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

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

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.

Study Overview

• Status: Terminated
• Conditions: Genital Neoplasms, Male; Prostatic Neoplasms; Prostatic Diseases; Genital Diseases, Male
• Intervention / Treatment: Drug: EPI-506

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • British Columbia Cancer Agency - Vancouver Centre
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Scottsdale Healthcare Hospitals DBA HonorHealth
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: EPI-506; Part I: Ascending doses of EPI-506 administered orally to define the maximum tolerated dose.

Drug: EPI-506; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Objective: Biomarkers	Circulating tumor cells (CTCs) with emphasis on androgen receptor splice variants (AR-V7)	12-24 months
Exploratory Objective: Pain assessments	Assessed by Brief Pain Inventory-Short Form (BPI-SF) instrument	12-24 months

Collaborators and Investigators

• Sponsor: ESSA Pharmaceuticals
• Investigators: Study Director: Frank Perabo, MD, PhD, ESSA Pharmaceuticals Corp.; Principal Investigator: Robert B. Montgomery, MD, Seattle Cancer Care Alliance; Principal Investigator: Kim N. Chi, MD, British Columbia Cancer Agency - Vancouver Centre

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: October 22, 2015
• First Submitted That Met QC Criteria: November 13, 2015
• First Posted (Estimate): November 17, 2015

Study Record Updates

• Last Update Posted (Actual): March 1, 2018
• Last Update Submitted That Met QC Criteria: February 27, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Prostate Cancer; Metastatic castration-resistant prostate cancer
• Additional Relevant MeSH Terms: Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Neoplasms; Prostatic Diseases; Genital Neoplasms, Male
• Other Study ID Numbers: EPI-506-CS-0001