Denis Georges Bosc

A phase I clinical study of VB4-845: weekly intratumoral administration of an anti-EpCAM recombinant fusion protein in patients with squamous cell carcinoma of the head and neck.

VB4-845 is a scFv-Pseudomonas exotoxin A fusion construct that targets epithelial cell adhesion molecule (EpCAM). A phase I trial was conducted to determine the maximum tolerated dose (MTD) of VB4-845 when administered as weekly intratumoral (IT) injections to patients with squamous cell carcinoma of the head and neck (SCCHN). Secondary objectives included the evaluation of the safety, tolerability, pharmacokinetic profile, and immunogenicity, and a preliminary assessment of tumor response. Twenty patients with advanced, recurrent SCCHN were treated weekly for four weeks in ascending dose cohorts of 100, 200, 330, 500, 700, and 930 μg. The MTD was established as 930 μg with a dose limiting toxicity of elevated liver enzymes in two of five patients. VB4-845 therapy was well tolerated with common treatment-related adverse events of injection site reactions, fever, gastrointestinal disorders, and elevated liver enzyme levels. All patients developed antibodies to VB4-845 by the end of the study, but only seven patients had neutralizing antibodies. Preliminary efficacy data found 87.5% of EpCAM-positive patients had a positive response to VB4-845 therapy. Noninjected dermal metastases were also resolved in one patient. VB4-845 IT therapy is safe and feasible and warrants further clinical evaluation for the treatment of SCCHN.

Preclinical Assessment of an Anti-EpCAM Immunotoxin: Locoregional Delivery Provides a Safer Alternative to Systemic Administration

VB4-845 is a recombinant immunotoxin that is comprised of a truncated form of Pseudomonas exotoxin A (ETA) genetically-linked to a humanized scFv fragment, (4D5MOCB), specific to epithelial cell adhesion molecule (EpCAM). EpCAM is overexpressed on a wide variety of human tumors and thus represents a suitable target antigen for immunotoxin therapy. Preclinical studies were used to evaluate the benefit of locoregional administration of an ETA-based immunotoxin versus systemic delivery. Repeated subcutaneous (s.c.) administration of VB4-845 (up to 77.8 microg/kg) in rats resulted in minimal adverse effects, except for injection-site reactions, while repeated systemic administration elicited symptoms consistent with vascular leak syndrome. S.c. weekly doses of the drug in cynomolgus monkeys resulted in minimal adverse effects limited to injection-site reactions and a transient elevation of liver enzymes in 1 animal. Toxicokinetics showed rapid clearance of the drug, with the development of an immune response by day 14 following repeated injections. These results argue that the local administration of VB4-845 has advantages with respect to safety over systemic administration and may be an effective alternative method for targeting those cancers that are amenable to local routes of administration.