirubin ≤3×ULN in patients with documented&#xD;
                  Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or in the presence of liver&#xD;
                  metastases&#xD;
&#xD;
               -  ALT and AST ≤2.5×ULN if no demonstrable liver metastases or ≤5×ULN in the&#xD;
                  presence of liver metastases&#xD;
&#xD;
               -  Creatinine ≤ 1.5 x UNL or measured creatinine clearance (CL) &gt;40 mL/min or&#xD;
                  Calculated creatinine CL&gt;40 mL/min by the Cockcroft-Gault formula (Cockcroft and&#xD;
                  Gault 1976) or by 24-hour urine collection for determination of creatinine&#xD;
                  clearance (see section 4.1.).&#xD;
&#xD;
          7. Evidence of post-menopausal status or negative urinary or serum pregnancy test for&#xD;
             female pre-menopausal patients (see section 4.1.).&#xD;
&#xD;
          8. Patient is willing and able to comply with the protocol for the duration of the study&#xD;
             including undergoing treatment and scheduled visits and examinations including follow&#xD;
             up.&#xD;
&#xD;
          9. Have histologically and/or cytologically confirmed head and neck squamous cell&#xD;
             carcinoma from the specific sites: oral cavity, oropharynx, larynx or hypopharynx that&#xD;
             is recurrent/Mestastasic (R/M) and not amenable to curative therapy by surgery or&#xD;
             radiation.&#xD;
&#xD;
         10. For patients in R/M disease: has undergone ≥1 previous regimens of cytoreductive&#xD;
             chemo-therapies including prior exposure to anti-PD-(L)1. Patients have progressed or&#xD;
             be refractory to anti-PD1 or anti-PDL1 therapy. Note: anti-PD1 or Anti-PDL1 therapy&#xD;
             with other agents is acceptable. For patients with locally advanced disease those who&#xD;
             has progressed in the last 6 months to previous line that include anti-PD1 or anti&#xD;
             PD-L1 in the radical treatment.&#xD;
&#xD;
         11. Subjects must have at least 1 lesion that is measurable using RECIST guidelines.&#xD;
             RECIST lesions must not have been previously treated with surgery, radiation therapy,&#xD;
             or radiofrequency ablation unless there is documented progression after therapy.&#xD;
&#xD;
         12. Subjects must consent to provide paired pretreatment and on-treatment tumor biopsies&#xD;
             (1 pre; 2 post).&#xD;
&#xD;
         13. Levels of neutralizing antibodies against adenovirus ≤1/350 dilution&#xD;
&#xD;
         14. All patients are required to have a fibroscan assessment performed during the&#xD;
             screening period. Patients with fibrosis value ≥9.5 kPa will not be eligible.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine&#xD;
             therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal&#xD;
             antibodies) within 4 weeks (28 days) prior to the first dose of study treatment.&#xD;
             Enrolment with a shorter period of time might be allowed upon discussion with the&#xD;
             Study Physician/Medical Monitor according data of sufficient washout time form PK&#xD;
             properties of the agent.&#xD;
&#xD;
          2. Concurrent enrolment in another clinical study, unless it is an observational&#xD;
             (non-interventional) clinical study or during the follow-up period of an&#xD;
             interventional study.&#xD;
&#xD;
          3. Previous treatment PD1/PD-L1 inhibition (including Durvalumab) is a specific entry&#xD;
             criterion, but patients:Must not have experienced a toxicity that led to permanent&#xD;
             discontinuation of prior immunotherapy.&#xD;
&#xD;
               -  All AEs while receiving prior immunotherapy must have completely resolved or&#xD;
                  resolved to baseline prior to screening for this study.&#xD;
&#xD;
                  o Exception: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if&#xD;
                  they are stably maintained on appropriate replacement therapy and are&#xD;
                  asymptomatic.&#xD;
&#xD;
               -  Must not have experienced a ≥Grade 3 immune related AE or an immune related&#xD;
                  neurologic or ocular AE of any grade while receiving prior immunotherapy.&#xD;
&#xD;
               -  Must not have required the use of additional immunosuppression other than&#xD;
                  corticosteroids for the management of an AE, not have experienced recurrence of&#xD;
                  an AE if re-challenged, and not currently require maintenance doses of &gt; 10 mg&#xD;
                  prednisone or equivalent per day.&#xD;
&#xD;
          4. Presently has a second malignancy other than SCCHN, or history of treatment for&#xD;
             invasive cancer other that SCCHN in the past 3 years except for:&#xD;
&#xD;
               1. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence&#xD;
                  of disease.&#xD;
&#xD;
               2. Previously treated non-invasive in-situ carcinoma.&#xD;
&#xD;
               3. Cervical carcinoma stage 1B or less.&#xD;
&#xD;
               4. Non-invasive basal cell and squamous cell skin carcinoma.&#xD;
&#xD;
               5. Radically treated prostate cancer (prostatectomy or radiotherapy) with normal&#xD;
                  prostate-specific antigen, and not requiring ongoing antiandrogen hormonal&#xD;
                  therapy.&#xD;
&#xD;
               6. Other malignancy treated with curative intent and with no known active disease ≥3&#xD;
                  years before the first dose of study drug and of low potential risk for&#xD;
                  recurrence.&#xD;
&#xD;
               7. Patients with other malignancies treated with curative intent and with no known&#xD;
                  active disease &lt; 3 years and at low risk of recurrence, may be eligible upon&#xD;
                  discussion with the Medical Monitor.&#xD;
&#xD;
          5. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3&#xD;
             electrocardiograms (ECGs) using Fridericia's Correction (within 15 minutes at 5&#xD;
             minutes apart).&#xD;
&#xD;
          6. Current or prior use of immunosuppressive medication within 28 days before the first&#xD;
             dose of VCN-01/durvalumab, with the exceptions of intranasal and inhaled&#xD;
             corticosteroids or systemic corticosteroids at physiological doses, which are not to&#xD;
             exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Exceptions defined in&#xD;
             section 4.2.&#xD;
&#xD;
          7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the&#xD;
             exception of alopecia, vitiligo, and the laboratory values considered not clinically&#xD;
             significant or correctable by the investigator. The eligibility of patients who are&#xD;
             still experiencing irreversible toxicity that is not reasonably expected to be&#xD;
             exacerbated by the study drugs in this study (eg, hearing loss) must be reviewed and&#xD;
             approved by the Study Physician. Patients with Grade ≥2 neuropathy or hearing loss&#xD;
             will be evaluated on a case-by-case basis after consultation with the Study&#xD;
             physician/Medical Monitor.&#xD;
&#xD;
          8. Has experienced immune-related AEs (irAEs) while receiving prior immunotherapy&#xD;
             (including anti-CTLA4 treatment) and assessed as CTCAE grade ≥3&#xD;
&#xD;
          9. Has an active or prior documented autoimmune or inflammatory disorder (including but&#xD;
             not limited to inflammatory bowel disease [e.g., colitis or Crohn's disease],&#xD;
             diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus,&#xD;
             Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'&#xD;
             disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). (See section 4.2 for&#xD;
             details and exceptions.)&#xD;
&#xD;
         10. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.&#xD;
&#xD;
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone&#xD;
             replacement therapy) is acceptable.&#xD;
&#xD;
         11. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of&#xD;
             radiation within 4 weeks of the first dose of study drug.&#xD;
&#xD;
         12. Major surgical procedure (as defined by the Investigator) within 28 days prior to the&#xD;
             first dose of IP. Note: Local surgery of isolated lesions for palliative intent or&#xD;
             other minor procedures are acceptable.&#xD;
&#xD;
         13. History of allogenic organ transplantation.&#xD;
&#xD;
         14. Uncontrolled intercurrent illness, including but not limited to, uncontrolled ongoing&#xD;
             or active infection (including viral emergent infections), symptomatic congestive&#xD;
             heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled&#xD;
             cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal&#xD;
             conditions associated with diarrhea, or psychiatric illness/social situations that&#xD;
             would limit compliance with study requirement, substantially increase risk of&#xD;
             incurring AEs or compromise the ability of the patient to give written informed&#xD;
             consent. Exception: patients who are finalizing their antibiotic treatment (for&#xD;
             example 3 days left of a total of 7 or 10) for a respiratory tract infection are&#xD;
             allowed to be included.&#xD;
&#xD;
         15. History of leptomeningeal carcinomatosis&#xD;
&#xD;
         16. Has untreated central nervous system (CNS) metastases identified either on the&#xD;
             baseline brain imaging obtained during the screening period or identified prior to&#xD;
             signing the ICF. Patients whose brain metastases have been treated may participate&#xD;
             provided they show radiographic stability (defined as 2 brain images, both of which&#xD;
             are obtained after treatment to the brain metastases. These imaging scans should both&#xD;
             be obtained at least four weeks apart and show no evidence of intracranial&#xD;
             progression). In addition, any neurologic symptoms that developed either as a result&#xD;
             of the brain metastases or their treatment must have resolved or be stable either,&#xD;
             without the use of steroids, or with stable doses of anticonvulsants and/or steroids.&#xD;
             Steroid dose must be ≤10mg/day of prednisone or its equivalent (and anticonvulsants)&#xD;
             for at least 14 days prior to the start of treatment.&#xD;
&#xD;
         17. Has a history of primary immunodeficiency&#xD;
&#xD;
         18. Active infection including tuberculosis (clinical evaluation that includes clinical&#xD;
             history, physical examination and radiographic findings, and TB testing in line with&#xD;
             local practice), hepatitis B (positive HBV surface antigen (HBsAg) result), hepatitis&#xD;
             C (positive HCV RNA), or human immunodeficiency virus (positive HIV 1/2 antibodies).&#xD;
             Patients with a past or resolved HBV infection (defined as the presence of hepatitis B&#xD;
             core antibody [HBcAb] and absence of HBsAg) are eligible. HBV DNA must be obtained in&#xD;
             these patients prior to treatment. HBV carriers of those patients requiring antiviral&#xD;
             therapy treatment of hepatitis B virus or Hepatitis C are not eligible to participate.&#xD;
             Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain&#xD;
             reaction is negative for HCV RNA. Patients with past or resolved tuberculosis are&#xD;
             eligible.&#xD;
&#xD;
         19. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:&#xD;
             Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to&#xD;
             30 days after the last dose of IP.&#xD;
&#xD;
         20. Female patients who are pregnant or breastfeeding or male or female patients of&#xD;
             reproductive potential who are not willing to employ effective birth control&#xD;
             (according to the HMA CTFG guidelance) from screening to 90 days after the last dose&#xD;
             of durvalumab.&#xD;
&#xD;
         21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug&#xD;
             excipients.&#xD;
&#xD;
         22. Viral syndrome diagnosed during the two weeks before inclusion&#xD;
&#xD;
         23. Patients receiving full-dose anticoagulant/antiplatelet therapy.&#xD;
&#xD;
         24. Patients with Li Fraumeni syndrome or with previous known retinoblastoma protein&#xD;
             pathway germinal deficiency.&#xD;
&#xD;
         25. Judgment by the investigator that the patient is unsuitable to participate in the&#xD;
             study and the patient is unlikely to comply with study procedures, restrictions and&#xD;
             requirements.&#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>Institut Català D'Oncologia</name>
      <address>
        <city>Hospitalet de Llobregat</city>
        <state>Barcelona</state>
        <zip>08908</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari Vall D'Hebron</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>November 9, 2018</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 10, 2019</study_first_posted>
  <last_update_submitted>March 25, 2022</last_update_submitted>
  <last_update_submitted_qc>March 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 28, 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, Squamous Cell</mesh_term>
    <mesh_term>Head and Neck Neoplasms</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03799744
org study id: ICO-VCN-H&N-2018
secondary id: 2018-001095-38
nct id: NCT03799744
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a Phase I Study to Evaluate the Safety, Tolerability, and Efficacy of VCN-01 in
      Combination With Durvalumab (MEDI4736) in Subjects With Recurrent/Metastatic Squamous Cell
      Carcinoma of the Head and Neck.

      VCN-01 is a genetically modified oncolytic adenovirus characterized by the presence of four
      independent genetic modifications on the backbone of the wild-type HAd5 adenovirus genome,
      encoding human PH20, that confer tumor selectivity and anti-tumor activity.

      Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa
      subclass that inhibits binding of PD-L1.

      The proposed mechanism of action (MOA) for durvalumab is interference in the interaction of
      PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases
      the inhibition of immune responses, including those that may result in tumor elimination.
-  Research Hypothesis The presence of VCN-01 into the tumor after systemic administration
           will help to overcome the observed resistance to durvalumab and other PD1/PD-L1
           checkpoint inhibitors.

        -  Primary objectives To evaluate the safety and tolerability of a single intravenous
           injection of VCN-01 combined with durvalumab in two administration regimens (concomitant
           or durvalumab starting two weeks later "sequential schedule"), and to determine the
           recommended phase II dose (RP2D) of the combination.

        -  Study design This is a phase I trial, multicenter, open label, and dose escalation
           study. Patients will be entered at each dose level, according to a planned dose
           escalation schedule. Absence of unacceptable toxicity at the previous dose is required
           for entering a patient in the subsequent level.

        -  Number of Centers: up to 3

        -  Number of Patients: 15-20 patients

        -  Study Population: Patients with metastatic squamous cell carcinoma of the head and neck
           who have progressed during or after treatment with immune-checkpoint inhibitors.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: This is a phase I trial, multicenter, open label, and dose escalation study. Patients will be entered at each dose level, according to a planned dose escalation schedule. Absence of unacceptable toxicity at the previous dose is required for entering a patient in the subsequent level.
The investigational treatment will be a single i.v. VCN-01 dose combined with concomitant i.v. durvalumab (MEDI4736) 1500 mg Q4W (Arm I) or durvalumab starting two weeks after VCN-01 administration, "sequential schedule" (Arm II). Patient recruitment in Arm I and Arm II will be performed in parallel based on slot availability. Only one single dose of VCN-01 will be administered to each patient during the trial. Durvalumab will be administered Q4W until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion.
primary purpose: Treatment
masking: None (Open Label)
measure: Safety by means of Adverse Events (AEs)
time frame: through study completion, an average of 2 years
description: Incidence of Adverse Events as assessed by CTCAE v4.0
measure: Objective response rate (ORR)
time frame: On Cycle 3 (+/- 3 days, each cycle is 28 days), and then every 2 cycles (± 7 days) until disease progression or withdrawal (an average of 2 years)
description: Proportion of patients with reduction in tumor burden of a predefined amount assessed by CT or MRI
measure: Progression Free Survival (PFS)
time frame: On Cycle 3 (+/- 3 days, each cycle is 28 days), and then every 2 cycles (± 7 days) until disease progression or withdrawal (an average of 2 years)
description: Time from study enrollment until disease progression or death assessed by CT or MRI
measure: Maximum Plasma Concentration (Cmax ) of VCN-01
time frame: For both arms: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1, 2, 4, 6, 24 and 48 hours post VCN-01 administration.
description: The maximum (or peak) concentration that VCN-01 achieves in plasma after its administration.
measure: Tmax of VCN-01
time frame: VCN-01 and Durvalumab concomitant arm: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, 24 hours and 48 hours post VCN-01 administration. VCN-01 and Durvalumab sequential: On day 1
description: Time to Maximum Plasma Concentration of VCN-01
measure: AUC of VCN-01
time frame: VCN-01 and Durvalumab concomitant arm: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, 24 hours and 48 hours post VCN-01 administration. VCN-01 and Durvalumab sequential: On day 1
description: The definite integral in a plot of drug concentration in blood plasma vs. time.
measure: Apparent Half-Life (t1/2) of VCN-01
time frame: VCN-01 and Durvalumab concomitant arm: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, 24 hours and 48 hours post VCN-01 administration. VCN-01 and Durvalumab sequential: On day 1
description: The time it takes for half to be removed
measure: Elimination rate constant of VCN-01
time frame: VCN-01 and Durvalumab concomitant arm: On day 1 pre-dose (within 15 minutes prior to VCN-01 infusion) and then 30 minutes, 1 hours, 2 hours, 4 hours, 6 hours, 24 hours and 48 hours post VCN-01 administration. VCN-01 and Durvalumab sequential: On day 1
description: The rate at which VCN-01 is removed from the body.
measure: VCN-01 viral shedding in blood
time frame: VCN-01 and Durvalumab concomitant arm: On day 1: pre-dose and then, 4 hours, 24 hours and 48 hours post dose, on day 8, day 15, day 22 of cycle 1 (each cycle is 28 days), then on day1 of subsequent durvalumab cycles and at the final visit. Arm II: On day
description: Determination of VCN-01 levels in peripheral blood samples
measure: anti-VCN-01 antibodies
time frame: At screening, on day 1 pre-dose (within 15 minutes prior to VCN-01 ) in both arms. In concomitant arm: at day1 of subsequent durvalumab cycles (each cycle is 28 days), and at the final visit. In sequential arm: at day15 on cycle 1, at day1 of subsequent
description: Assessment of Blood levels of neutralizing anti-VCN-01 antibodies
measure: VCN-01 viral shedding in stool and sputum
time frame: VCN-01 and Durvalumab concomitant arm: at day 1, 8, 15 and 22 on cycle 1 (each cycle is 28 days) And at day1 of subsequent durvalumab cycles. VCN-01 and Durvalumab sequential: at day -14, -7, 1, 8, 15 on cycle 1 and at day 1 of subsequent durvalumab
description: Determination of VCN-01 levels in stool and sputum
measure: Immunological changes induced by the combination of VCN-01 and durvalumab.
time frame: VCN-01 and Durvalumab concomitant arm: On day 1: pre-dose, at 30 minutes, 6 hours, 24 hours, 48 hours, at day 8 on cycle 1 (each cycle is 28 days), at day 1of cycle 2 and at the final visit. VCN-01 and Durvalumab sequential: On day 1, 15 minutes before
description: Study of the Immunological changes induced by the combination of VCN-01 and durvalumab by assessment of blood levels of circulating Interleukin 6 and Interleukin 10
measure: Changes in Microbiome in stool (VCN-01 and Durvalumab concomitant arm)
time frame: On day 1: pre-dose and 1st deposition after-dose (the first deposition occurred from day 1 to day 7), day 8, day 15, day 22 on cycle 1 (each cycle is 28 days).
description: Analyse the microbiome in stool, prior and after VCN-01 administration
measure: Changes in Microbiome in stool (VCN-01 and Durvalumab sequential)
time frame: On day -14 (pre-dose and 1st deposition after-dose), day -7, Day 1, day 8 and day15 on cycle 1 (each cycle is 28 days).
description: Analyse the microbiome in stool, prior and after VCN-01 administration
measure: Circulating free DNA (cfDNA) in plasma analysis (VCN-01 and Durvalumab concomitant arm)
time frame: Pre-dose on day 1 (within 15min prior to VCN-01 infusion) and at day 8 on cycle 1, at day 1 on cycle 2, at day 1 on cycle 3 and at day 1 on cycle 4 (within 15min prior durvalumab administration) (each cycle is 28 days).
description: To analyse the circulating free DNA (cfDNA) in plasma obtained from samples collected prior and post VCN-01 treatment.
measure: Circulating free DNA (cfDNA) in plasma analysis (VCN-01 and Durvalumab sequential)
time frame: On day -14 pre-dose and 1st deposition after-dose(the first deposition occurred from day -14 to day -8), day -7, day 1, day 8 and day15 on cycle 1 (each cycle is 28 days).
description: To analyse the circulating free DNA (cfDNA) in plasma obtained from samples collected prior and post VCN-01 treatment.
arm group label: VCN-01 and Durvalumab; concomitant.
arm group type: Experimental
description: Combination VCN-01 (single iv dose) with Durvalumab, Concomitant schedule; Dose Escalation of VCN-01
arm group label: VCN-01 and Durvalumab; sequential
arm group type: Experimental
description: Combination VCN-01 (single iv dose) with Durvalumab, Delayed schedule (14 days); Dose Escalation of VCN-01
intervention type: Genetic
intervention name: VCN-01
description: Dose level 1: 3.3x10^12 viral particles/patient and Dose level 2: 1x10^13 viral particles/patient
arm group label: VCN-01 and Durvalumab; concomitant.
arm group label: VCN-01 and Durvalumab; sequential
intervention type: Biological
intervention name: Durvalumab
description: Dose: 1500 mg Q4W
arm group label: VCN-01 and Durvalumab; concomitant.
arm group label: VCN-01 and Durvalumab; sequential
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Head and Neck Neoplasms
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Recurrence
mesh term: Durvalumab