<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/NCT03294486</url>
  </required_header>
  <id_info>
    <org_study_id>P150936</org_study_id>
    <secondary_id>2015-004452-21</secondary_id>
    <nct_id>NCT03294486</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of the ONCOlytic VIRus Armed for Local Chemotherapy, TG6002/5-FC, in Recurrent Glioblastoma Patients</brief_title>
  <acronym>ONCOVIRAC</acronym>
  <official_title>Safety and Efficacy of the ONCOlytic VIRus Armed for Local Chemotherapy, TG6002/5-FC, in Recurrent Glioblastoma Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Transgene</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Glioblastoma is the most common and the most aggressive primary brain cancer in adults.&#xD;
      Indeed, despite very intensive treatments (i.e. maximal safe surgery, radiotherapy and&#xD;
      several lines of cytotoxic chemotherapies), inducing significant adverse events, the&#xD;
      prognosis of glioblastoma patients remains dismal with a median overall survival of ~15&#xD;
      months. Therefore, more efficient and less toxic therapies are urgently needed to improve&#xD;
      survival and quality of life of glioblastoma patients.&#xD;
&#xD;
      The oncolytic virus TG6002 has shown efficacy and good safety profile in several preclinical&#xD;
      models of glioblastoma in vitro (i.e. cell line) and in vivo (i.e. xenografts in Swiss/Nude&#xD;
      mice). Comprehensive toxicology studies of TG6002/Flucytosine have been completed in rabbits&#xD;
      and monkeys supporting safety investigations of TG6002/Flucytosine in human patients.&#xD;
&#xD;
      Taken these data all together, TG6002/Flucytosine appears as a very promising therapeutic&#xD;
      strategy in glioblastoma patients that merits consideration for early phase clinical trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Phase 1:&#xD;
&#xD;
      This is a Phase 1, open-label, dose-escalation trial using an accelerated titration 3+3&#xD;
      design in patients with recurrent glioblastoma. Eligible patients will first be consecutively&#xD;
      enrolled in a one-patient cohort at lowest dose level and then in 3-patients cohorts up to a&#xD;
      DLT observation. In case a DLT is observed specific rules apply to enrol additional (from 3&#xD;
      to 5) patients in the same cohort and to proceed to higher doses. All patients within a given&#xD;
      cohort will be treated with the same dose schedule of TG6002, administered as 3 weekly IV&#xD;
      infusions at Days 1, 8, and 15. Following the 1st and 2nd infusion of TG6002 on Day 1 and 8,&#xD;
      patients will be given oral 5-FC for 3 days starting on Day 5 and 12 and ending on Day 7 and&#xD;
      14, respectively. Following the 3rd infusion of TG6002 on Day 15, patients will be given oral&#xD;
      5-FC for 21 days starting on Day 19 and ending on Day 39 (end of treatment). Patients will be&#xD;
      followed until documented tumor progression.&#xD;
&#xD;
      The starting dose of 1 x 105 pfu is determined after toxicology results in the most sensitive&#xD;
      species on which a security factor (100x) has been applied; accelerated titration will&#xD;
      consist in one patient being administered with the starting dose and one-log dose increment&#xD;
      between the three first cohorts.&#xD;
&#xD;
      The maximum tolerated dose (MTD) is defined as the highest TG6002 dose level at which at most&#xD;
      1 Dose-Limiting Toxicity (DLT) is observed in 6 patients exposed to that dose level.. The DLT&#xD;
      period is defined as the interval between the first TG6002 IV infusion (Day 1) and the 8th&#xD;
      day of the 21-day 5-FC treatment occurring on Day 26.&#xD;
&#xD;
      Between consecutive cohorts during dose escalation, an at least 3-week safety interval will&#xD;
      be applied, starting from the completion of the DLT period of the last patient of the&#xD;
      previous cohort (D26), before the infusion of the first patient of the next higher dose&#xD;
      cohort (D47). The initiation of the next higher dose cohort will be determined following an&#xD;
      analysis by the DSMB of the safety results from one cycle of TG6002 treatment in combination&#xD;
      with 5-FC.&#xD;
&#xD;
      Phase 2a:&#xD;
&#xD;
      Based on the outcome of the Phase 1 dose-escalation cohorts, i.e. RP2D, the Phase 2a will&#xD;
      include 24 patients. Patients will be treated IV at the RP2D.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 12, 2017</start_date>
  <completion_date type="Anticipated">September 2021</completion_date>
  <primary_completion_date type="Anticipated">May 2019</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Phase 1 :&#xD;
Dose-escalation trial using an accelerated titration 3+3 design. Eligible patients will first be consecutively enrolled in a one-patient cohort at lowest dose level and then in 3-patients cohorts up to a DLT observation. All patients within a given cohort will be treated with the same dose schedule of TG6002. Following the 1st and 2nd infusion of TG6002 patients will be given oral 5-FC for 3 days starting on Day 5 and 12 and ending on Day 7 and 14, respectively. Following the 3rd infusion of TG6002 on Day 15, patients will be given oral 5-FC for 21 days starting on Day 19 and ending on Day 39 (end of treatment).&#xD;
Phase 2a Patients will be treated IV at the Recommended Phase 2 dose (RP2D).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participant with Dose Limiting Toxicities defined as Any of the following treatment-related adverse events (AEs) is evaluated and reported from Day 1 through Day 26; as assessed by NCI-CTCAE, version 4.03</measure>
    <time_frame>Through day 1 to day 26</time_frame>
    <description>For Phase 1&#xD;
Assessment of safety and tolerability :&#xD;
Number of Participant with Dose Limiting Toxicities defined as Any of the following treatment-related adverse events (AEs) is evaluated and reported from Day 1 through Day 26; as assessed by NCI-CTCAE, version 4.03:&#xD;
Any Grade 4 toxicity (except isolated Grade 4 lymphopenia lasting ≤ 7 days);&#xD;
Grade 3 or 4 hypotension, disseminated intravascular coagulation (DIC), or allergic reaction/hypersensitivity;&#xD;
Grade 3 skin lesions: ulcerative dermatitis or skin changes with pain interfering with function;&#xD;
Number of skin lesions ≥ 10 corresponding to infection possibly or probably related to the administration of TG6002;&#xD;
Grade 3 non-hematologic toxicity persisting for &gt;7 days except increase in ASAT and/or ALAT (&gt; 5x ULN), which may last &gt;7 days if total bilirubin is normal or Grade 1;&#xD;
Flu-like symptoms that do not respond to standard treatments;&#xD;
Grade 3 hematologic toxicity persisting for &gt; 7 days</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of patients without documented tumor progression at 6 months from date of first TG6002 infusion according to Response Assessment Neuro-Oncology Criteria (Wen et al., 2010, JCO, PMID:20231676)</measure>
    <time_frame>at 6 months according to RANO criteria</time_frame>
    <description>For Phase 2a Number of patients without documented tumor progression at 6 months from date of first TG6002 infusion according to Response Assessment Neuro-Oncology Criteria (Wen et al., 2010, JCO, PMID:20231676)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>TG6002 recommended dose prior to the Phase 2a part of the study (RP2D) in combination with 5-FC (Maximum Plasma Concentration [Cmax])</measure>
    <time_frame>through study completion an average of 24 months</time_frame>
    <description>Phase 1 The Recommended Phase 2 Dose (RP2D) is the dose recommended by the DSMB for Phase 2a investigation: the DSMB performed a complete review of the available results about safety and efficacy from the first phase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>through study completion : every 2 months the first year and then every 3 months from day 67 until the date of first documented progression or date of death from any cause wichever came first, assessed up to 51 months</time_frame>
    <description>After the end of the treatment patients will be followed in the neurology department according to standards of care. In case of withdrawal, patients and/or their specified contacts could be contacted for survival and information on possible subsequent anti-cancer therapy and their general safety and efficacy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relative quantification of circulating viral DNA</measure>
    <time_frame>Day1, Day2, Day 15, Day 26</time_frame>
    <description>Relative quantification of circulating viral DNA : Quantification of the viral genome by Quantitative Polymerase Chain Reaction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-FC</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-FC</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Tmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-FC</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of AUC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-FC</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of CI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-FC</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of MRT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-FC</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Vd/F</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-Fluorouraril (5-FU)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-Fluorouraril (5-FU)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Tmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-Fluorouraril (5-FU)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of AUC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-Fluorouraril (5-FU)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of CI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-Fluorouraril (5-FU)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of MRT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of 5-Fluorouraril (5-FU)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Vd/F</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of AUC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Tmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of CI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of MRT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)</measure>
    <time_frame>Day0, Day7, Day 14, Day 26</time_frame>
    <description>Measurement of Vd/F</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Viral shedding in saliva, urine and feces</measure>
    <time_frame>Day2, Day7</time_frame>
    <description>by Quantitative Polymerase Chain Reaction and plaque assays (if q-PCR positive)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Humoral response</measure>
    <time_frame>Baseline, Day 39</time_frame>
    <description>Measurement of Blood anti-vaccinia virus and anti-FCU1 antibodies in blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Isolation of peripheral blood mononuclear cells (PBMC);</measure>
    <time_frame>Day 0, Day 26, Day 39</time_frame>
    <description>Determine immunoprofile, potential predictive marker of efficacy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolic Response</measure>
    <time_frame>Baseline, Day 39, Day 67</time_frame>
    <description>using PET-MRI ([18F]FDOPA -PET scans)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability : Incidence of Treatment; evaluation of treatement-releated adverse events</measure>
    <time_frame>through study completion an average of 51 months</time_frame>
    <description>Complete review of serious and unserious adverse events</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">78</enrollment>
  <condition>Glioblastoma</condition>
  <condition>Brain Cancer</condition>
  <arm_group>
    <arm_group_label>Combination of TG6002 and flucytosine (5-FC, Ancotil®)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients within a given cohort will be treated with the same dose schedule of TG6002, administred as 3 weekly IV infusions at days 1, 8 and 15. following the 1st and 2nd infusions of TG6002, patients will be given oral 5-FC for 3 days starting on day 5 and 12 . following the 3rd infusion, patients will be given oral 5-FC for 21 days starting on day 19.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Combination of TG6002 and 5-flucytosine (5-FC, Ancotil®)</intervention_name>
    <description>Phase 1, TG6002 administered in a total volume of 250mL of saline solution (0.9 %) as three intravenous infusions at the following doses:&#xD;
Dose 1 : 5.0 log10 pfu •Dose 2 : 6.0 log10 pfu •Dose 3 : 7.0 log10 pfu •Dose 4 : 7.5 log10 pfu&#xD;
Dose 5 : 8.0 log10 pfu •Dose 6 : 8.5 log10 pfu Additional dose levels •Dose 2-1 : 5.5 log10 pfu •Dose 3-2 : 6.5 log10 pfu Phase 2a, treatment IV at the recommended Phase 2 dose 5-Flucytosine (5-FC) is provided in its commercial packaging with brand name ANCOTIL 500 mg, tablet (Ancotil®) marketed by MEDA Pharma: polypropylene tube containing 100 tablets.&#xD;
5-FC administered orally as 500 mg tablets taken 4 times per day (qid). Daily starting dose is 200 mg/kg. The daily dose will be adjusted at Day 19 following the measurement of 5-FC plasma concentration at steady state (Day 7), which should be kept below 100 mg/L.</description>
    <arm_group_label>Combination of TG6002 and flucytosine (5-FC, Ancotil®)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &gt; 18 years.&#xD;
&#xD;
          2. Karnofsky performance status ≥ 70.&#xD;
&#xD;
          3. Histologically confirmed primary glioblastoma with unequivocal progression after at&#xD;
             least the first line standard of care (concurrent chemoradiotherapy and adjuvant&#xD;
             chemotherapy) at least 3 months after the completion of radiotherapy.&#xD;
&#xD;
          4. At least one measurable lesion, according to RANO criteria.&#xD;
&#xD;
          5. Availability of biological material (tumor) for review processes.&#xD;
&#xD;
          6. No treatment with another investigational drug within 4 weeks before inclusion.&#xD;
&#xD;
          7. No surgery within 4 weeks before inclusion.&#xD;
&#xD;
          8. If reoperation is conducted an early post-surgery MRI, within 48 hours is needed.&#xD;
&#xD;
          9. Standard-of-Care MRI showing a target lesion performed within 2 weeks prior to&#xD;
             inclusion.&#xD;
&#xD;
         10. Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.&#xD;
&#xD;
         11. Non-enzyme inducing antiepileptic drugs (non-EIAED). Patients previously on EIAED must&#xD;
             be switched to non-EIAED at least 2 weeks prior to inclusion.&#xD;
&#xD;
         12. No previous cancer except: (i) cancer in remission for at least 5 years, (ii) skin&#xD;
             carcinoma, or (iii) in situ carcinoma of the uterine cervix.&#xD;
&#xD;
         13. Absence of any unstable disease (heart, liver, renal and respiratory failure).&#xD;
&#xD;
         14. Absence of serious conditions (as judged by the investigator) that could interfere&#xD;
             with the treatment (i.e. infection, immunosuppression defined as CD4+ lymphocytes &lt;&#xD;
             200/µL).&#xD;
&#xD;
         15. Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/L, platelets ≥ 100 x 109&#xD;
             cells/L and Hb ≥ 10.0 g/dL).&#xD;
&#xD;
         16. Normal liver function: bilirubin &lt; 1.5 x upper limit of the normal range (ULN),&#xD;
             alkaline phosphatase and transaminases (ASAT, ALAT) &lt; 3 x ULN.&#xD;
&#xD;
         17. Normal renal function: calculated (Cockcroft-Gault) or measured creatinine clearance ≥&#xD;
             60 mL/min.&#xD;
&#xD;
         18. Absence of pregnancy:&#xD;
&#xD;
               -  Women of childbearing potential (WOCBP) must be using an adequate method of&#xD;
                  contraception to avoid pregnancy throughout the study and 6 months beyond stop of&#xD;
                  treatment and must have a negative serum or urine pregnancy test (minimum&#xD;
                  sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the&#xD;
                  start of investigational product;&#xD;
&#xD;
               -  Post menopause is defined as a documented serum follicle stimulating hormone&#xD;
                  (FSH) level ≥ 35 mIU/mL.&#xD;
&#xD;
         19. Females should not be breast feeding.&#xD;
&#xD;
         20. Patients must use a barrier method of contraception (e.g. condom for either male,&#xD;
             female patients or partners of female patients) during TG6002 treatment period and for&#xD;
             a minimum of 6 months following the last treatment with TG6002. In addition, to&#xD;
             minimize the risk of pregnancy, female patients or female partners of male patients&#xD;
             who are of childbearing potential must use an additional effective method of&#xD;
             contraception (e.g. one of the following: hormonal contraception, occlusive cap,&#xD;
             intrauterine device -IUD- or intrauterine system -IUS-, male sterilization, or true&#xD;
             abstinence).&#xD;
&#xD;
         21. Before patient inclusion and study related procedures (that would not have been&#xD;
             performed as part as standard care), written informed consent must be given according&#xD;
             to International Conference on Harmonization-Good Clinical Practices (ICH/GCP), and&#xD;
             national/local regulations.&#xD;
&#xD;
         22. Patient affiliated to social security. 23. Approval of participation, following&#xD;
             discussion with the multidisciplinary board of neuro-oncology, in the best interest of&#xD;
             patient and in absence of any other reasonable therapeutic alternative.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Immunodeficiency:&#xD;
&#xD;
               -  CD4+ lymphocyte count &lt;200/µL, in any case ;&#xD;
&#xD;
               -  HIV infection;&#xD;
&#xD;
               -  Immunosuppressive therapy, including high dose corticosteroids (at a dose ≥ 20 mg&#xD;
                  per day of prednisone or equivalent, at the inclusion visit).&#xD;
&#xD;
          2. History of severe exfoliative skin condition (e.g. eczema or atopic dermatitis)&#xD;
             requiring systemic therapy for more than 4 weeks within 2 years of TG6002 treatment&#xD;
             initiation.&#xD;
&#xD;
          3. History of a severe systemic reaction or side-effect as a result of a previous&#xD;
             smallpox vaccination, such as systemic vaccinia, eczema vaccinatum, encephalitis,&#xD;
             myocarditis, or pericarditis.&#xD;
&#xD;
          4. Patients with significant gastro-intestinal (GI) tract disease or resection leading to&#xD;
             significant impairment of GI absorption or bacterial overgrowth.&#xD;
&#xD;
          5. Known deficiency in dihydropyrimidine dehydrogenase (DPD).&#xD;
&#xD;
          6. Hypersensitivity to flucytosine.&#xD;
&#xD;
          7. Hypersensitivity to egg proteins.&#xD;
&#xD;
          8. Hypersensitivity to gentamicin.&#xD;
&#xD;
          9. History of severe drug allergy.&#xD;
&#xD;
         10. Received systemic anti-cancer therapy within 4 weeks prior to first administration of&#xD;
             TG6002.&#xD;
&#xD;
         11. Prior gene therapy.&#xD;
&#xD;
         12. Other medical condition or laboratory abnormality or active infection that in the&#xD;
             judgment of the principal investigator may increase the risk associated with study&#xD;
             participation or may interfere with interpretation of study results and /or otherwise&#xD;
             make the patient inappropriate for entry into this study.&#xD;
&#xD;
         13. Patient unable or unwilling to comply with the protocol requirements and/or unwilling&#xD;
             to sign an informed consent form.&#xD;
&#xD;
         14. Patient deprived of liberty or under legal protection measure.&#xD;
&#xD;
         15. Weight &gt; 100kg.&#xD;
&#xD;
         16. Antiviral therapy (as ribavirin)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ahmed IDBAIH, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ahmed IDBAIH, MD</last_name>
    <phone>01 42 16 03 85</phone>
    <email>ahmed.idbaih@aphp.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Groupe Hospitalier Pitié-Salpêtrière</name>
      <address>
        <city>Paris</city>
        <zip>75651</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ahmed IDBAIH, MD</last_name>
      <phone>01 42 16 03 85</phone>
      <email>ahmed.idbaih@aphp.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>November 2017</verification_date>
  <study_first_submitted>August 2, 2017</study_first_submitted>
  <study_first_submitted_qc>September 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <last_update_submitted>November 3, 2017</last_update_submitted>
  <last_update_submitted_qc>November 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 6, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Glioblastoma</keyword>
  <keyword>Oncolytic viruses</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Flucytosine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03294486
org study id: P150936
secondary id: 2015-004452-21
nct id: NCT03294486
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Glioblastoma is the most common and the most aggressive primary brain cancer in adults.
      Indeed, despite very intensive treatments (i.e. maximal safe surgery, radiotherapy and
      several lines of cytotoxic chemotherapies), inducing significant adverse events, the
      prognosis of glioblastoma patients remains dismal with a median overall survival of ~15
      months. Therefore, more efficient and less toxic therapies are urgently needed to improve
      survival and quality of life of glioblastoma patients.

      The oncolytic virus TG6002 has shown efficacy and good safety profile in several preclinical
      models of glioblastoma in vitro (i.e. cell line) and in vivo (i.e. xenografts in Swiss/Nude
      mice). Comprehensive toxicology studies of TG6002/Flucytosine have been completed in rabbits
      and monkeys supporting safety investigations of TG6002/Flucytosine in human patients.

      Taken these data all together, TG6002/Flucytosine appears as a very promising therapeutic
      strategy in glioblastoma patients that merits consideration for early phase clinical trial.
Phase 1:

      This is a Phase 1, open-label, dose-escalation trial using an accelerated titration 3+3
      design in patients with recurrent glioblastoma. Eligible patients will first be consecutively
      enrolled in a one-patient cohort at lowest dose level and then in 3-patients cohorts up to a
      DLT observation. In case a DLT is observed specific rules apply to enrol additional (from 3
      to 5) patients in the same cohort and to proceed to higher doses. All patients within a given
      cohort will be treated with the same dose schedule of TG6002, administered as 3 weekly IV
      infusions at Days 1, 8, and 15. Following the 1st and 2nd infusion of TG6002 on Day 1 and 8,
      patients will be given oral 5-FC for 3 days starting on Day 5 and 12 and ending on Day 7 and
      14, respectively. Following the 3rd infusion of TG6002 on Day 15, patients will be given oral
      5-FC for 21 days starting on Day 19 and ending on Day 39 (end of treatment). Patients will be
      followed until documented tumor progression.

      The starting dose of 1 x 105 pfu is determined after toxicology results in the most sensitive
      species on which a security factor (100x) has been applied; accelerated titration will
      consist in one patient being administered with the starting dose and one-log dose increment
      between the three first cohorts.

      The maximum tolerated dose (MTD) is defined as the highest TG6002 dose level at which at most
      1 Dose-Limiting Toxicity (DLT) is observed in 6 patients exposed to that dose level.. The DLT
      period is defined as the interval between the first TG6002 IV infusion (Day 1) and the 8th
      day of the 21-day 5-FC treatment occurring on Day 26.

      Between consecutive cohorts during dose escalation, an at least 3-week safety interval will
      be applied, starting from the completion of the DLT period of the last patient of the
      previous cohort (D26), before the infusion of the first patient of the next higher dose
      cohort (D47). The initiation of the next higher dose cohort will be determined following an
      analysis by the DSMB of the safety results from one cycle of TG6002 treatment in combination
      with 5-FC.

      Phase 2a:

      Based on the outcome of the Phase 1 dose-escalation cohorts, i.e. RP2D, the Phase 2a will
      include 24 patients. Patients will be treated IV at the RP2D.
intervention model: Sequential Assignment
intervention model description: Phase 1 :
Dose-escalation trial using an accelerated titration 3+3 design. Eligible patients will first be consecutively enrolled in a one-patient cohort at lowest dose level and then in 3-patients cohorts up to a DLT observation. All patients within a given cohort will be treated with the same dose schedule of TG6002. Following the 1st and 2nd infusion of TG6002 patients will be given oral 5-FC for 3 days starting on Day 5 and 12 and ending on Day 7 and 14, respectively. Following the 3rd infusion of TG6002 on Day 15, patients will be given oral 5-FC for 21 days starting on Day 19 and ending on Day 39 (end of treatment).
Phase 2a Patients will be treated IV at the Recommended Phase 2 dose (RP2D).
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participant with Dose Limiting Toxicities defined as Any of the following treatment-related adverse events (AEs) is evaluated and reported from Day 1 through Day 26; as assessed by NCI-CTCAE, version 4.03
time frame: Through day 1 to day 26
description: For Phase 1
Assessment of safety and tolerability :
Number of Participant with Dose Limiting Toxicities defined as Any of the following treatment-related adverse events (AEs) is evaluated and reported from Day 1 through Day 26; as assessed by NCI-CTCAE, version 4.03:
Any Grade 4 toxicity (except isolated Grade 4 lymphopenia lasting ≤ 7 days);
Grade 3 or 4 hypotension, disseminated intravascular coagulation (DIC), or allergic reaction/hypersensitivity;
Grade 3 skin lesions: ulcerative dermatitis or skin changes with pain interfering with function;
Number of skin lesions ≥ 10 corresponding to infection possibly or probably related to the administration of TG6002;
Grade 3 non-hematologic toxicity persisting for >7 days except increase in ASAT and/or ALAT (> 5x ULN), which may last >7 days if total bilirubin is normal or Grade 1;
Flu-like symptoms that do not respond to standard treatments;
Grade 3 hematologic toxicity persisting for > 7 days
measure: Number of patients without documented tumor progression at 6 months from date of first TG6002 infusion according to Response Assessment Neuro-Oncology Criteria (Wen et al., 2010, JCO, PMID:20231676)
time frame: at 6 months according to RANO criteria
description: For Phase 2a Number of patients without documented tumor progression at 6 months from date of first TG6002 infusion according to Response Assessment Neuro-Oncology Criteria (Wen et al., 2010, JCO, PMID:20231676)
measure: TG6002 recommended dose prior to the Phase 2a part of the study (RP2D) in combination with 5-FC (Maximum Plasma Concentration [Cmax])
time frame: through study completion an average of 24 months
description: Phase 1 The Recommended Phase 2 Dose (RP2D) is the dose recommended by the DSMB for Phase 2a investigation: the DSMB performed a complete review of the available results about safety and efficacy from the first phase
measure: Overall Survival (OS)
time frame: through study completion : every 2 months the first year and then every 3 months from day 67 until the date of first documented progression or date of death from any cause wichever came first, assessed up to 51 months
description: After the end of the treatment patients will be followed in the neurology department according to standards of care. In case of withdrawal, patients and/or their specified contacts could be contacted for survival and information on possible subsequent anti-cancer therapy and their general safety and efficacy
measure: Relative quantification of circulating viral DNA
time frame: Day1, Day2, Day 15, Day 26
description: Relative quantification of circulating viral DNA : Quantification of the viral genome by Quantitative Polymerase Chain Reaction
measure: Blood pharmacokinetics of 5-FC
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Cmax
measure: Blood pharmacokinetics of 5-FC
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Tmax
measure: Blood pharmacokinetics of 5-FC
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of AUC
measure: Blood pharmacokinetics of 5-FC
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of CI
measure: Blood pharmacokinetics of 5-FC
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of MRT
measure: Blood pharmacokinetics of 5-FC
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Vd/F
measure: Blood pharmacokinetics of 5-Fluorouraril (5-FU)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Cmax
measure: Blood pharmacokinetics of 5-Fluorouraril (5-FU)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Tmax
measure: Blood pharmacokinetics of 5-Fluorouraril (5-FU)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of AUC
measure: Blood pharmacokinetics of 5-Fluorouraril (5-FU)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of CI
measure: Blood pharmacokinetics of 5-Fluorouraril (5-FU)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of MRT
measure: Blood pharmacokinetics of 5-Fluorouraril (5-FU)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Vd/F
measure: Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Cmax
measure: Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of AUC
measure: Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Tmax
measure: Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of CI
measure: Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of MRT
measure: Blood pharmacokinetics of final metabolite a-fluoro-B-alanine(FBAL)
time frame: Day0, Day7, Day 14, Day 26
description: Measurement of Vd/F
measure: Viral shedding in saliva, urine and feces
time frame: Day2, Day7
description: by Quantitative Polymerase Chain Reaction and plaque assays (if q-PCR positive)
measure: Humoral response
time frame: Baseline, Day 39
description: Measurement of Blood anti-vaccinia virus and anti-FCU1 antibodies in blood
measure: Isolation of peripheral blood mononuclear cells (PBMC);
time frame: Day 0, Day 26, Day 39
description: Determine immunoprofile, potential predictive marker of efficacy
measure: Metabolic Response
time frame: Baseline, Day 39, Day 67
description: using PET-MRI ([18F]FDOPA -PET scans)
measure: Safety and tolerability : Incidence of Treatment; evaluation of treatement-releated adverse events
time frame: through study completion an average of 51 months
description: Complete review of serious and unserious adverse events
arm group label: Combination of TG6002 and flucytosine (5-FC, Ancotil®)
arm group type: Experimental
description: All patients within a given cohort will be treated with the same dose schedule of TG6002, administred as 3 weekly IV infusions at days 1, 8 and 15. following the 1st and 2nd infusions of TG6002, patients will be given oral 5-FC for 3 days starting on day 5 and 12 . following the 3rd infusion, patients will be given oral 5-FC for 21 days starting on day 19.
intervention type: Drug
intervention name: Combination of TG6002 and 5-flucytosine (5-FC, Ancotil®)
description: Phase 1, TG6002 administered in a total volume of 250mL of saline solution (0.9 %) as three intravenous infusions at the following doses:
Dose 1 : 5.0 log10 pfu •Dose 2 : 6.0 log10 pfu •Dose 3 : 7.0 log10 pfu •Dose 4 : 7.5 log10 pfu
Dose 5 : 8.0 log10 pfu •Dose 6 : 8.5 log10 pfu Additional dose levels •Dose 2-1 : 5.5 log10 pfu •Dose 3-2 : 6.5 log10 pfu Phase 2a, treatment IV at the recommended Phase 2 dose 5-Flucytosine (5-FC) is provided in its commercial packaging with brand name ANCOTIL 500 mg, tablet (Ancotil®) marketed by MEDA Pharma: polypropylene tube containing 100 tablets.
5-FC administered orally as 500 mg tablets taken 4 times per day (qid). Daily starting dose is 200 mg/kg. The daily dose will be adjusted at Day 19 following the measurement of 5-FC plasma concentration at steady state (Day 7), which should be kept below 100 mg/L.
arm group label: Combination of TG6002 and flucytosine (5-FC, Ancotil®)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ahmed IDBAIH, MD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Ahmed IDBAIH, MD
phone: 01 42 16 03 85
email: ahmed.idbaih@aphp.fr
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Brain Neoplasms
mesh term: Flucytosine
sharing ipd: Undecided