A Phase 3, Randomized, Active-Controlled, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of EN3348 (MCC) as Compared with Mitomycin C in the Intravesical Treatment of Subjects with BCG Recurrent or Refractory Non-Muscle Invasive Bladder Cancer

Bladder cancer is the most common malignant tumor in the urinary tract,
accounting for over 3.3% of all cancers. An estimated 357,000 new bladder
cancer cases occurred worldwide in 2002 and approximately 145,000 deaths, with
population-based 5-year survival rates ranging from 40% to 80%. Bladder cancer
is relatively common in developed countries, where 63% of all incident cases
occur.
Urothelial (also known as transitional cell) carcinoma is by far the most
common histological subtype, accounting for more than 90% of all bladder
cancers. Urothelial carcinoma (UC) can be subdivided into subtypes according to
their invasiveness (ie, non-muscle invasive or muscle invasive) or shape (ie,
papillary or flat). The majority of UC (70%-75%) present as non-muscle invasive
bladder cancers (NMIBC)
A transurethral resection of a bladder tumor (TURBT) is the standard initial
treatment for non-muscle invasive bladder cancer of all visible lesions. The
TURBT also confirms the diagnosis and allows pathologic examination of the
resected tumor specimen for stage and grade. However, most of these tumors (60%
to 70%) have a tendency to recur after TURBT and some (15% to 25%) are at high
risk for progression to muscle invasion. As a result, adjuvant intravesical
instillations with chemotherapeutic or immunotherapeutic agents have been used
in conjunction with TURBT and have shown to reduce tumor recurrences.
Although intravesical chemotherapeutic agents have been shown to reduce tumor
recurrences, none of these agents has proven to be of benefit in preventing
disease progression. Bacillus Calmette-Guérin (BCG), an immunotherapeutic
agent, has shown to prolong the time to development of muscle invasion.
Despite a high initial complete response rate with BCG, a significant number of
subjects will eventually fail BCG therapy and notable toxicities are observed
with continued, prolonged use of BCG. In fact, BCG failures of 30% and 33% have
been reported for CIS and high grade T1 tumors, respectively. Guidelines from
the American Urological Association (AUA), National Comprehensive Cancer
Network (NCCN), and the European Association of Urology (EAU) have recommended
cystectomy for patients who have recurrent or persistent disease.
These efficacy and toxicity considerations have led to the search for more
effective and safer therapeutic agents for non-muscle invasive bladder cancer.
Mycobacterial cell wall-DNA complex (MCC), prepared from Mycobacterium phlei
(M. phlei) is one such agent.

The primary objective of this study is to evaluate the efficacy of EN3348 as
compared with mitomycin C in the treatment of subjects with BCG recurrent or
refractory NMIBC.

The secondary objective is to evaluate the safety of EN3348 as compared with
mitomycin C in the treatment of subjects with BCG recurrent or refractory
NMIBC.

This is a phase 3, randomized, active-controlled, open-label, multicenter study
designed to evaluate the efficacy and safety of EN3348 in subjects with BCG
recurrent or refractory NMIBC (Ta high grade, T1, carcinoma in situ [CIS]).
The randomization will be 1:1 and stratified by geographical region (North
America, India, Europe), tumor pathology (CIS versus no CIS), prior BCG
response (refractory versus recurrent), and prior intravesical (IVe)
chemotherapy (yes/no) using minimization technique.

Duration of Treatment: Subjects will receive study treatment with either EN3348
or mitomycin C for up to 12 months. This study consists of 4 phases:
Screening Phase (-8 Weeks): Subjects will be qualified for study entry by
review of inclusion and exclusion criteria during the Screening Phase, which
will last up to 8 weeks.
Induction Phase (6 Weeks): Subjects will receive weekly instillations of either
EN3348 or mitomycin C for total of 6 doses.
Maintenance Phase (10 Months): Subjects will receive monthly instillations of
study drug for up to an additional 10 doses (up to Month 12). In addition,
subjects will undergo disease assessments every 3 months, with a mandatory
biopsy required at Month 6.
Subjects will have completed the Maintenance Phase after completing the Month
12 instillation.
Follow-Up Phase (Up to Approximately 24 Months):
All randomized subjects, regardless of number of study drug instillations
received, will be followed until the End of Study. For an individual subject,
the end of study can be achieved by completing all required assessments through
the termination of the trial or earlier due to early discontinuation or
withdrawal of informed consent.
Assessments will be conducted every 3 months for months 13 through 24 and every
6 months from Month 25 through Month 36/End of Study.

Subjects will receive weekly instillations of either EN3348 or mitomycin C for
total of 6 doses during induction phase and monthly instillations of study drug
for up to an additional 10 doses (up to Month 12) during maintanace phase.

In addition to the side effects which are possible as a result of study drugs
administration, patients may experience discomforts or risks associated with
such study procedures as cystoscopy, bladder biopsy/TURBT, urinary
catheterization, anesthesia, blood drawing.

Considering the dual mechanisms of action and clinical activity of EN3348 in
the BCG refractory and recurrent settings and its safety advantage of
containing no live mycobacteria, it may offer a treatment option for patients
whose disease is refractory or recurrent after BCG.