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Clinical Trial
. 2010 Nov 15:4:313-20.
doi: 10.2147/DDDT.S14071.

A Phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCGrefractory and BCG-intolerant patients

Mark Kowalski  1 , Joycelyn Entwistle, Jeannick Cizeau, Demi Niforos, Shauna Loewen, Wendy Chapman, Glen C MacDonald
Affiliations
Clinical Trial

A Phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCGrefractory and BCG-intolerant patients

Mark Kowalski et al. Drug Des Devel Ther. .

Abstract

Purpose: A Phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of the immunotoxin VB4-845 in patients with nonmuscle-invasive bladder cancer (NMIBC) refractory to or intolerant of bacillus Calmette-Guerin (BCG). Secondary objectives included evaluation of the safety, tolerability, pharmacokinetics, immunogenicity, and efficacy of VB4-845.

Patients and methods: Sixty-four patients with Grade 2 or 3, stage Ta or T1 transitional cell carcinoma or in situ carcinoma, either refractory to or intolerant of BCG therapy, were enrolled. Treatment was administered in ascending dose cohorts ranging from 0.1 to 30.16 mg. After receiving weekly instillations of VB4-845 to the bladder via catheter for 6 consecutive weeks, patients were followed for 4-6 weeks post-therapy and assessed at week 12.

Results: An MTD was not determined, as a dose-limiting toxicity was not identified over the dose range tested. VB4-845 therapy was safe and well tolerated with most adverse events reported as mild; as a result, no patients were removed from the study in response to toxicity. By the end of the study, the majority of patients had developed antibodies to the exotoxin portion of VB4-845. A complete response was achieved in 39% of patients at the 12-week time point.

Conclusions: VB4-845 dosed on a weekly basis for 6 weeks was very well tolerated at all dose levels. Although an MTD was not determined at the doses administered, VB4-845 showed evidence of an antitumor effect that warrants further clinical investigation for the treatment of NMIBC in this patient population.

Keywords: Pseudomonas exotoxin A; anti-EpCAM; fusion protein; targeted therapy.

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Figures

Figure 1
Figure 1
Immunohistochemical staining of EpCAM on TCC of the bladder. Tissue samples were formalin fixed, paraffin embedded, and mounted onto coated microscope slides. Test slides containing A) normal bladder, C) EpCAM-negative TCC, and E) EpCAM-positive TCC tissue sections were incubated with the primary antibody VB4-845 and VB4-845 cell surface binding detected with a secondary antibody, rabbit anti-Pseudomonas ETA (Sigma, catalog no. P2318, St. Louis, MO, USA). Specificity of EpCAM staining was demonstrated with the corresponding control slides, B) normal bladder, D) EpCAM-negative TCC, and F) EpCAMpositive TCC, treated only with the secondary antibody. Membranous staining (2+) is only apparent with the EpCAM-positive TCC tissue section E) incubated with both VB4-845 and the secondary antibody. All pictures are shown at 100 × magnification.
Figure 2
Figure 2
Percentage of patients experiencing treatment-related adverse events (AEs) by grade per dose level. Of the 41 patients experiencing AEs, 20 patients experienced AEs related to treatment. AEs at each dose level are proportioned according to the grade level. If a patient experienced an AE more than once, only the event with the highest grade was included in the calculation. The dose levels and corresponding total number of AEs are as follows: 0.01, n = 9; 0.20, n = 0; 0.33, n = 6; 0.66, n = 12; 1.32, n = 1; 2.64, n = 9; 5.28, n = 6; 10.56, n = 1; 13.73, n = 6; 17.85, n = 1; 23.20, n = 7; and 30.16, n = 2.
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