Comparison of Docetaxel/Prednisone to Docetaxel/Prednisone in Combination With OGX-011 in Men With Prostate Cancer

Study Overview
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Brief Summary
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This Phase 3 study has been designed to confirm that adding custirsen to standard first-line docetaxel/prednisone treatment can slow tumor progression and enhance survival outcomes compared to standard first-line docetaxel/prednisone treatment alone. This will be a randomized, open-label, multicenter, international trial. Treatment will consist of docetaxel/prednisone/custirsen vs. docetaxel/prednisone. A total of at least 1000 patients will be randomized. Patients will be randomly assigned with equal probability to the two arms.

Official Title
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A Randomized Phase 3 Study Comparing Standard First-Line Docetaxel/Prednisone to Docetaxel/Prednisone in Combination With Custirsen (OGX-011) in Men With Metastatic Castrate Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Custirsen
* Drug: Docetaxel
* Drug: Prednisone
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age ≥ 18 years on the date of consent. Histological or cytological diagnosis of adenocarcinoma of the prostate. Metastatic disease on chest, abdominal, or pelvic CT and/or bone scan. Systemic chemotherapy indicated due to progression while on or after androgen ablative therapy defined as: Progressive measurable disease: at least a 20% increase in the sum of the longest diameters of measurable lesions over the smallest sum observed -or- the appearance of one or more new lesions as assessed by CT scan during hormone ablation treatment. Measurable lesions are nodal or visceral soft-tissue lesions with nodal lesions ≥ 20 mm in diameter or visceral/soft-tissue lesions ≥ 10 mm in diameter (see Section 6.3.1.1 ). OR Bone Scan Progression: appearance of 2 or more new lesions on bone scan during hormone ablation treatment. OR Increasing serum prostate-specific antigen (PSA) level: Two consecutive increases in PSA levels documented over a previous reference value obtained at least one week apart are required. If the third PSA value is less than the second, an additional fourth test to confirm a rising PSA is acceptable. A minimum starting value of 5.0 ng/mL is required for study randomization. Baseline laboratory values as stated below: Creatinine ≤ 1.5 x upper limit of normal (ULN). Bilirubin ≤ 1.1 x ULN (unless elevated secondary to conditions such as Gilbert's disease). Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) ≤ 1.5 x ULN. Castrate serum testosterone level (< 50 ng/dL-or-< 1.7 nmol/L). Must be willing to continue primary androgen suppression with gonadotropin-releasing hormone (GnRH) analogues (either agonists or antagonists) throughout the study, unless treated with bilateral orchiectomy. Adequate bone marrow function defined at screening as absolute neutrophil count (ANC) ≥ 1.5 x 10^9 cells /L and platelet count ≥ 100 x 10^9 /L. Karnofsky score ≥ 70% (see Appendix 17.2). At least 28 days has passed since completing radiotherapy (exception for radiotherapy: at least 7 days since completing a single fraction of ≤ 800 centigray (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. At least 4 weeks have passed since receiving any investigational agent at the time of randomization. Has recovered from any other therapy-related toxicity to ≤ grade 2, (except alopecia, anemia and any signs or symptoms of androgen deprivation therapy). Patient must be willing to not add, delete or change their current bisphosphonate or denosumab usage throughout study treatment to assure that adverse event reporting is not confounded by changing their bisphosphonate or denosumab usage (unless withdrawn or changed as a result of bisphosphonate or denosumab associated toxicity). Patients receiving more than 10 mg of prednisone per day (or steroid equivalent) at screening must be willing to have the dose reduced to 10 mg of prednisone per day for at least 7 days prior to randomization and maintained throughout study treatment. Written informed consent must be obtained prior to any protocol-specific procedures being performed. Exclusion Criteria Received any other cytotoxic chemotherapy as treatment for prostate cancer. Received any cycling, intermittent or continuous hormonal treatment 28 days prior to randomization with the exception of the continuous GnRH analogues required in Inclusion Criteria #6. Participated in a prior clinical study evaluating custirsen. History of or current documented brain metastasis 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 non-melanomatous skin or superficial bladder cancer) defined as requiring anticancer therapy or at high risk of recurrence during the study. Active second malignancy (except non melanomatous skin or superficial bladder cancer) defined as requiring cancer therapy or at high risk of reoccurrence during the study 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Custirsen, Docetaxel, Prednisone<br>Three doses of 640 mg custirsen administered intravenously (IV) as a loading dose between Days -9 to -1. Custirsen, 640 mg, given IV weekly on Days 1, 8, and 15 of each 21-day cycle. Docetaxel (75 mg/M^2 via intravenous injection) on Day 1 of every 21 days plus prednisone (5 mg tablets taken by mouth) twice each day and dexamethasone (8 mg by mouth twice a day for 3 days beginning one day before docetaxel administration). Treatment continues for 10 cycles or until unacceptable toxicity or disease progression. | Drug: Custirsen<br> <br> * Other names: OGX-011;Drug: Docetaxel<br> <br> Drug: Prednisone<br> <br> Drug: Dexamethasone<br>* Dexamethasone 8 mg by mouth twice a day for 3 days beginning one day before docetaxel administration to reduce the incidence and severity of hypersensitivity reactions and fluid retention.<br>|
| Active Comparator: Docetaxel, Prednisone<br>Docetaxel (75 mg/M^2 via intravenous injection) on Day 1 of every 21 days plus prednisone (5 mg tablets taken by mouth) twice each day and dexamethasone (8 mg by mouth twice a day for 3 days beginning one day before docetaxel administration). Treatment continues for 10 cycles or until unacceptable toxicity or disease progression. | Drug: Docetaxel<br> <br> Drug: Prednisone<br> <br> Drug: Dexamethasone<br>* Dexamethasone 8 mg by mouth twice a day for 3 days beginning one day before docetaxel administration to reduce the incidence and severity of hypersensitivity reactions and fluid retention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimates for Time to Death (Overall Survival) | Time from the date of randomization to death from any cause. After stopping treatment, patients were followed every 4 weeks until disease progression and then followed every 12 weeks until death. | Randomization (approximately Day -12) to longest survival follow-up (Day 971). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Were Alive Without Event At Day 140 | Patients who were alive without event (AWE) are patients who had their Milestone Day 140 Disease Status performed per protocol (Day 125 - Day 155 window), were not determined to have disease progression by the investigator on that window and confirmed as not having progressive disease (NONPD) by the Central Imagine Lab independent review. | Day 125-155 | 
| Percentage of Participants with Adverse Events | An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the administration, at any dose, of a medicinal or therapeutic product whether or not considered related to that product. Severity was rated by the investigator on a scale of 1 (mild) to 5 (death). A severity of 3 = Severe or medically significant but not immediately life-threatening. A severity of 4 = Life-threatening. Serious AEs include death (death due to progressive disease were not reported as an SAE), a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. | Docetaxel/prednisone/custirsen arm: Days -9 up to Day 743. Docetaxel/prednisone arm: Day 1 up to Day 400. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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custirsen sodium, prostate cancer, overall survival, Metastatic Castrate Resistant Prostate Cancer