Safety, Pharmacokinetic and Proof-of-Concept Study of ARN-509 (Apalutamide) in Castration-Resistant Prostate Cancer (CRPC)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and activity of ARN-509 in men with advanced castration resistant prostate cancer. Patients will first be enrolled into Phase 1 of the study to identify a tolerable dose for the Phase 2 portion of the study. In the Phase 2, 3 different cohorts of patients will be enrolled to evaluate the safety and activity of ARN-509.

Official Title
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An Open-Label, Phase 1/2, Safety, Pharmacokinetic and Proof-of-Concept Study of ARN-509 in Patients With Progressive Advanced Castration-Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: ARN-509 (Phase 1)
* Drug: ARN-509 (Phase 2)


Participation Criteria
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Eligibility Criteria
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NON-METASTATIC CRPC Inclusion Criteria Histologically or cytologically proven prostate cancer with high risk for development of metastases, defined as either a PSA value >=8 ng/mL within the last 3 months or PSA Doubling Time <=10 months Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration) Castrate levels of serum testosterone of less than or equal to 50 ng/dL Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 A life expectancy of at least 3 months Exclusion Criteria Distant metastases, including CNS and vertebral or meningeal involvement Prior treatment with MDV3100 Prior treatment with abiraterone Prior treatment with ketoconazole Concurrent treatment with medications known to have seizure potential Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible. QTc > 450 msec History of seizure or condition that may predispose to seizure Evidence of severe or uncontrolled systemic disease or HIV infection METASTATIC CRPC, TREATMENT-NAIVE Inclusion Criteria Histologically or cytologically proven prostate cancer with progressive disease based on either PSA or radiographic progression Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration) Castrate levels of serum testosterone of less than or equal to 50 ng/dL Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 A life expectancy of at least 3 months Exclusion Criteria History of, or current metastases in the brain or untreated spinal cord compression Prior treatment with MDV3100 Prior treatment with abiraterone Prior treatment with ketoconazole Concurrent treatment with medications known to have seizure potential Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible. QTc > 450 msec History of seizure or condition that may predispose to seizure Evidence of severe or uncontrolled systemic disease or HIV infection METASTATIC CRPC, CHEMOTHERAPY-NAIVE, POST-ABIRATERONE Inclusion Criteria Histologically or cytologically proven prostate cancer with progressive disease based on either PSA or radiographic progression Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration) Castrate levels of serum testosterone of less than or equal to 50 ng/dL Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 A life expectancy of at least 3 months Patients must have received a minimum of 6 months of abiraterone treatment prior to disease progression Exclusion Criteria History of, or current metastases in the brain or untreated spinal cord compression Prior treatment with MDV3100 Prior treatment with ketoconazole Concurrent treatment with medications known to have seizure potential Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible. QTc > 450 msec History of seizure or condition that may predispose to seizure Evidence of severe or uncontrolled systemic disease or HIV infection

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohort (Phase 1)<br>ARN-509 will be administered at a starting dose of 30 milligram per day (mg/day), with escalations to 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 390 mg, and 480 mg daily. Once Recommended Phase 2 Dose (RP2D) has been selected, Phase 1 participants being treated at the lower dose levels will be allowed to escalate to the RP2D level at the discretion of the primary investigator. | Drug: ARN-509 (Phase 1)<br>* ARN-509 will be administered at a starting dose of 30 milligram per day (mg/day), with escalations to 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 390 mg, and 480 mg daily.<br>|
| Experimental: Non-metastatic CRPC (Phase 2)<br>Participants with non-metastatic, treatment-naive Castration-Resistant Prostate Cancer (CRPC) with rapidly rising Prostate Specific Antigen (PSA) will be enrolled. ARN-509 will be administered at Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), determined in Phase 1. | Drug: ARN-509 (Phase 2)<br>* ARN-509 will be administered at Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), determined in Phase 1.<br>|
| Experimental: Treatment-naive metastatic CRPC (Phase 2)<br>Participants with treatment-naive metastatic CRPC will be enrolled. ARN-509 will be administered at MTD and/or RP2D, determined in Phase 1. | Drug: ARN-509 (Phase 2)<br>* ARN-509 will be administered at Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), determined in Phase 1.<br>|
| Experimental: Post-abiraterone metastatic CRPC (Phase 2)<br>Participants with metastatic CRPC that are chemotherapy-naive, but have been previously treated with abiraterone will be enrolled. ARN-509 will be administered at MTD and/or RP2D, determined in Phase 1. | Drug: ARN-509 (Phase 2)<br>* ARN-509 will be administered at Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), determined in Phase 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and 2: Percentage of Participants With Greater Than or Equal to (>=) 50 Percent (%) Reduction in Prostate-Specific Antigen (PSA) at Week 12 | Percentage of participants with >=50% decrease in PSA compared to baseline were assessed at Week 12. PSA progression was defined by the protocol-specific Prostate Cancer Working Group 2 (PCWG2) criteria: PSA increase greater than or equal to [>=] 25 percent [%] and >=2 nanogram per milliliter [ng/mL] above the nadir confirmed >=3 weeks later; or >=25% and >=2 ng/mL above baseline PSA after 12 weeks. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and 2: Median Time to PSA Progression | Time to PSA progression was measured as the time interval from the date of the first dose to the date of PSA progression as defined by the PCWG2 criteria. PCWG2 criteria: For participants who achieved >=50% decrease from the baseline PSA, assessment of time to disease progression was when the PSA increased 25% and at a minimum of 2 ng/mL above the nadir at 3 or more weeks later. For participants without a PSA decrease, the time for progression was calculated at the time when the PSA progression was >=25% and >=2 ng/mL after 12 weeks. | Up to approximately 7 years | 
| Phase 2: Median Metastasis-Free Survival (MFS) | MFS was defined as the time from the start of treatment until new metastatic lesions were observed on Computed Tomography/ Magnetic Resonance Imaging (CT/MRI) scans or radionuclide bone scans (according to PCWG2 criteria: appearance of >=2 new lesions, and, for the first reassessment only, a confirmatory scan performed 6 or more weeks later that showed at least 2 or more additional new lesions) or death, whichever occurred first. | Up to approximately 7 years | 
| Phase 1 and 2: Progression-free Survival (PFS) | PFS was defined as the time from randomization to the radiographic disease progression or death, whichever occurred first. Radiographic progression defined by at least one of the following: a) Soft tissue progression by modified RECIST confirmed on repeat imaging >= 6 weeks later; b) Progression by bone scans: 1) first bone scan with >= 2 new lesions compared to baseline observed <12 weeks from start date and confirmed on a second bone scan >=6 weeks later that showed >=2 additional lesions (a total of >=4 new lesions compared to baseline); or 2) first bone scan with >=2 new lesions compared to baseline observed >=12 weeks from start date and the new lesions verified on the next bone scan >=6 weeks later (a total of >=2 new lesions compared to baseline). | Up to approximately 7 years | 
| Phase 1 and 2: Objective Response Rate | Objective Response Rate was defined as the percentage of participants with best overall response (OR) of confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors, Version 1.0 (RECIST). Where, CR defined as disappearance of all target lesions. Any pathological lymph nodes must had reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions. Confirmed responses were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response. | Up to approximately 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Metastatic, Rising PSA, Castration-Resistant, Treatment-Naive, Post-abiraterone