Trial of TG4023 Combined With Flucytosine in Liver Tumors

Hepatocellular Carcinoma Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00978107
• Other study ID #: TG4023.01
• Secondary ID: Eudra CT 2008-00
• Status: Completed
• Phase: Phase 1
• First received: September 15, 2009
• Last updated: July 15, 2014
• Start date: September 2009
• Est. completion date: September 2011

Study information

• Verified date: July 2014
• Source: Transgene
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: September 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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,

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

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.

Locations

Country	Name	City	State
France	Hôpitaux Civils de Colmar	Colmar
France	Institut Paoli Calmette,	Marseille
France	Hôpitaux Civils de Lyon,	Pierre Benite
France	Centre René Gauducheau	Saint Herblain
France	Hôpitaux Universitaires de Strasbourg	Strasbourg
France	Institut Claudius Regaud	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
Transgene

Country where clinical trial is conducted

France, 

References & Publications (1)

Erbs P, Findeli A, Kintz J, Cordier P, Hoffmann C, Geist M, Balloul JM. Modified vaccinia virus Ankara as a vector for suicide gene therapy. Cancer Gene Ther. 2008 Jan;15(1):18-28. Epub 2007 Nov 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximal tolerated dose		6 months	Yes
Secondary	Tumor response of injected and non-injected lesions Viral dissemination Proof of concept: 5-FU concentration in plasma and in tumors		1 year	No