Golnerminogene pradenovec

AdGV.EGR.TNF.11D (TNFerade™ Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-α) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-α has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFerade™ Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC).

TNFerade™ Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 10(9) to 4 × 10(11) PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1-5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment.

Fourteen patients were treated. DLT was reached at a dose level of 3 (4 × 10(11) PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-α, and TNF-α receptors. Adenoviral DNA was detected in three biopsies from one patient.

TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 10(10) PU. Monitoring for thrombotic events is indicated.

TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy.

In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m2 per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 1011 particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m2 intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity.

The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05).

SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC.