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:

• 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.
• 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).
• 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:

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

• ANC ≥ 1.5 x 109 cells /L, platelet count ≥ .100 x 109 /L, and hemoglobin ≥ 9 g/dL without transfusion.
• Creatinine ≤ 1.5 x upper limit of normal (ULN).
• Total bilirubin ≤ 1.1 x ULN (unless elevated secondary to conditions such as Gilbert's disease).
• SGPT (ALT) and SGOT (AST) ≤ 2.5 x ULN.
• 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.