Endoscopy 2006; 39 - N3B
DOI: 10.1055/s-2006-947613

Long-term data for endoscopic ultrasound (EUS) and percutanous (PTA) guided intratumoral TNFerade gene delivery combined with chemoradiation in the treatment of locally advanced pancreatic cancer (LAPC)

J Farrell 1, N Senzer 1, N Hanna 2, T Chung 3, J Nemunaitis 4, A Rosemurgy 5, M Javle 6, T Reid 7, M Posner 8, K Chang 9, J Macko 10, JR Hecht 1
  • 1UCLA, Los Angeles, US
  • 2University of Maryland, Baltimore, US
  • 3Medical College of Virginia, Richmond, US
  • 4Mary Crowley Medical Research Center, Dallas, US
  • 5University of South Florida, Tampa, US
  • 6Rosewell Park Cancer Institute, Buffalo, US
  • 7University of California, San Diego, San Diego, US
  • 8University of Chicago, Chicago, US
  • 9University of California, Irvine, Irvine, US
  • 10GenVec, Gaithersburg, US

Background: TNFerade is a replication-deficient adenoviral vector containing the TNF-α gene regulated by a chemoradiation-inducible promoter, Egr-1. This large dose-selection phase II study compared the safety and activity of EUS or PTA delivery of TNFerade with chemoradiation in patients with LAPC. Methods: Dose-escalating design was used. 5-week treatment consisted of weekly injections of 4×109, 4×1010, 4×1011 or 1×1012 pu TNFerade, continuous infusion 5-FU and radiation. TNFerade was delivered by PTA or EUS guided intratumoral injections. Endpoints: Safety, tumor response and progression, CA 19–9 and survival. EUS and PTA groups were compared. Results: 50 pts completed this study (n=27 (EUS), n=23 (PTA)). Dose-limiting toxcities (DLTs) occurred in a PTA patient and 3 EUS patients, setting the maximally tolerated dose (MTD) at 4×1011 pu. Serum TNF-αmax was 129 pg/ml. Compared with the first 2 cohorts (n=30), the MTD (n=11) was associated with greater locoregional control of treated tumors, longer progression-free survival, a greater proportion of patients with stable or decreasing CA 19–9, a greater percentage (45%) of patients resected, and improved median survival (6.6, 8.8, 11.2, and 10.9 months, in the 4×109, 4×1010, 4×1011 or 1×1012 pu cohorts, respectively). At the MTD, 4/5 patients reassessed as surgically resectable achieved pathologically negative margins, and 3 survived >24 months. Disease control and survival were for both the PTA and EUS group. Conclusions: EUS or PTA guided intratumoral delivery of TNFerade, combined with chemoradiation shows promise in the treatment of LAPC. The dose of 4×1011 pu TNFerade is generally well tolerated with encouraging indications of activity, and will be tested in the randomized phase of this study. EUS and PTA are similarly effective for delivery of TNFerade and did not interfere with subsequent surgical resection.