A Randomized Phase II Study of OGX-427 (a Second-Generation Antisense Oligonucleotide to Heat Shock Protein-27) in Patients With Castration Resistant Prostate Cancer Who Have Not Previously Received Chemotherapy for Metastatic Disease
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
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
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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
The primary efficacy endpoint is defined as the proportion of patients without disease progression at the 12-week evaluation after treatment with prednisone given with or without OGX-427.
Kim N Chi, MD
BC Cancer Agency - Vancouver Center
Canada: Health Canada
|University of Washington/Seattle Cancer Care Alliance||Seattle, Washington 98109|