Study of Intratumoral REOLYSIN® in Combination With Gemcitabine and Cisplatin as Neoadjuvant Therapy in Muscle-invasive Transitional Cell Carcinoma of the Bladder

Reovirus Serotype 3 - Dearing Strain (REOLYSIN®) is a naturally occurring, ubiquitous,
non-enveloped human reovirus. Reovirus has been shown to replicate selectively in
Ras-transformed cells causing cell lysis. Activating mutations in Ras or mutations in
oncogenes signaling through the Ras pathway may occur in as many as 80% of human tumors. The
specificity of the reovirus for Ras-transformed cells, coupled with its relatively
nonpathogenic nature in humans, makes it an attractive anti-cancer therapy candidate.

This is an open-label study of intratumoral REOLYSIN® in combination with standard of care
neoadjuvant cisplatin/gemcitabine in patients with histologically and clinically confirmed
muscle-invasive bladder cancer (T2-4) with or without pelvic lymph node involvement (N1-2)
in Stage III and IV with no distant metastases (M0) and no prior systemic therapy for
bladder cancer.

Treatment with intratumoral REOLYSIN® and chemotherapy is planned for 3 cycles followed by
radical cystectomy or until unacceptable toxicity or another discontinuation criterion is
met.

Two sequential treatment cohorts will be enrolled.

Patients in Cohort 1 will receive intratumoral REOLYSIN® on Cycle 1 Day 1, then 7-14 days
later patients will receive intratumoral REOLYSIN® on Cycle 2 Day 1 plus intravenous
neoadjuvant chemotherapy for 2 cycles (every 3 weeks) starting from Cycle 2 Day 2 followed
by radical cystectomy. Three patients will be enrolled in this cohort. If there is a Dose
Limiting Toxicity the cohort will be expanded to an additional 3 patients.

Upon completion of Cohort 1, Cohort 2 will be open to enrollment of 3 patients to receive 3
cycles of standard neoadjuvant chemotherapy on Day 1 and Day 8 of each cycle and
intratumoral REOLYSIN® on Day 2 of each cycle (every 3 weeks). If there is a Dose Limiting
Toxicity the cohort will be expanded to an additional 3 patients.

An Expansion Cohort will follow with up to 12 patients to be enrolled following either
Cohort 1 or Cohort 2 treatment regimen based on the results of Cohort 1 and Cohort 2.

Inclusion Criteria:

- Histologically and clinically confirmed muscle-invasive bladder cancer (T2-4) with or
without pelvic lymph nodes involvement (N1-2) in Stage III and IV (M0).

- ECOG performance status ≤2.

- Adequate liver function with a bilirubin within normal limits. Transaminases up to 3
x ULN (Grade 1) and alkaline phosphatase may be up to 2.5 x ULN (Grade 1).

- Adequate bone marrow function, as defined by neutrophils count of ≥1,500/mm3, and
platelet count ≥100,000/ mm3.

- Adequate renal function (serum creatinine ≤1.5 times the ULN).

- Negative pregnancy test and reliable and appropriate contraceptive method during the
study for a woman of childbearing potential. All female patients of childbearing age
and all male patients with partners of childbearing age should use a reliable method
of contraception, such as the barrier method, throughout the study and for 60 days
after last treatment.

- Informed of the investigational nature of this study and must sign a written informed
consent in accordance with institutional and federal guidelines.

Exclusion Criteria:

- Received any prior therapy for invasive bladder cancer including surgery, radiation
therapy, chemotherapy or any other systemic anti-cancer therapy (prior intravesical
therapy for non-invasive bladder cancer is acceptable including intravesical BCG
and/or mitomycin and interferon).

- Evidence of lymph nodes or other metastatic disease beyond the pelvis (N3 and/or M1).

- Pre-existing immunosuppressive or connective tissue disorders that require immune
suppressive drugs.

- History of HIV or active hepatitis.

- Any serious concurrent illness including; but not limited to, unstable angina
pectoris, uncompensated congestive cardiac failure; myocardial infarct in the
previous 6 months; cardiac arrhythmias or psychiatric illness that would limit
compliance with study requirements.

- Pregnant or lactating.

- A history of hypersensitivity to gemcitabine and cisplatin or any component of the
formulation.

- A prior malignancy, other than non-melanoma skin cancer, unless they have completed
therapy at least 5 years prior to start of study and have no evidence of recurrent or
residual disease.

- Unwilling or unable to sign informed consent document.

- In social situations that would limit compliance with study requirements.