Abstract 1361: A Phase I trial of VB-111, a tissue and condition specific vascular disruptive anti-angiogenic agent, based on novel Vascular Targeting System™, VTS™, for treatment of patients with advanced metastatic cancer
Authors: Triozzi Pierre , Brenner Andrew , Giles Francis J. , Cohen Yael C. , Breitbart Eyal , Bangio Livnat , Borden Ernest C. 
Published: February 2011

Abstract
Introduction: VB-111 is a vascular disruptive and anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5, E1 deleted), which contains a modified murine pre-proendothelin promoter, a novel Vascular Targeting System™, VTS™, and a fas and human tumor necrosis factor (TNF) receptor chimeric transgene. This modified promoter specifically expresses the fas chimera transgene in tumor vessel endothelium, leading to targeted apoptosis. In vitro and in vivo studies have shown that VB-111 has significant antitumor activity. We report here the results of a Phase I dose escalation study for evaluation of the safety, PK, immune and tumor responses of a single dose of VB-111.
Methods: Eligible patients had to have progressing, advanced solid tumors, with no existing curative therapy, and adequate organ function and performance status. VB-111 was administered as a single intravenous infusion at escalating doses ranging from 1×106 to 3×1012 viral particles (VPs) in six successive cohorts. Patients had frequent clinical and laboratory safety evaluations. Tumor response was evaluated on day 28 and day 56.
Results: Twenty seven patients enrolled in two cancer centers between November 2007 and August 2009. Cohorts 1 to 5 included three patients each; Cohort 6 was expanded to 12 patients. VB-111 was well tolerated; no dose limiting toxicities (DLT) classified as CTCAE Grade 3 or higher, were observed. Most patients in Cohorts 5 and 6 developed self-limited fever and chills lasting up to 24 hours. Neutralizing antibodies (Abs) to Ad-5 at baseline were elevated in over half of the patients. In Cohort 6, a significant increase in IL-6 blood levels occurred 6 hours post-dosing, and returned to baseline by day 4. No significant changes occurred with the other measured cytokines (IL-8, VEGF, FGF, and TNF-alpha). Ad-5 DNA blood levels were detected by qRT-PCR and declined gradually within 1 to 28 days post dosing; rate of decline was not related to the presence of baseline Ad-5 neutralizing Abs. As expected from the specificity of VB-111, no expression of the Fas chimeric transgene in the blood was found. On day 56 evaluation, one of the 15 patients in Cohorts 1 to 5 had stable disease (SD); among the 12 Cohort-6 patients, Four had SD on day 56, and one patient (with papillary thyroid carcinoma) had partial response (PR) persisting for 12 months post dosing.
Conclusions: VB-111 was found to be safe and well tolerated in patients with advanced metastatic cancer at a single administration of up to 3×1012 VPs. No DLT were observed, and the maximal tolerated dose has not been reached. SD and PR were observed in patients. Viral distribution, cytokine and Ab response data supports repeat dosing at 3-6 week intervals. Further dose escalation, repeat dosing as well as evaluation in specific tumors will be explored in future studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1361.