A Study of EPI-7386 in Combination With Abiraterone Acetate Plus Prednisone, or Apalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC)

Study Overview
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Brief Summary
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The purpose of this study is to determine safety, including dose limiting toxicities, and the recommended phase 2 dose (RP2D) of EPI-7386 in separate combinations with (a) abiraterone acetate plus prednisone or prednisolone (AAP) and (b) apalutamide (dose-finding) and to determine the antitumor activity of EPI-7386 in separate combinations with (a) AAP and (b) apalutamide (dose-expansion).

Official Title
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A Phase 1b Study of EPI-7386 in Combination With Abiraterone Acetate Plus Prednisone or Apalutamide in mCRPC (ARES: Androgen Receptor Eradication Study)

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: EPI-7386
* Drug: Abiraterone Acetate
* Drug: Prednisone or Prednisolone
* Drug: Apalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed prostate adenocarcinoma Must be able to continue Gonadotropin-releasing hormone agonist (GnRHa) during the study if not surgically castrate Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1, or 2 Must be able to swallow oral medicines Contraceptive use by men (and female partners of men enrolled in the study who are of childbearing potential or are pregnant) (birth control) use should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies Willing and able to adhere to the prohibitions and restrictions specified in this protocol Exclusion Criteria: Known central nervous system (CNS) metastases Non-metastatic castration-resistant prostate cancer (CRPC) (biochemical or locoregional disease only) is excluded from trial participation Evidence of predominant neuroendocrine/small cell carcinoma features in archival or baseline tumor biopsy specimen(s) Symptomatic or impending spinal cord compression, except if participant has received definitive treatment and demonstrates evidence of clinically stable disease Known disorder affecting gastrointestinal absorption

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: EPI-7386 + Abiraterone Acetate Plus Prednisone (AAP)<br>Participants with metastatic castration-resistant prostate cancer (mCRPC) will receive EPI-7386 + AAP to determine the recommended phase 2 dose (RP2D) dose of EPI-7386 in combination with AAP in dose finding portion of the study. In dose expansion portion of the study, participants will receive EPI-7386 RP2D in combination with AAP. | Drug: EPI-7386<br>* EPI-7386 will be administered orally once daily.<br>Drug: Abiraterone Acetate<br>* Abiraterone Acetate will be administered orally once daily.<br>Drug: Prednisone or Prednisolone<br>* Prednisone or Prednisolone will be administered orally twice daily.<br>|
| Experimental: Group B: EPI-3786 + Apalutamide<br>Participants with mCRPC will receive EPI-7386 + apalutamide to determine RP2D dose of EPI-7386 in combination with apalutamide in dose finding portion of the study. In dose expansion portion of the study, participants will receive EPI-7386 RP2D in combination with apalutamide. | Drug: EPI-7386<br>* EPI-7386 will be administered orally once daily.<br>Drug: Apalutamide<br>* Apalutamide will be administered orally once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Up to 3 Years 3 Months | 
| Number of Participants with AEs by Severity | Number of participants with AEs by severity will be reported. | Up to 3 Years 3 Months | 
| Number of Participants with Dose-limiting Toxicities (DLT) | The DLTs are specific adverse events and are defined as any of the following: high grade non-hematologic toxicity, or hematologic toxicity. | Up to 28 days of Cycle 1 (each cycle of 28 days) | 
| Composite Response Rate | Composite response rate at 12 weeks, defined as either 90 percent (%) reduction in prostate-specific antigen (PSA) level from baseline (PSA-90), or objective response (confirmed per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) in participants with measurable disease, or both at 12 weeks. | At 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) of EPI-7386 and Abiraterone | Cmax is defined as the maximum observed serum concentration of EPI-7386 and abiraterone. | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) of EPI-7386 and Abiraterone | Tmax is defined as the time to reach maximum observed serum concentration of EPI-7386 and abiraterone. | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Area Under the Curve From Time Zero to tau (AUC[0-tau]) of EPI-7386 and Abiraterone | AUC(0-tau) is defined as area under the curve from time 0 to tau hours post dose of EPI-7386 and abiraterone. | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Minimum Observed Serum Concentration (Cmin) of EPI-7386 and Abiraterone | Cmin is the minimum observed serum concentration of EPI-7386 and abiraterone. | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Observed Accumulation Index Based on Cmax (ARCmax) of EPI-7386 and Abiraterone | The observed accumulation ratio for Cmax, determined after multiple dose administration of EPI-7386 and abiraterone (Cycle[C] 2 Day[D] 1/C1D1 and C3D1/C1D1). | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Accumulation Ratio for AUCtau (AR AUCtau) of EPI-7386 and Abiraterone | The observed accumulation ratio for AUCtau, determined after multiple dose administration of EPI-7386 and abiraterone (C2D1/C1D1 and C3D1/C1D1). | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Maximum Observed Serum Concentration (Cmax) of EPI-7386 and Apalutamide | Cmax is defined as the maximum observed serum concentration of EPI-7386 and apalutamide. | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) of EPI-7386 and apalutamide | Tmax is defined as the time to reach maximum observed serum concentration of EPI-7386 and apalutamide. | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Area Under the Curve From Time Zero to tau (AUC[0-tau]) of EPI-7386 and Apalutamide | AUC(0-tau) is defined as area under the curve from time 0 to tau hours post dose of EPI-7386 and apalutamide. | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Minimum Observed Serum Concentration (Cmin) of EPI-7386 and Apalutamide | Cmin is the minimum observed serum concentration of EPI-7386 and apalutamide. | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Observed Accumulation Index Based on Cmax (ARCmax) of EPI-7386 and Apalutamide | The observed accumulation ratio for Cmax, determined after multiple dose administration EPI-7386 and apalutamide (C2D1/C1D1 and C3D1/C1D1). | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Accumulation Ratio for AUCtau (AR AUCtau) of EPI-7386 and Apalutamide | The observed accumulation ratio for AUCtau, determined after multiple dose administration EPI-7386 and Apalutamide (C2D1/C1D1 and C3D1/C1D1). | Day 1 of each cycle up to 3 cycles (each cycle of 28 days) | 
| Serum Prostate-Specific Antigen (PSA) | Serum PSA concentration will be measured. | Up to 3 Years 3 Months |