Study in Japan and Ex-Japan to Characterize the Pharmacokinetic and Pharmacodynamic Response to Orteronel (TAK-700) in Chemotherapy-Naive Participants With Castration-Resistant Prostate Cancer

Study Overview
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Brief Summary
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This is a double-blind, placebo-controlled, multiregional Phase1/2 study to characterize the pharmacokinetic and pharmacodynamic responses to orteronel when administered concomitantly with prednisone in Chemotherapy-Naive Participants With Castration-Resistant Prostate Cancer

Detailed Description
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The drug being tested in this study is called orteronel. Orteronel is being tested to treat adult males who have adenocarcinoma of the prostate. This study will look at the pharmacokinetics (how the drug moves through the body) and pharmacodynamics (how the drug effects the body) in people who take orteronel in addition to prednisone. The study will enroll approximately 144 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the eight treatment groups (4 in Japan, 4 in Ex-Japan) which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). In Japan: Participants were randomized in a ratio of 2:1:2:1 200 mg orteronel or Placebo-matching orteronel [(dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient] twice daily (BID) + prednisone 300 mg orteronel, or Placebo-matching orteronel, BID + prednisone Ex-Japan Participants were randomized in a ratio of 2:1:2:1 200 mg orteronel or Placebo-matching orteronel, BID in Cycle 1 + prednisone 400 mg orteronel, or Placebo-matching orteronel ,BID in Cycle 1 + Prednisone Participants initially randomized to placebo received 4 weeks of placebo and then 12 weeks of active treatment with orteronel then entered a follow-up period treatment period. Participants initially randomized to orteronel received 16 weeks of treatment then entered a follow-up treatment period. This multi-centre trial will be conducted worldwide. The overall time to participate in this study is approximately 3.2 years. Participants will make multiple visits to the clinic and a final visit 30 to 40 days after receiving their last dose of study drug for a follow-up assessment.

Official Title
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A Study in Japan and Ex-Japan to Characterize the Pharmacokinetic and Pharmacodynamic Response to Orteronel (TAK-700) in Chemotherapy-Naive Patients With Castration-Resistant Prostate Cancer

Conditions
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Prostate Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male participants 18 years or older Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma Prior surgical castration or concurrent use of an agent for medical castration [e.g. Gonadotropin-releasing hormone (GnRH) analogue] Prostate-Specific Antigen (PSA) ≥ 2 ng/mL at screening Progressive disease based on PSA and/or radiographic criteria Exclusion Criteria: Prior therapy with orteronel, ketoconazole, aminoglutethimide, or abiraterone. Known hypersensitivity to compounds related to orteronel, orteronel excipients, prednisone (or commercially available equivalent), or GnRH analogue. All antiandrogen therapy (including bicalutamide) is excluded within 4 weeks before the first dose of study drug. Any other therapies for prostate cancer, other than GnRH analogue therapy, such as progesterone, medroxyprogesterone, progestins (megesterol), or 5- alpha reductase inhibitors (e.g., finasteride or dutasteride), must be discontinued 2 weeks before the first dose of study drug. Continuous daily use of oral prednisone (or commercially available equivalent), oral dexamethasone, or other systemic corticosteroids for more than 2 weeks within the 3 months before screening (inhaled, nasal, and local steroids [e.g., joint injection] are allowed). Prior chemotherapy for prostate cancer, with the exception of neoadjuvant/adjuvant therapy as part of initial primary treatment for local disease that was completed 2 or more years before screening. Please note that there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria. Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Placebo + Orteronel 200 mg (Japan)<br>Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 (28 days) followed by orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | Drug: Orteronel<br>* Orteronel tablets<br>Drug: Orteronel Placebo<br>* Orteronel placebo-matching tablets<br>Drug: Prednisone<br>* Prednisone 5 mg<br>|
| Experimental: Orteronel 200 mg (Japan)<br>Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | Drug: Orteronel<br>* Orteronel tablets<br>Drug: Prednisone<br>* Prednisone 5 mg<br>|
| Other: Placebo + Orteronel 300 mg (Japan)<br>Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 followed by orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | Drug: Orteronel<br>* Orteronel tablets<br>Drug: Orteronel Placebo<br>* Orteronel placebo-matching tablets<br>Drug: Prednisone<br>* Prednisone 5 mg<br>|
| Experimental: Orteronel 300 mg (Japan)<br>Orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | Drug: Orteronel<br>* Orteronel tablets<br>Drug: Prednisone<br>* Prednisone 5 mg<br>|
| Other: Placebo + Orteronel 200 mg (Ex-Japan)<br>Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 followed by orteronel 200 mg, tablets, orally, twice daily in 28 day cycles outside of Japan (Ex-Japan) for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | Drug: Orteronel<br>* Orteronel tablets<br>|
| Experimental: Orteronel 200 mg (Ex-Japan)<br>Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | Drug: Orteronel<br>* Orteronel tablets<br>Drug: Prednisone<br>* Prednisone 5 mg<br>|
| Other: Placebo + Orteronel 400 mg (Ex-Japan)<br>Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 followed by orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | Drug: Orteronel<br>* Orteronel tablets<br>Drug: Orteronel Placebo<br>* Orteronel placebo-matching tablets<br>Drug: Prednisone<br>* Prednisone 5 mg<br>|
| Experimental: Orteronel 400 mg (Ex-Japan)<br>Orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | Drug: Orteronel<br>* Orteronel tablets<br>Drug: Prednisone<br>* Prednisone 5 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL After 4 Weeks of Treatment in Japan | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. | Baseline and Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL in Ex-Japan | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. | Baseline and Week 4 | 
| Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. | Baseline and Week 4 | 
| Percent Change From Baseline in Serum Testosterone Level After 12 Weeks of Treatment | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. | Baseline and Week 12 | 
| Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment | A 50% PSA response rate (PSA50) was defined as PSA reduction ≥ 50% from Baseline. | Baseline and Week 4 | 
| Percentage of Participants With PSA50 After 12 Weeks of Treatment | A 50% PSA response rate (PSA50) was defined as PSA reduction ≥ 50% from Baseline. | Baseline and Week 12 | 
| Absolute Values for Testosterone | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | 
| Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Serum Ultra low level quantification of DHEA-S was measured by liquid chromatography and mass spectrometry (LC/MS) at a central laboratory. | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | 
| Absolute Values for Adrenocorticotropic Hormone (ACTH) | Serum ACTH was measured by immunometric assay at the central laboratory. | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | 
| Absolute Values for Corticosterone | Serum Corticosterone was measured by high pressure liquid chromatography with mass spectrometry at the central laboratory. | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | 
| Absolute Values for Cortisol | Serum Cortisol was measured by immunometric assay at the central laboratory. | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | 
| Absolute Values for Prostate-Specific Antigen (PSA) | Serum PSA was measured at the central laboratory. | Baseline and Cycle 2 Day 1 | 
| Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | 
| AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | AUC(0-12) is measure of area under the curve over the dosing interval where the length of the dosing interval is time 0 to 12 hours in this study. | Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. | Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | 
| AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Cumulative amount of urine excreted time 0 to 24 hour. | Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | 
| Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Maximum observed steady-state plasma concentration during a dosing interval. | Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | 
| Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax at steady state. | Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | 
| AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval. | Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | 
| Rac: Accumulation Index for Orteronel and M-I Metabolite | Rac was calculated as the ratio of AUCtau to AUC12hr. | Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | 
| Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Observed predose plasma concentration at steady state. | Cycle 1 Day 8 Predose | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding),symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. | From signing of the informed consent form through 30 days after the last dose of study drug, approximately 3.2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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orteronel,, CRPC,, castrate resistant prostate cancer,, TAK-700