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Trial of TG4023 Combined With Flucytosine in Liver Tumors

Primary Purpose

Hepatocellular Carcinoma

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
MVA-FCU1, flucytosine
Sponsored by
Transgene
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring Hepatic tumors, Metastatic colorectal cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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,

Sites / Locations

  • Hôpitaux Civils de Colmar
  • Institut Paoli Calmette,
  • Hôpitaux Civils de Lyon,
  • Centre René Gauducheau
  • Hôpitaux Universitaires de Strasbourg
  • Institut Claudius Regaud

Outcomes

Primary Outcome Measures

Maximal tolerated dose

Secondary Outcome Measures

Tumor response of injected and non-injected lesions Viral dissemination Proof of concept: 5-FU concentration in plasma and in tumors

Full Information

First Posted
September 15, 2009
Last Updated
July 15, 2014
Sponsor
Transgene
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1. Study Identification

Unique Protocol Identification Number
NCT00978107
Brief Title
Trial of TG4023 Combined With Flucytosine in Liver 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.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2014
Overall Recruitment Status
Completed
Study Start Date
September 2009 (undefined)
Primary Completion Date
September 2011 (Actual)
Study Completion Date
September 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Transgene

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma
Keywords
Hepatic tumors, Metastatic colorectal cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Biological
Intervention Name(s)
MVA-FCU1, flucytosine
Other Intervention Name(s)
5-FC
Intervention Description
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.
Primary Outcome Measure Information:
Title
Maximal tolerated dose
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Tumor response of injected and non-injected lesions Viral dissemination Proof of concept: 5-FU concentration in plasma and in tumors
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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,
Facility Information:
Facility Name
Hôpitaux Civils de Colmar
City
Colmar
ZIP/Postal Code
68000
Country
France
Facility Name
Institut Paoli Calmette,
City
Marseille
ZIP/Postal Code
13000
Country
France
Facility Name
Hôpitaux Civils de Lyon,
City
Pierre Benite
ZIP/Postal Code
69495
Country
France
Facility Name
Centre René Gauducheau
City
Saint Herblain
ZIP/Postal Code
44800
Country
France
Facility Name
Hôpitaux Universitaires de Strasbourg
City
Strasbourg
ZIP/Postal Code
67000
Country
France
Facility Name
Institut Claudius Regaud
City
Toulouse
ZIP/Postal Code
31000
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
17992203
Citation
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.
Results Reference
background
PubMed Identifier
28177438
Citation
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.
Results Reference
derived

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Trial of TG4023 Combined With Flucytosine in Liver Tumors

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