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Home » Bladder Cancer, EU Health, Health

Vicinium: A recombinant targeted protein therapeutic for Non-muscle invasive bladder cancer

Submitted by on 30 Sep 2016 – 17:08

Vicinium is currently being evaluated in a single arm, registrational phase 3 clinical trial in the USA and Canada in patients with high grade Non Muscle Invasive Bladder Cancer (NMIBC). Dr Gregory Adams, Chief Development Officer and Steve Hurley, Chief Executive Officer and Dr Glen MacDonald, Viventia Bio, write about why Vicinium is expected to be effective in elderly patients with waning immune systems

The global prevalence of bladder cancer is estimated at 2.7 million with 430,000 new cases of bladder cancer diagnosed and 165,000 deaths in 2012 (5). The opportunity exists to decrease the morbidity and mortality associated with bladder cancer through the development and implementation of more effective interventions employed before the disease invades the muscle lining the bladder and becomes systemic. Vicinium, a targeted therapeutic agent that is currently in phase 3 clinical trial, directly addresses this need.

Vicinium is a recombinant fusion protein consisting of a single chain antibody fragment (scFv) linked to a truncated form of Pseudomonas exotoxin A (ETA), a potent protein-based toxin that kills cells by inhibiting protein translation. (1) The scFv portion of Vicinium specifically targets epithelial cell adhesion molecule (EpCAM), which is overexpressed in many tumors, including bladder cancer (3), while exhibiting limited expression in normal bladder tissue.

EpCAM overexpression often correlates with more aggressive disease and is considered to be a cancer stem cell marker (2). As Vicinium does not cross the cell membrane without first binding to EpCAM, it is not capable of targeting healthy bladder tissue.
Vicinium is currently being evaluated in a single arm, registrational phase 3 clinical trial in the USA and Canada in patients with high grade Non Muscle Invasive Bladder Cancer (NMIBC). It is administered in the same manner as BCG, by intravesical instillation, and is therefore easily handled by practicing urologists.

Vicinium’s recommended dose of 30 mg per instillation was established in a phase 1 dose escalation clinical trial, which examined doses ranging from 0.1 to 30 mg given weekly for a total of 6 weeks to patients with high grade BCG-refractory or intolerant NMIBC (3). All doses were well tolerated and no dose limiting toxicities or significant systemic exposures were observed. The highest dose, 30 mg, was selected, as it was believed to be associated with the greatest level of tumor exposure to the agent. A total of 64 patients were treated in this study, with a complete response of 41% at three months.

Vicinium was next evaluated in a phase 2 trial conducted in the United States and Canada comparing a standard BCG-like regimen of once a week for 6-week induction phase with a longer once a week for 12-week induction phase (3). Both arms were followed by three maintenance cycles of
weekly Vicinium administration for 3 consecutive weeks, every three months (e.g., standard BCG-like schedule). 
Patients (n=46) with BCG-refractory (defined as not achieved disease-free status at 6 months or recurred within 6 months of last BCG treatment cycle) carcinoma in situ (CIS) with or without concurrent Ta or T1 were enrolled in this study.

Tumor response was assessed via cystoscopy, urine cytology and biopsies, with a complete response defined by negative urine cytology and the lack of histological evidence of disease at 3 months. While both induction phase regimens were associated with CR rates of 40% at three months, the 12-week induction regimen was associated with higher 12 months CR rates and longer median time to recurrence than the 6-week induction regimen, 17% (408 days median time to recurrence) vs. 13% (272 days median time to recurrence), respectively.

A majority of patients reported at least one side effect, however they were generally mild to moderate local bladder symptoms, including: 
dysuria (painful urination), pollakiuria (frequent urination), hematuria (blood in the urine), nocturia (waking up at night to urinate)
or bladder pain. Overall, Vicinium was found to be safe, well-tolerated and exhibited clinical efficacy with greater efficacy associated with a longer course of induction therapy.

Observation of a longer median time to recurrence in the phase 2 trial in the group that was given more drug in the induction phase (e.g., the 12-week induction phase) suggested that increasing the number of doses of Vicinium would lead to even greater and more prolonged CR rates. Therefore, we modified both the induction and maintenance phase dosing in the phase 3 trial such that the induction phase is now 6 weeks of twice-a-week dosing followed by 6 weeks of once-a-week dosing.

The frequency of the maintenance dosing was also increased to once every other week for the remainder of the two-year study. We believe that increasing the number of doses in the induction phase may increase the CR rate at 3 three months and that the increased frequency of the maintenance phase dosing will prevent more patients from recurring.

Vicinium is the only targeted therapeutics in advanced development for the treatment of NMIBC. As it functions by blocking protein production in targeted cells rather than inducing immune stimulation, Vicinium is expected to be effective in elderly patients with waning immune systems – a population that can be less responsive to agents like BCG that depend upon a robust immune function.
1. Biggers, K and Scheinfeld, N. VB4-845, A conjugated recombinant antibody and immunotoxin for head and neck cancer and bladder cancer. Current Opinion in Molecular Therapeutics. 10:176-86, 2008.
2. Brunner, A, Schaefer, G, Veits, L, Bruner, B Prelog, M and Ensinger C EpCAM Overexpression is Associated with High-grade Urothelial Carcinoma in the Renal Pelvis. Anticancer Research, 28:125-8, 2008.
3. Kowalski, M, Entwistle, J, Cizeau, J, Niforos, D, Loewen, S, Chapman, W and MacDonald, GC. A Phase I study of an intravesically administered immunotoxin targeting epcAM for the treatment of nonmuscle-invasive bladder cancer in Bcg- refractory and Bcg-intolerant patients. Drug Design, Development and Therapy. 4:313-320, 2010.
4. Kowalski, M, Guindon, J, Brazas, L, Moore, C, Entwistle, J, Cizeau, J, Jewett, MAS and MacDonald, GC. A Phase II Study of Oportuzumab Monatox: An Immunotoxin Therapy for Patients with Noninvasive Urothelial Carcinoma In Situ Previously Treated with Bacillus Calmette-Guérin
5. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, and Jemal A. Global cancer statistics, 2012 CA: A Cancer Journal for Clinicians, 65:87-108, 2015.