Comparison of Cabazitaxel/Prednisone Alone or in Combination With Custirsen for 2nd Line Chemotherapy in 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 cabazitaxel/prednisone treatment can slow tumor progression and enhance survival outcomes compared to standard cabazitaxel/prednisone treatment in men with metastatic castrate resistant prostate cancer (CRPC). This will be a randomized, open-label, multicenter, international trial. Treatment will consist of cabazitaxel/prednisone/custirsen vs. cabazitaxel/prednisone. A total of approximately 630 patients will be randomized with equal probability to the two arms.

Detailed Description
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Until recently, options for second-line chemotherapy in CRPC have included docetaxel retreatment, mitoxantrone, or other chemotherapies, without proven clinical benefit. In 2010, a Phase 3 second-line chemotherapy trial (TROPIC) showed a survival advantage for cabazitaxel, a semi-synthetic taxane selected to overcome the emergence of taxane resistance, when compared to mitoxantrone. Clusterin is a stress-activated cytoprotective chaperone up-regulated by a variety of anti-cancer therapies that confers treatment resistance when over-expressed. Inhibition of clusterin expression using custirsen has been shown to enhance tumor cell death following treatment with chemotherapy. The clinical activity of custirsen in combination with the taxane docetaxel has been shown in two Phase 2 studies. Given the results observed using a taxane as either first-line or second-line chemotherapy in CRPC, combination with custirsen may decrease taxane resistance and enhance the survival benefit of taxane therapy. Thus, a combination of custirsen with cabazitaxel may further enhance survival in second-line taxane chemotherapy for CRPC.

Official Title
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A Randomized Phase 3 Study Comparing Cabazitaxel/Prednisone in Combination With Custirsen (OGX-011) to Cabazitaxel/Prednisone for Second-Line Chemotherapy in Men With Metastatic Castrate Resistant Prostate Cancer (AFFINITY)

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: cabazitaxel
* Drug: prednisone
* Drug: custirsen sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of adenocarcinoma of the prostate Metastatic disease on chest, abdominal, or pelvic CT scan and/or bone scan Previous first-line treatment for CRPC with a docetaxel-containing regimen Current progressive disease Increasing serum PSA level (for patients who progress based only on increasing serum PSA level, a minimum starting value of 5.0 ng/mL is required) Baseline laboratory values as defined Willing to continue primary androgen suppression with gonadotropin-releasing hormone (GnRH) analogues (unless treated with bilateral orchiectomy) Karnofsky score ≥70% At least 21 days have passed since completing radiotherapy At least 21 days have passed since receiving any investigational agent at the time of randomization At least 21 days have passed since major surgery Recovered from any docetaxel therapy-related neuropathy to ≤grade 1 at the time of randomization Recovered from all therapy related toxicity to ≤grade 2 (except alopecia, anemia, and any signs or symptoms of androgen deprivation therapy) at the time of randomization Able to tolerate a starting dose of 25 mg/m² cabazitaxel Willing to not add, delete, or change current bisphosphonate or denosumab usage Able to tolerate oral prednisone at 10 mg per day Competent to provide written informed consent Exclusion Criteria: Received any other cytotoxic chemotherapy beyond the first-line docetaxel-containing regimen as treatment for prostate cancer Received prior radioisotope with strontium 89 or samarium 153 Received any cycling, intermittent, or continuous hormonal treatment within 21 days prior to randomization with the exception of the continuous GnRH analogues (prior treatment with abiraterone or MDV3100 is allowed as long as 21 days have passed since last dose) Participated in a prior Phase 3 clinical study evaluating custirsen regardless of study arm assignment Requiring ongoing treatment during the study with medications known to be either strong CYP3A inhibitors or strong CYP3A inducers History of or current documented brain metastasis or carcinomatous meningitis, treated or untreated Current symptomatic cord compression requiring surgery or radiation therapy Active second malignancy (except non melanomatous skin or superficial bladder cancer) defined in general as requiring anticancer therapy or at high risk of recurrence during the study Uncontrolled medical condition or significant concurrent illness that in the opinion of the Investigator would preclude protocol therapy Known severe hypersensitivity to taxanes or polysorbate 80-containing drugs Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device
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: Cabazitaxel plus Custirsen<br>cabazitaxel, prednisone, and custirsen sodium | Drug: cabazitaxel<br>* Cabazitaxel (25mg/m² IV) is administered on day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or completion of 10 cycles<br>Drug: prednisone<br>* Prednisone (10 mg PO) is administered daily until disease progression, unacceptable toxicity, or completion of 10 cycles<br>Drug: custirsen sodium<br>* Custirsen is administered as 3 loading doses (640 mg IV each) within 9 days, followed by weekly custirsen (640 mg IV) during each 21-day cycle until disease progression, unacceptable toxicity, or completion of 10 cycles<br>* Other names: TV-1011;|
| Active Comparator: Cabazitaxel<br>cabazitaxel and prednisone | Drug: cabazitaxel<br>* Cabazitaxel (25mg/m² IV) is administered on day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or completion of 10 cycles<br>Drug: prednisone<br>* Prednisone (10 mg PO) is administered daily until disease progression, unacceptable toxicity, or completion of 10 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival in the intent-to-treat population | To determine whether the survival for patients randomized to the investigational arm (cabazitaxel/prednisone plus custirsen) is consistent with longer survival as compared to patients randomized to the control arm (cabazitaxel/prednisone). | 3.4 years | 
| Survival in the poor-prognosis patient population | To determine whether the survival for patients randomized to the investigational arm (cabazitaxel/prednisone plus custirsen) and identified as having poor prognosis is consistent with longer survival as compared to patients randomized to the control arm (cabazitaxel/prednisone) and identified as having poor prognosis. | 2.7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival at Day 140 | To compare the arms with respect to the proportion of patients having a milestone Day 140 status of Alive Without Event (within the window of Day 125-155 post-randomization). An event is defined as disease progression or death on or before Day 140. | From randomization to Day 125 to Day 155 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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custirsen sodium, prostate cancer, metastatic castrate resistant prostate cancer, overall survival