Safety and Anti-Tumor Study of Oral EPI-506 for Patients With Metastatic Castration-Resistant Prostate Cancer

Study Overview
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Brief Summary
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The study will consist of 2 parts: Part I (Dose Escalation) and Part II (Dose Expansion). In Part I, patients will participate in single, multiple, and long-term dosing periods using EPI-506 to determine safety, pharmacokinetics, the maximum tolerated dose, and preliminary indications of anti-tumor activity. Part I is an open-label, adaptive 3 + 3 design, dose-escalation study. Approximately six dose levels of EPI-506 will be studied, beginning at 80 mg/day. Enrolled patients may be allowed to escalate to a subsequent dose cohort after their initial twelve weeks. Additional patients may be enrolled at any safe dose level prior to or concurrent with enrolling patients in Part II. In Part II, 3 patient populations; post-abiraterone metastatic castration-resistant prostate cancer (mCRPC) but enzalutamide-naïve, post-enzalutamide mCRPC but abiraterone-naïve, and post-abiraterone and enzalutamide mCRPC will be studied at the recommended Phase 2 dose (RP2D) determined in Part I over 12 weeks of daily dosing. Approximately 120 patients (40 in each cohort) will be enrolled.

Official Title
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A Phase 1/2 Open-Label Study to Assess the Safety, Pharmacokinetics, and Anti-Tumor Activity of Oral EPI-506 in Patients With Metastatic Castration-Resistant Prostate Cancer

Conditions
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Prostatic Neoplasms, Genital Neoplasms, Male, Genital Diseases, Male, Prostatic Diseases

Intervention / Treatment
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* Drug: EPI-506


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adenocarcinoma of the Prostate Metastatic Disease with at least one lesion on bone scan and/or soft tissue on CT/MRI Demonstrated progression on abiraterone and/or enzalutamide Demonstrated PSA progression within 12 weeks of study participation Castrate testosterone levels at screening with continued Luteinizing hormone-releasing hormone (LHRH) therapy Eastern Cooperative Oncology Group (ECOG) score between 0-1 Asymptomatic or mildly symptomatic Exclusion Criteria: Candidates for cytotoxic chemotherapy Received more than one line of chemotherapy Received more than one treatment course of enzalutamide or abiraterone Inadequate washout of prohibited hormonally active agents or other prior treatments for prostate cancer (PCa) Known intra-cerebral disease or brain mets Spinal cord compression within 6 months Prior treatment with investigative androgen receptor (AR) agents

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPI-506<br>Part I: Ascending doses of EPI-506 administered orally to define the maximum tolerated dose. | Drug: EPI-506<br>* Patients will receive EPI-506 as an oral softgel capsule. Part 1: Approximately six dose levels of EPI-506 will be studied, beginning at 80 mg/day. During the Single-Dose Period, patients will first receive a dose of EPI-506 in the fasted state followed by 2 days of washout, and then patients will receive a second dose of EPI-506 in the fed state followed by 2 days of washout. Patients will then enter the Multiple Dosing and Long-term Dosing Period where they will receive once or twice daily dosing in a fed or fasted state until they meet discontinuation criteria. Part 2: The dose in Part 2 will be determined in Part 1 of the study. Patients will receive the Part 2 dose daily until they meet discontinuation criteria.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Safety and tolerability assessed by vital signs, laboratory measurements, and frequency and severity of treatment-related adverse events |  | 12 weeks | 
| Part II: Prostate-specific antigen (PSA) response rate |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Define the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) |  | 9 months | 
| Part I: Pharmacokinetics (PK) profile of EPI-506 | Assessed by plasma area under the plasma concentration-time curve (AUC) | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-506 | Assessed by maximum concentration (Cmax) | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-506 | Assessed by observed pre-dose plasma concentration during multiple dosing (Ctrough) | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-506 | Assessed by time to reach Cmax (tmax) | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-506 | Assessed by apparent terminal elimination half-life (t1/2) | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-506 | Assessed by apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-506 | Assessed by apparent clearance after extravascular administration (CL/F) | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-002 | Assessed by AUC | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-002 | Assessed by Cmax | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-002 | Assessed by Ctrough | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-002 | Assessed by tmax | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-002 | Assessed by t1/2 | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-002 | Assessed by Vz/F | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Pharmacokinetics (PK) profile of EPI-002 | Assessed by CL/F | Pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, and 48h after dose; Day 8 at pre-dose, and at 15min, 30min 1h, 2h, 4h, 6h, 8h, 12h, 24h after dose. | 
| Part I: Food effect on PK | Following a single-dose of EPI-506 on Days 1 and 4 assessed by AUC | 6 days | 
| Part I: Food effect on PK | Following a single-dose of EPI-506 on Days 1 and 4 assessed by Cmax | 6 days | 
| Part I: Food effect on PK | Following a single-dose of EPI-506 on Days 1 and 4 assessed by Ctrough | 6 days | 
| Part I: Food effect on PK | Following a single-dose of EPI-506 on Days 1 and 4 assessed by tmax | 6 days | 
| Part I: Food effect on PK | Following a single-dose of EPI-506 on Days 1 and 4 assessed by t1/2 | 6 days | 
| Part I: Food effect on PK | Following a single-dose of EPI-506 on Days 1 and 4 assessed by Vz/F | 6 days | 
| Part I: Food effect on PK | Following a single-dose of EPI-506 on Days 1 and 4 assessed by CL/F | 6 days | 
| Part I: PSA | Evaluated as a Pharmacodynamic (PD) marker of response | Baseline to Week 12 | 
| Part II: Safety and tolerability assessed by vital signs, laboratory measurements, and frequency and severity of treatment-related adverse events |  | 12 months | 
| Part II: To evaluate the PK of EPI-506 | Assessed by AUC | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-506 | Assessed by Cmax | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-506 | Assessed by Ctrough | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-506 | Assessed by tmax | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-506 | Assessed by t1/2 | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-506 | Assessed by Vz/F | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-506 | Assessed by CL/F | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-002 | Assessed by AUC | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-002 | Assessed by Cmax | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-002 | Assessed by Ctrough | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-002 | Assessed by tmax | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-002 | Assessed by t1/2 | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-002 | Assessed by Vz/F | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: To evaluate the PK of EPI-002 | Assessed by CL/F | Day 8 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after dose; Week 12 at pre-dose, and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after dose. | 
| Part II: Time to PSA progression |  | 12 months | 
| Part II: Radiographic progression | Radiographic progression evaluated per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1 | 12 weeks | 
| Part II: Objective response | Radiographic progression evaluation per mRECIST v1.1 in patients with measurable soft tissue disease at baseline | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Metastatic castration-resistant prostate cancer