Naamit Sher

A phase I trial of VB-111, a tissue- and condition-specific dual action vascular disruptive and antiangiogenic agent, for treatment of patients with advanced metastatic cancer.

3038 Background: VB-111 is a tissue and condition specific vascular disrupting and anti-angiogenic agent based on a novel Vascular Targeting System (VTS) which contains the modified angiogenic specific pre-proendothelin promoter, and a FAS/TNF receptor chimeric transgene. Preclinical studies have shown that VB-111 has significant antitumor activity. We report the results of a phase I single-dose escalation study of VB-111 in patients with advanced metastatic solid tumors. METHODS Eligible patients had 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 1X1010 to 1X1013 viral particles in seven successive cohorts. Primary and secondary endpoints were safety and efficacy at 56 days post dosing, respectively. RESULTS Thirty three patients enrolled in two cancer centers. VB-111 was well tolerated; most patients in Cohorts 5 to 7 developed self-limited fever and chills. Neutralizing antibodies to Ad-5 at baseline were elevated in over half of the patients. Ad-5 DNA blood levels gradually declined within 1 to 56 days post dosing; some patients had up to 103 copies/ µg genomic DNA at day 56. As expected from the specificity of VB-111, no expression of the Fas chimeric transgene in the blood was found. However, in a patient with esophageal cancer, transgene expression was detected in the aspirate from a subcutaneous metastasis 4 and 28 days after treatment. Three out of 14 (21%) evaluable patients in cohorts 1 to 5 vs. 9 out of 18 evaluable patients in cohorts 6 and 7 (50%) had stable disease at day 56. One patient with papillary thyroid carcinoma had PR at 6 months, which persisted for 18 months. Three patients, one with neuroendocrine and two with thyroid carcinoma had a significant decline in tumor-markers. CONCLUSIONS VB-111 was found to be safe, well tolerated and showed some evidence for anti-tumor effect in patients with advanced metastatic cancer at a single administration of up to 1X1013 VPs. Repeat dose administration as well as evaluation in specific tumors will be explored in future studies.