Clinical trial NCT00978107: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatocellular Carcinoma
Keywords: Hepatic tumors
Metastatic colorectal cancer
Lead sponsor: Transgene
Sponsor class: INDUSTRY
First posted: 2009-09-16
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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,

Primary outcomes:
measure: Maximal tolerated dose
timeFrame: 6 months
Secondary outcomes:
measure: Tumor response of injected and non-injected lesions Viral dissemination Proof of concept: 5-FU concentration in plasma and in tumors
timeFrame: 1 year
Other outcomes:
Locations:
city: Colmar
country: France
facility: Hôpitaux Civils de Colmar
city: Marseille
country: France
facility: Institut Paoli Calmette,
city: Pierre Benite
country: France
facility: Hôpitaux Civils de Lyon,
city: Saint Herblain
country: France
facility: Centre René Gauducheau
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg
city: Toulouse
country: France
facility: Institut Claudius Regaud
Study officials:
References:
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.
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.