Trial of TG4023 Combined With Flucytosine in Liver Tumors

A Phase I, Open-label, Dose-escalating Study of the Safety or Percutaneous Intra-tumoral Injection of TG4023 (MVA-FCU1) Combined With Systemic Administration of 5-fluorocytosine in Patients With Primary or Secondary Hepatic Tumors.

This trial is a phase I, open-label, dose-escalating study of the safety or percutaneous intra-tumoral injection of TG4023 (MVA-FCU1) combined with systemic administration of 5-fluorocytosine in patients with primary or secondary hepatic tumors.

Inclusion Criteria:

• Patients with advanced disease without any other standard of care treatment options:

  • hepatic metastases of colorectal cancer (CRC) or of other cancers
  • Hepatocellular carcinoma (HCC)

• At least one unresectable target tumor located in the liver, measuring 2-5 cm and accessible to IT administration of TG4023 and amenable to radiological measurement using RECIST,

• Weight ≤ 100 kg,

• Patients with stable disease, who have to discontinue chemotherapy because of intolerance,

• ECOG performance status ≤ 2,

• Life expectancy ≥ 3 months,

• Hematology:

  • Absolute neutrophil count > 1,500/mm3,
  • Hemoglobin > 9g/dL,
  • Platelet count > 100,000/mm3,
  • Prothrombin time international normalized ratio (INR) ≤ 2; partial thromboplastin time ≤ 1.66 times upper limit of normal (ULN),

• Biochemistry:

  • Total bilirubin ≤ 3 x ULN,

  • Aspartate amino-transferase (AST), alanine amino-transferase (ALT), alkaline phosphatase

    • 5.0 x ULN,

  • Creatinin clearance ≥ 40 mL/min,

  • Total albumin ≥ 30 g/L,

• Anti-vitamin K anticoagulants should have been switched for low-molecular weight heparin prior to TG4023 injection,

• Signed, written Independent Ethics Committee (IEC)-approved informed consent.

Exclusion Criteria:

• Child-Pugh stage C hepatic insufficiency,
• Impaired renal function (creatinin clearance < 40 mL/min),
• Known deficiency in dihydropyrimidine dehydrogenase (DPD) or total DPD deficiency diagnosed at baseline in those patients not previously treated with 5-FU-related compounds,
• Ascites,
• Brain metastases,
• Significant impairment of gastro-intestinal (GI) tract absorption capacity, such as total gastrectomy, gastric mucosal atrophy, extensive intestinal resections or malabsorption disease will not be treated by oral 5-FC,
• History of bleeding disorders,
• Pregnant or breast-feeding women,
• Human Immunodeficiency Virus (HIV) positive,
• Chronic use of immunodepressants within 4 weeks prior to TG4023 injection or immune-depressed patients,
• Hypersensitivity to 5-FC,
• Hypersensitivity to egg proteins,
• Concomitant or previous chemotherapy or targeted therapy within 4 weeks prior to TG4023 injection and last treatment with bevacizumab (Avastin®) within 2 months prior to TG4023 injection,
• Concomitant treatment with anti-inflammatory drugs: systemic cortico-steroids and non-steroidal anti-inflammatory drugs (NSAIDs),
• Prior gene therapy,
• Prior participation in any other research protocol involving an IMP within 2 months prior to TG4023 injection,
• Major surgery within 6 weeks of TG4023 injection,