A Phase 2 Study Comparing Chemotherapy in Combination With OGX-427 or Placebo in Patients With Bladder Cancer

The incidence of bladder cancer in 2010 in the US and Canada combined is estimated to be
77,680, with 16,520 deaths and in Europe in 2008 was 110,500 with 38,200 deaths. The most
common histological type is transitional cell cancer (TCC). Most cases (70%) present with
superficial or non-invasive disease which, in general, has a good prognosis. However, at
diagnosis, 20% of patients will have advanced disease (muscular invasion) and 5% will
present with metastatic disease. In addition, 50-70% of superficial tumors will recur and a
significant proportion will evolve to muscular involvement within 5 years. Radical
cystectomy is the treatment of choice for patients with operable invasive disease. Patients
who present with locally inoperable disease due to local extension into organs other than
the bladder or involvement of regional lymph nodes do not have this option, and, despite
radical cystectomy, 50% of patients will recur either regionally (~30%) or systemically
(~70%) following cystectomy. Following recurrence, few patients can be cured.

Before the advent of chemotherapy, survival of patients with metastatic TCC was <6 months.
Today, TCC is felt to be a chemotherapy sensitive disease, and systemic chemotherapy is the
treatment of choice for patients with inoperable, locally advanced, or metastatic disease.

This study evaluates the safety and efficacy of the standard chemotherapy (gemcitabine and
cisplatin) in combination with OGX-427 at two dose levels (600 mg and 1000 mg) or placebo in
patients with advanced TCC who have not previously received chemotherapy for metastatic
disease and are not candidates for potential curative surgery or radiotherapy.

Inclusion Criteria:

1. Age ≥ 18 years at the time of consent

2. Histologically documented metastatic or locally inoperable advanced TCC of the
urinary tract (bladder, urethra, ureter and renal pelvis) (T4b, N2, N3 or M1 disease)
NOTE: Certain mixed histologies that are predominately (≥ 50%) TCC are eligible:
squamous, adenocarcinoma, and undifferentiated. Mixed undifferentiated histology
requires IHC consistent with a TCC origin. Mixed small-cell histologies are excluded.

3. Measurable disease defined as at least one target lesion that has not been irradiated
and can be accurately measured in at least one dimension by RECIST 1.1 criteria

4. No prior systemic chemotherapy with the following exceptions:

- Prior use of radiosensitizing single agent therapy is allowed

- Prior neoadjuvant and adjuvant chemotherapy may be allowed

5. Minimum of 21 days since prior major surgery or radiation therapy

6. Karnofsky performance status ≥70%

7. Required laboratory values at baseline:

- ANC ≥ 1.5x109 cells/L

- platelet count ≥ 125 x 109/L

- Calculated creatinine clearance ≥60 mL/minute

- bilirubin ≤ 1.5 x ULN (≤ 2.5 x ULN if secondary to Gilbert's disease)

- AST and ALT ≤ 3.0 x ULN

8. If of child-bearing potential, willing to use contraceptives

9. Willing to give written informed consent

Exclusion Criteria:

1. A candidate for potential curative surgery or radiotherapy

2. Intravesical therapy within the last 3 months

3. Documented brain metastasis or carcinomatous meningitis, treated or untreated. NOTE:
Brain imaging is not required unless the patient has symptoms or physical signs of
CNS disease.

4. Peripheral neuropathy ≥Grade 2

5. Known serious hypersensitivity to gemcitabine, cisplatin or carboplatin

6. Current serious, uncontrolled medical condition such as congestive heart failure,
angina, hypertension, arrhythmia, diabetes mellitus, infection, etc. or any condition
such as a psychiatric illness which in the opinion of the investigator would make the
patient unacceptable for the protocol

7. Cerebrovascular accident, myocardial infarction or pulmonary embolus within 6 months
of randomization

8. Active second malignancy (except non-melanomatous skin cancer): active secondary
malignancy is defined as a current need for cancer therapy or a high possibility
(>30%) of recurrence during the study

9. Pregnant or nursing (must have a negative serum or urine pregnancy test within 72
hours prior to randomization)

10. Participating in a concurrent clinical trial of an experimental drug, vaccine or
device. Participation in an observational study is allowed.