OGX-427 in Castration Resistant Prostate Cancer Patients

Prostate cancer is the most common cancer diagnosed and the second most common cause of
cancer death in men in North America.

Patients with metastatic disease have a poor prognosis, and although hormonal therapy in the
form of medical or surgical castration can induce significant long-term remissions,
development of androgen independent disease is inevitable. The current standard of care for
CRPC is mainly palliative in its intent, and there are only limited proven treatment options
which include: analgesia, radiation, bisphosphonates and chemotherapy such as mitoxantrone or
docetaxel, with only the last treatment being associated with an overall survival benefit.

With the early commencement of androgen deprivation therapy and frequent use of PSA for
monitoring disease progression, an increasing population of patients with CRPC is now being
identified by a rising PSA rather than by new disease or symptoms. Early intervention with
chemotherapy is of unknown benefit in these patients, and thus represents an appropriate
group for phase II studies to evaluate novel agents with acceptable toxicity profiles.

Heat shock protein (Hsp) family members, including Hsp27, have attracted attention as new
therapeutic targets for cancer. Hsp27 is a small, ATP-independent Hsp which is highly
conserved across species. Hsp27 is expressed in prostate cancer and other malignancies.
Expression of Hsp27 is induced by cell stress, including cytotoxic chemotherapy, radiation
therapy, and hormone therapy. Overexpression of Hsp27 confers a resistant phenotype and is
implicated in castration resistant progression of prostate cancer.

OGX 427 is a second generation antisense oligonucleotide (ASO) that inhibits expression of
Hsp27. A number of in vitro and in vivo pharmacological studies have demonstrated that OGX
427 (or an Hsp27 ASO) has single-agent activity in reducing Hsp27 mRNA and protein,
inhibiting cell proliferation, and inducing apoptosis in several human cancer cell lines. OGX
427 has also demonstrated chemosensitizing activity both in vitro and in vivo in combination
with several cytotoxic drugs, including docetaxel. In an ongoing Phase I trial, OGX-427 has
been administered as a single agent in doses from 200 to 1000 mg with weekly infusions
occurring after a loading dose period of three infusions within the first 10 days of
initiating treatment. OGX-427 treatment has been well tolerated, with the majority of the
adverse events and laboratory toxicities reported being Grade 1 or Grade 2, although a
symptom complex of rigors, pruritus, and erythema during or shortly after infusion of drug
has required steroid prophylaxis and/or treatment in some patients at higher doses. No
maximum tolerated dose has been identified based on toxicity. OGX 427 administration in
combination with docetaxel is ongoing in the above-mentioned Phase 1 study.

Low dose corticosteroids have been shown to have some activity against prostate cancer with a
beneficial effect on quality of life (QOL). Since chemotherapy for prostate cancer is
palliative, low-dose prednisone has been used both as a single agent and added to
chemotherapy regimens.

This Phase 2 study has been designed to evaluate the anti-tumor effects of OGX-427 plus
low-dose prednisone versus low-dose prednisone alone in men with CRPC who have not previously
received chemotherapy for metastatic or locally recurrent disease.

Inclusion Criteria

- Age ≥ 18 years on the date of consent.

- ECOG performance status of 0 or 1.

- Histological or cytological diagnosis of adenocarcinoma of the prostate.

- Metastatic disease on chest, abdominal, or pelvic CT and/or bone scan for which no
curative therapy exists.

- Progression of prostate cancer. Progression is defined by one or more of the
following:

1. Increasing serum PSA level: two consecutive increases in PSA levels documented
over a previous reference value obtained at least one week apart. If the third
PSA value is less than the second, an additional fourth test to confirm a rising
PSA is acceptable. The last confirmation PSA value must be obtained within the 14
days prior to randomization. A minimum starting value of 2.0 ng/mL is required
for study randomization.

2. Progressive measurable disease: at least a 20% increase in the sum of the
diameters of measurable lesions over the smallest sum observed or the appearance
of one or more new lesions as assessed by CT scan. Measurable lesions are nodal
or visceral soft-tissue lesions with nodal lesions ≥ 15 mm in diameter at the
shortest axis and visceral/soft-tissue lesions ≥ 10 mm in longest diameter (See
Section 6.4).

3. Bone Progression: appearance of 2 or more new lesions on bone scan (or other
imaging).

- All patients who have not had a surgical orchiectomy must continue treatment with LHRH
agonist or antagonist to maintain a castrate level of testosterone.

- Patient must fulfill "Prior Therapy" criteria as follows:

1. Chemotherapy: No prior chemotherapy for metastatic disease is permissible.
(Exception: neoadjuvant/adjuvant chemotherapy if received > 12 months prior to
randomization.)

2. Hormone therapy: prior surgical or medical castration therapy is required. Prior
treatment with non-steroidal antiandrogens, abiraterone or other experimental
hormone therapy (e.g. MDV3100, YAK-700) is allowed provided a minimum of at least
14 days have passed since completing therapy and randomization in the study.

3. Experimental therapy: prior non-cytotoxic experimental therapy is permitted
provided a minimum of at least 14 days has passed since completing therapy prior
to randomization.

4. Radiation: prior external beam radiation is permitted provided a minimum of at
least 28 days have passed since completing radiotherapy at the time of
randomization (or following disease progression and prior to receiving therapy at
the time of cross-over). Exception for radiotherapy: at least 7 days must have
passed since completing single fraction of ≤ 800 cGy.

5. Corticosteroids: prior corticosteroid therapy is permitted. Within 4 days
following randomization, all patients must be taking prednisone 5 mg BID.

- Baseline laboratory values as stated below:

1. ANC ≥ 1.5 x 109 cells /L, platelet count ≥ .100 x 109 /L, and hemoglobin ≥ 9 g/dL
without transfusion.

2. Creatinine ≤ 1.5 x upper limit of normal (ULN).

3. Total bilirubin ≤ 1.1 x ULN (unless elevated secondary to conditions such as
Gilbert's disease).

4. SGPT (ALT) and SGOT (AST) ≤ 2.5 x ULN.

5. Castrate serum testosterone level (< 50 ng/dL-or-< 1.7 nmol/L).

- Recovery from all toxicities of prior therapy to ≤ grade 2 by NCI CTCAE, version 3.0.
(Exception: any toxicity that in the view of the Investigator is not a clinically
significant safety risk for further therapy administration, including, but not limited
to: anemia, fatigue, erectile dysfunction, hot flashes, lymphedema of an extremity,
dizziness, cough, and urinary incontinence).

- Must be willing to use effective contraception, if of child bearing potential,
throughout study treatment and for 3 months after completion of study treatment.

- Must be willing not to change (add or subtract) bone protecting therapy
(bisphosphonates and/or denosumab) during the study unless changed for toxicity.

- Written informed consent must be obtained prior to any protocol-specific procedures
being performed.

Exclusion Criteria

- Unable to tolerate a dose of 10 mg of prednisone a day.

- Requiring an amount of opioids to control pain > 30 mg of a morphine-equivalent per
day.

- Known coagulopathy or actively receiving warfarin (Coumadin) therapy.

- Documented brain metastases, or carcinomatous meningitis, treated or untreated (Brain
imaging for asymptomatic patients is not required).

- Current symptomatic cord compression requiring surgery or radiation therapy (once
successfully treated and there has been no progression, patients are eligible for the
study).

- Active second malignancy (except adequately treated non-melanomatous skin cancer or
other solid tumors curatively treated with no evidence of disease > 3 years).

- History of allergic reactions to therapeutic antisense oligonucleotides.

- Uncontrolled medical conditions such as heart failure, myocardial infarction,
uncontrolled hypertension, stroke or treatment of a major active infection within 3
months of randomization, as well as any significant concurrent medical illness that in
the opinion of the Investigator would preclude protocol therapy.

- Planned concomitant participation in another clinical trial of an experimental agent,
vaccine, or device. Concomitant participation in observational studies is acceptable.