Study Comparing Orteronel Plus Prednisone in Participants With Metastatic Castration-Resistant Prostate Cancer.

Study Overview
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Brief Summary
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This is a randomized, double-blind, multicenter, phase 3 study evaluating orteronel plus prednisone compared with placebo plus prednisone in men with metastatic, castration-resistant prostate cancer (mCRPC) that has progressed following Docetaxel-based therapy

Official Title
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A Phase 3, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or Following Docetaxel-based Therapy.

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Orteronel
* Drug: Prednisone
* Drug: Orteronel Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each participant must meet all of the following inclusion criteria: Voluntary written consent Male 18 years or older Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma Radiograph-documented metastatic disease Progressive disease Prior surgical castration or concurrent use of an agent for medical castration Progressive disease during or following 1 or 2 regimens of cytotoxic chemotherapy, 1 of which must have included docetaxel. Must have received greater than or equal to (>=) 360 milligram per square meter (mg/m^2) of docetaxel within a 6-month period. Participants who were clearly intolerant to docetaxel or develop progressive disease before receiving >= 360 mg/m^2 are also eligible if they have received at least 225 mg/m^2 of docetaxel within a 6-month period and meet the other study entry criteria. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 Even if surgically sterilized, participants must practice effective barrier contraception during the entire study treatment period and for 4 months after the last dose of study drug, OR Abstain from heterosexual intercourse Screening laboratory values as specified in protocol Stable medical condition Life expectancy of 6 months or more Participants who have had up to 2 prior chemotherapy treatments are eligible to participate Exclusion Criteria: Participants meeting any of the following exclusion criteria are not to be enrolled in the study: Known hypersensitivity to orteronel, prednisone or gonadotropin-releasing hormone (GnRH) analogue Received prior therapy with orteronel, aminoglutethimide, ketoconazole or abiraterone Any other therapies for prostate cancer, except for GnRH analogue therapy, must be discontinued 2 weeks before the first dose of study drug Radioisotope therapy or external beam radiation therapy within 4 weeks of first dose of study drug Documented central nervous system metastases Treatment with any investigational compound within 30 days prior to first dose of study drug (Participants who are in long-term follow-up following active treatment in other trials are eligible) Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected Uncontrolled cardiovascular condition as specified in study protocol Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C Unwilling or unable to comply with protocol Known gastrointestinal disease or procedure that could interfere with oral absorption or tolerance of orteronel Uncontrolled nausea, vomiting, or diarrhea despite appropriate medical therapy Prostate cancer confined to just the prostrate bed or immediate adjacent tissue

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Orteronel + prednisone<br> | Drug: Orteronel<br>* Orteronel tablets<br>* Other names: TAK-700;Drug: Prednisone<br>* Prednisone tablets<br>|
| Placebo Comparator: Placebo + prednisone<br> | Drug: Prednisone<br>* Prednisone tablets<br>Drug: Orteronel Placebo<br>* Orteronel placebo-matching tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was calculated from the date of participant randomization to the date of participant death due to any cause. Participants without documentation of death at time of the analysis were censored as of the date the participant was last known to be alive, or the data cutoff date, whichever was earlier. | Baseline until death (approximately up to 4.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-free Survival (rPFS) | rPFS was defined as the time from randomization until radiographic disease progression or death due to any cause, whichever occurred first. Radiographic disease progression was defined as the occurrence of 1 or more of the following: The appearance of 2 or more new lesions on radionuclide bone scan as defined by prostate cancer working group (PCWG)2; Should 2 or more new bone lesions be evident at the first assessment (8-week assessment) on treatment, 2 or more additional new lesions must have been evident on a confirmatory assessment at least 6 weeks later; One or more new soft tissue/visceral organ lesions identified by computed tomography (CT)/magnetic resonance imaging (MRI); Progression as defined by response evaluation criteria in solid tumors (RECIST) 1.1 criteria. | Baseline until disease progression or death, whichever occurred first (approximately up to 4.5 years) | 
| Percentage of Participants Achieving 50 Percent Reduction From Baseline in Prostate Specific Antigen (PSA50 Response) at Week 12 | The PSA50 was defined as the percentage of participants who had a PSA decline of at least 50 percent (%) from baseline. | Week 12 | 
| Percentage of Participants With Pain Response at Week 12 | Pain response was defined as the occurrence of 1 of the following and confirmed by an additional assessment, at least 3 weeks but not more than 5 weeks later: A greater than or equal to (>=) 2 point reduction from baseline in BPI-SF worst pain score without an increase in analgesic use; or a 25 percent (%) or more reduction in analgesic use from baseline without an increase in worst pain score from baseline. | Week 12 | 
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) |  | Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58) | 
| Number of Participants With Abnormal Physical Examination Findings |  | Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58) | 
| Number of Participants With TEAEs Related to Vital Signs |  | Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58) | 
| Number of Participants With TEAEs Related to Weight |  | Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58) | 
| Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status | ECOG assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours [hrs]), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead. Worst change was defined as the worst overall change that occurred in ECOG status at any measured time point during the treatment period. | Baseline up to End-of-treatment (EOT) (Cycle 59 Day 58) | 
| Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings |  | Cycle 59 Day 58 | 
| Number of Participants With TEAEs Categorized Into Investigations Related to Chemistry, Hematology or Steroid Hormone Panel |  | Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58) | 
| Percentage of Participants Achieving PSA50 Response at Any Time During the Study | The PSA50 was defined as the percentage of participants who had a PSA decline of at least 50% from baseline. | Cycle: 4, 7, 10, 13, 16, 19, 22, and 25 | 
| Percentage of Participants Achieving 90 Percent Reduction From Baseline in Prostate Specific Antigen (PSA90 Response) at Week 12 | The PSA90 was defined as the percentage of participants who had a PSA decline of at least 90% from baseline. | Week 12 | 
| Percentage of Participants Achieving PSA90 Response at Any Time During the Study | The PSA90 was defined as the percentage of participants who had a PSA decline of at least 90% from baseline. | Cycle: 7, 10, 13, 16, 19, 22, and 25 | 
| Best PSA Response at Any Time During the Study | The PSA50 was defined as the percentage of participants who had a PSA decline of at least 50% from baseline. PSA90 was defined as the percentage of participants who had a PSA decline of at least 90% from baseline. | Cycle: 4, 7, 10, 13, 16, 19, 22, and 25 | 
| Time to PSA Progression | Time to PSA progression was defined as time from randomization to a PSA increase of 25% and PSA rise of at least 2 nanogram per milliliter (ng/mL) above the lowest value observed post baseline or, if no PSA decline occurred post baseline, above the baseline PSA. | Baseline until the final on treatment assessment or until end of short term follow-up following discontinuation of treatment, whichever occurred later (approximately up to 4.5 years) | 
| Number of Participants With Shifts From Baseline Between Favorable and Unfavorable Categories in Circulating Tumor Cell Count (CTC) | A favorable CTC count was defined as less than (<) 5 counts per (/) 7.5 mililiter (mL) in whole blood. An unfavorable CTC count was defined as >=5 counts/7.5 mL in whole blood. | Baseline and EOT (Cycle 59 Day 58) | 
| Percentage of Participants With Objective Response | Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1. The overall objective response was defined as a complete response (CR) or partial response (PR). A complete response (CR) was defined as the disappearance of all target lesions determined by computerized tomography (CT) or MRI. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to <10 millimetre (mm). A PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of longest diameters of non-lymph node lesions and of the short diameter(s) or short axis of lymph nodes. | Baseline until disease progression or death, whichever occurred first (approximately up to 4.5 years) | 
| Time to Pain Progression | Time to pain progression was defined as the time from participant randomization to the first assessment date of pain progression. Pain progression was defined as the occurrence of 1 of the following and confirmed by an additional assessment, at least 3 weeks but not more than 5 weeks later: The brief pain inventory-short form (BPI-SF) worst pain score was >= 4 with a >= 2 point increase over baseline in BPI-SF worst pain score with stable or increased analgesic use; The BPI-SF worst pain score was >= 4 but not less than baseline with new or increased (relative to baseline) Step II or Step III analgesic use; The BPI-SF worst pain score was <= 3 but not less than baseline with new or increased (relative to baseline) Step III analgesic use. | Baseline until EOT visit or until end of short term follow-up, whichever occurred later (approximately up to 4.5 years) | 
| Time to Pain Response | Time to pain response was defined as the time from randomization until first pain response. Pain response was defined as the occurrence of 1 of the following and confirmed by an additional assessment, at least 3 weeks but not more than 5 weeks later: A >= 2 point reduction from baseline in BPI-SF worst pain score without an increase in analgesic use, or a 25% or more reduction in analgesic use from baseline without an increase in worst pain score from baseline. The analysis was performed by Kaplan-Meier method. | Baseline until disease progression or death, whichever occurred first (approximately up to 4.5 years) | 
| Number of Participants With Best Pain Response | Best pain response was evaluated in participants who had a pain response across the entire study were summarized by treatment group. The pain response was defined as a >=2-point reduction from baseline in BPI-SF worst pain score without an increase in analgesic use, or a 25% or more reduction in analgesic use from baseline without an increase in worst pain score from baseline. | Baseline until disease progression or death, whichever occurred first (approximately up to 4.5 years) | 
| Percentage of Participants With Health-related Quality of Life (HRQOL) Response at Week 12 | The global health status or quality of life (QOL) was measured as the HRQOL response rate at 12 weeks using the 2-item global health status index of the european organization for research and treatment of cancer-quality of life questionnaire-C30 (EORTC QLQ-C30) instrument. HRQOL response was defined as a 17-point increase from the baseline assessment on the QOL index, after the score had been linearly transformed to a 0 to 100 scale. EORTC QLQ-C30: included 5 functional scales (physical, role, cognitive, emotional, and social), 1 global health status, 3 symptom scales (fatigue, pain, nausea/vomiting) and 6 single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score representing better level of functioning or greater degree of symptoms. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy