Safety and Efficacy of the ONCOlytic VIRus Armed for Local Chemotherapy, TG6002/5-FC, in Recurrent Glioblastoma Patients

Inclusion Criteria: 1. Age \> 18 years. 2. Karnofsky performance status ≥ 70. 3. Histologically confirmed primary glioblastoma with unequivocal progression after at least the first line standard of care (concurrent chemoradiotherapy and adjuvant chemotherapy) at least 3 months after the completion of radiotherapy. 4. At least one measurable lesion, according to RANO criteria. 5. Availability of biological material (tumor) for review processes. 6. No treatment with another investigational drug within 4 weeks before inclusion. 7. No surgery within 4 weeks before inclusion. 8. If reoperation is conducted an early post-surgery MRI, within 48 hours is needed. 9. Standard-of-Care MRI showing a target lesion performed within 2 weeks prior to inclusion. 10. Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan. 11. Non-enzyme inducing antiepileptic drugs (non-EIAED). Patients previously on EIAED must be switched to non-EIAED at least 2 weeks prior to inclusion. 12. No previous cancer except: (i) cancer in remission for at least 5 years, (ii) skin carcinoma, or (iii) in situ carcinoma of the uterine cervix. 13. Absence of any unstable disease (heart, liver, renal and respiratory failure). 14. Absence of serious conditions (as judged by the investigator) that could interfere with the treatment (i.e. infection, immunosuppression defined as CD4+ lymphocytes \< 200/µL). 15. Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/L, platelets ≥ 100 x 109 cells/L and Hb ≥ 10.0 g/dL). 16. Normal liver function: bilirubin \< 1.5 x upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT, ALAT) \< 3 x ULN. 17. Normal renal function: calculated (Cockcroft-Gault) or measured creatinine clearance ≥ 60 mL/min. 18. Absence of pregnancy: * Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and 6 months beyond stop of treatment and must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product; * Post menopause is defined as a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL. 19. Females should not be breast feeding. 20. Patients must use a barrier method of contraception (e.g. condom for either male, female patients or partners of female patients) during TG6002 treatment period and for a minimum of 6 months following the last treatment with TG6002. In addition, to minimize the risk of pregnancy, female patients or female partners of male patients who are of childbearing potential must use an additional effective method of contraception (e.g. one of the following: hormonal contraception, occlusive cap, intrauterine device -IUD- or intrauterine system -IUS-, male sterilization, or true abstinence). 21. Before patient inclusion and study related procedures (that would not have been performed as part as standard care), written informed consent must be given according to International Conference on Harmonization-Good Clinical Practices (ICH/GCP), and national/local regulations. 22. Patient affiliated to social security. 23. Approval of participation, following discussion with the multidisciplinary board of neuro-oncology, in the best interest of patient and in absence of any other reasonable therapeutic alternative. Exclusion Criteria: 1. Immunodeficiency: * CD4+ lymphocyte count \<200/µL, in any case ; * HIV infection; * Immunosuppressive therapy, including high dose corticosteroids (at a dose ≥ 20 mg per day of prednisone or equivalent, at the inclusion visit). 2. History of severe exfoliative skin condition (e.g. eczema or atopic dermatitis) requiring systemic therapy for more than 4 weeks within 2 years of TG6002 treatment initiation. 3. History of a severe systemic reaction or side-effect as a result of a previous smallpox vaccination, such as systemic vaccinia, eczema vaccinatum, encephalitis, myocarditis, or pericarditis. 4. Patients with significant gastro-intestinal (GI) tract disease or resection leading to significant impairment of GI absorption or bacterial overgrowth. 5. Known deficiency in dihydropyrimidine dehydrogenase (DPD). 6. Hypersensitivity to flucytosine. 7. Hypersensitivity to egg proteins. 8. Hypersensitivity to gentamicin. 9. History of severe drug allergy. 10. Received systemic anti-cancer therapy within 4 weeks prior to first administration of TG6002. 11. Prior gene therapy. 12. Other medical condition or laboratory abnormality or active infection that in the judgment of the principal investigator may increase the risk associated with study participation or may interfere with interpretation of study results and /or otherwise make the patient inappropriate for entry into this study. 13. Patient unable or unwilling to comply with the protocol requirements and/or unwilling to sign an informed consent form. 14. Patient deprived of liberty or under legal protection measure. 15. Weight \> 100kg. 16. Antiviral therapy (as ribavirin)