OGX-427 in Metastatic Castrate-Resistant Prostate Cancer With Prostate-Specific Antigen Progression While Receiving Abiraterone

This Phase II study has been designed to evaluate the anti-tumor effects of adding OGX-427 to continuing abiraterone acetate and prednisone treatment in men with metastatic castrate-resistant prostate cancer (MCRPC) who have prostate-specific antigen (PSA) progression

OUTLINE: This is a multi-center study.

This is an open-label, randomized, Phase II clinical trial designed to evaluate the anti-tumor effects of OGX-427 and continuing abiraterone acetate and prednisone versus continuing abiraterone acetate and prednisone alone in men with MCRPC who have evidence of PSA progression but no evidence of symptomatic or radiographic progression that would require alternative therapy (e.g., needing radiation therapy for pain or significant progression of visceral metastases).

Patients on the control arm will be allowed to cross-over to receive OGX-427 following documented disease progression. Patients will be randomized with equal probability to one of the following arms:

EXPERIMENTAL ARM (Arm A):

OGX-427 Starting within 7 days of randomization, three loading doses of 600 mg intravenously (IV) within Week 1 if possible (up to 10 days of initiating treatment), followed by weekly doses of 800 mg IV

Continuation of standard therapy with abiraterone acetate 1000 mg by mouth (PO) daily and prednisone 10-20 mg PO daily

CONTROL ARM (Arm B):

Continuation of standard therapy with abiraterone acetate 1000 mg PO daily and prednisone 10-20 mg PO daily

After documented disease progression, patients on Arm B may opt to receive OGX-427 treatment (according to the Arm A schedule) following a screening evaluation (i.e., all inclusion and exclusion criteria have been met)

Both Arms:

Evaluations at 4 week-intervals. Disease assessments required at the milestone Day 60 assessment (expected to occur after 8 weeks of treatment and prior to Day 1, Week 9) and at 16, 24, 32, 40, and 48 weeks (if applicable) or until documented disease progression. Patients who are withdrawn from the study for a reason other than documented disease progression or patient withdrawal of consent will be followed every 4 weeks in the Off-Treatment Follow-up Period until documented disease progression.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Life Expectancy: Not Specified

Hematopoietic:

* Absolute neutrophil count (ANC) ≥ 1.5 x 109 cells /L, platelet count ≥ 100 x 109 /L, and hemoglobin ≥ 9 g/dL without transfusion

Hepatic:

* Total bilirubin ≤ 1.1 x upper limit of normal (ULN) unless elevated secondary to conditions such as Gilbert's disease, in which case a direct bilirubin ≤ ULN is required
* Serum glutamic pyruvic transaminase (SGPT), alanine transaminase (ALT) and alanine transaminase (SGOT) aspartate transaminase (AST) ≤ 3.0 x ULN

Renal:

* Creatinine ≤ 1.3 x ULN

Cardiac:

* Known left ventricular ejection fraction (LVEF) \<50% or New York Heart Association (NYHA) Functional Classification Class III or IV heart failure

Other:

* Castrate serum testosterone level (\< 50 ng/dL or \< 1.7 nmol/L)
* Potassium within normal limits

Eligibility Criteria:
Inclusion Criteria:

Subjects must meet ALL of the following criteria to be eligible for inclusion into the study.

* Histological or cytological diagnosis of adenocarcinoma of the prostate
* Metastatic disease on chest, abdominal, or pelvic computed tomography (CT) scan and/or bone scan
* Currently receiving abiraterone acetate and prednisone and meeting the following criteria:

  * Any PSA decline within 12 weeks from initiation of abiraterone acetate
  * Currently tolerating abiraterone acetate (1000 mg oral daily) and prednisone (10-20 mg oral daily)
  * PSA progression, defined as an increase in PSA which is ≥25% above the nadir and an absolute value of ≥2 ng/mL, which is confirmed by a second value ≥2 weeks later.
  * No evidence of symptomatic or radiographic progression that would require alternative therapy (e.g., needing radiation therapy for pain or significant progression of visceral metastases or \>33% increase in daily opioid use within 2 weeks prior to randomization).
* All patients who have not had a surgical orchiectomy must continue treatment with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist to maintain a castrate level of testosterone.
* Patient must fulfill "Prior Therapy" criteria as follows:

  * Chemotherapy: no more than 1 prior chemotherapy regimen for castrate-resistant prostate cancer (CRPC) is permitted; a minimum of at least 28 days must have passed since the last dose of chemotherapy.
  * Hormone therapy: hormonal androgen ablation therapy prior to abiraterone is required.
  * Experimental therapy: prior non-cytotoxic experimental therapy is permitted provided a minimum of at least 14 days has passed since completing therapy. Prior treatment with enzalutamide (MDV3100) is allowed.
  * Radiation: prior external beam radiation is permitted provided a minimum of at least 14 days have passed since completing radiotherapy (exception for radiotherapy: at least 7 days since completing a single fraction of ≤800 cGy to a restricted field or limited-field radiotherapy to non-marrow bearing area such as an extremity or orbit) at the time of randomization
* Must be willing to use effective contraception throughout study treatment and for 3 months after completion of study treatment if able to father a child.
* 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:

Subjects meeting ANY of the following exclusion criteria will NOT be eligible for inclusion into the study:

* Currently receiving abiraterone acetate in combination with any other anti-cancer agent (except prednisone)
* Documented brain metastases, or carcinomatous meningitis, treated or untreated (Brain imaging for asymptomatic patients is not required.)
* Cord compression requiring surgery or radiation therapy while on abiraterone treatment
* Active second malignancy (including lymphoid malignancies such as chronic lymphocytic leukemia or low grade lymphoma) defined, in general, as requiring anticancer therapy or at high risk of recurrence during the study; not including adequately treated non melanomatous skin cancer or other solid tumors curatively treated with no evidence of disease in \> 3 years
* History of allergic reactions to therapeutic antisense oligonucleotides
* Active autoimmune disease requiring treatment
* Participated in a prior Phase 3 clinical study evaluating custirsen regardless of study arm assignment (i.e., either control or investigational arm), or prior exposure to OGX-427
* Uncontrolled medical conditions such as 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.