In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 2605-2605
Abstract:
2605 Background: TG4023 is a non-integrative and non-propagative Modified Vaccinia virus Ankara (MVA) expressing a chimeric yeast transgene (FCU1) coding for cytosine deaminase and uracil phosphoribosyl transferase that transform the pro-drug 5-flucytosine (5-FC) respectively into 5-FU and 5-FUMP in infected cells; these derivatives then diffuse and kill additional tumor cells (bystander effect). Methods: This phase I study determined safety and Maximal Tolerated Dose (MTD) of a single intra-tumor injection of TG4023 combined with a 2-week dosing period of 5-FC 200 mg/kg/day. Plasma and tumor 5-FC (PK) and 5-FU (PD) concentrations were measured. Other assessments were tumor response, changes in tumor markers and immune response. Patient requirements were ≥ 1 injectable primary or metastatic unresectable liver tumor of 2-5 cm, no treatment option left, ECOG PS ≤ 2. Consenting patients were allocated to cohorts according to a 3+3 dose-escalating design driven by Dose-Limiting Toxicities (DLTs) and Data Safety Monitoring Board recommendations. Results: Among 16 enrolled patients (13 colorectal, 1 pancreatic and 1 liver cancers, 1 cancer of unknown primary) 6 were injected in one tumor with 10 7 plaque forming units (pfu) TG4023, 3 with 10 8 pfu and 7 with 4.10 8 pfu, using a multiport needle and ultrasound imaging guidance. 5-FC was given IV the first days then orally. One DLT (grade 3 transient increase in AST/ALT) was recorded at 4.10 8 pfu; other severe adverse events, diarrhea, hypertension, alkaline phosphatase increase were related to 5-FC; most frequent AEs were transient fever, asthenia, site injection pain, nausea/vomiting. 5-FU concentrations in tumor biopsies at Day 8 were 56±30 ng/g and 1.9± 2.6 ng/mL in plasma. 11/16 injected, 12/23 non-injected target tumors were stable and 10/16 patients progressed at week 6. One patient had a 3-fold decrease in CEA and CA 19.9. Conclusions: This study showed that vectorized gene therapy of liver tumors with TG4023/5-FC combination is feasible and safe, as supported by a high therapeutic index; MTD for TG4023 was 4.10 8 pfu for one injected tumor. A proof of concept of the in vivo conversion of the pro-drug 5-FC into 5-FU was obtained.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.2605
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
