Trial of TG4023 Combined With Flucytosine in Liver Tumors

NCT ID: NCT00978107

Last Updated: 2014-07-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-09-30
• Study Completion Date: 2011-09-30

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.

Conditions

Hepatocellular Carcinoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

MVA-FCU1, flucytosine

1. 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)

2. 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.

Intervention Type: BIOLOGICAL

Other Intervention Names

5-FC

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,

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Transgene

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Hôpitaux Civils de Colmar

Colmar, , France

Institut Paoli Calmette,

Marseille, , France

Hôpitaux Civils de Lyon,

Pierre-Bénite, , France

Centre René Gauducheau

Saint-Herblain, , France

Hôpitaux Universitaires de Strasbourg

Strasbourg, , France

Institut Claudius Regaud

Toulouse, , France

Countries

France

References

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. doi: 10.1038/sj.cgt.7701098. Epub 2007 Nov 9.

Reference Type: BACKGROUND

PMID: 17992203 (View on PubMed)

Husseini F, Delord JP, Fournel-Federico C, Guitton J, Erbs P, Homerin M, Halluard C, Jemming C, Orange C, Limacher JM, Kurtz JE. Vectorized gene therapy of liver tumors: proof-of-concept of TG4023 (MVA-FCU1) in combination with flucytosine. Ann Oncol. 2017 Jan 1;28(1):169-174. doi: 10.1093/annonc/mdw440.

Reference Type: DERIVED

PMID: 28177438 (View on PubMed)

Other Identifiers

Eudra CT 2008-005024-90

Identifier Type: -

Identifier Source: secondary_id

TG4023.01

Identifier Type: -

Identifier Source: org_study_id