Trial of TG4023 Combined With Flucytosine in Liver Tumors

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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.

Conditions
-----------------
Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Biological: MVA-FCU1, flucytosine


Participation Criteria
=================
Eligibility Criteria
-----------------
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,

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: MVA-FCU1, flucytosine|TG4023: single IT injection; possibility to re-administer once, Percutaneous IT injections, under radiological or ultrasound imaging guidance Dose-escalating schedule of administration: 107 pfu (Cohort #1), 108 pfu (Cohort #2) and 4x108 pfu (Cohort #3), MTD injected to up to 3 different lesions (Cohort #4) 5-FC (5-fluorocytosine)/flucytosine Dose and dosing schedule: Daily starting dose of 200 mg/kg; daily dose will be adjusted after measurement of 5-FC plasma concentration at steady state, which should be kept below 100 mg/L Duration: 2 weeks. Possible routes of administration: PO: 500 mg tablets, qid IV: 1% 250 mL vials, 45-minute infusions.|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal tolerated dose |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response of injected and non-injected lesions Viral dissemination Proof of concept: 5-FU concentration in plasma and in tumors |  | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatic tumors, Metastatic colorectal cancer