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

• ClinicalTrials.gov Identifier: NCT02606123
• Recruitment Status: Terminated
• First Posted: November 17, 2015
• Last Update Posted: March 1, 2018
• Sponsor: ESSA Pharmaceuticals
• Information provided by (Responsible Party): ESSA Pharmaceuticals

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Prostatic Neoplasms; Genital Neoplasms, Male; Genital Diseases, Male; Prostatic Diseases	Drug: EPI-506	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: October 2015
• Actual Primary Completion Date: December 2017
• Actual Study Completion Date: December 2017

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Part I: Safety and tolerability assessed by vital signs, laboratory measurements, and frequency and severity of treatment-related adverse events [ Time Frame: 12 weeks ]
2. Part II: Prostate-specific antigen (PSA) response rate [ Time Frame: 12 weeks ]

Secondary Outcome Measures :

1. Part I: Define the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) [ Time Frame: 9 months ]
2. Part I: Pharmacokinetics (PK) profile of EPI-506 [ Time Frame: 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. ]
   Assessed by plasma area under the plasma concentration-time curve (AUC)
3. Part I: Pharmacokinetics (PK) profile of EPI-506 [ Time Frame: 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. ]
   Assessed by maximum concentration (Cmax)
4. Part I: Pharmacokinetics (PK) profile of EPI-506 [ Time Frame: 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. ]
   Assessed by observed pre-dose plasma concentration during multiple dosing (Ctrough)
5. Part I: Pharmacokinetics (PK) profile of EPI-506 [ Time Frame: 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. ]
   Assessed by time to reach Cmax (tmax)
6. Part I: Pharmacokinetics (PK) profile of EPI-506 [ Time Frame: 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. ]
   Assessed by apparent terminal elimination half-life (t1/2)
7. Part I: Pharmacokinetics (PK) profile of EPI-506 [ Time Frame: 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. ]
   Assessed by apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
8. Part I: Pharmacokinetics (PK) profile of EPI-506 [ Time Frame: 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. ]
   Assessed by apparent clearance after extravascular administration (CL/F)
9. Part I: Pharmacokinetics (PK) profile of EPI-002 [ Time Frame: 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. ]
   Assessed by AUC
10. Part I: Pharmacokinetics (PK) profile of EPI-002 [ Time Frame: 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. ]
    Assessed by Cmax
11. Part I: Pharmacokinetics (PK) profile of EPI-002 [ Time Frame: 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. ]
    Assessed by Ctrough
12. Part I: Pharmacokinetics (PK) profile of EPI-002 [ Time Frame: 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. ]
    Assessed by tmax
13. Part I: Pharmacokinetics (PK) profile of EPI-002 [ Time Frame: 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. ]
    Assessed by t1/2
14. Part I: Pharmacokinetics (PK) profile of EPI-002 [ Time Frame: 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. ]
    Assessed by Vz/F
15. Part I: Pharmacokinetics (PK) profile of EPI-002 [ Time Frame: 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. ]
    Assessed by CL/F
16. Part I: Food effect on PK [ Time Frame: 6 days ]
    Following a single-dose of EPI-506 on Days 1 and 4 assessed by AUC
17. Part I: Food effect on PK [ Time Frame: 6 days ]
    Following a single-dose of EPI-506 on Days 1 and 4 assessed by Cmax
18. Part I: Food effect on PK [ Time Frame: 6 days ]
    Following a single-dose of EPI-506 on Days 1 and 4 assessed by Ctrough
19. Part I: Food effect on PK [ Time Frame: 6 days ]
    Following a single-dose of EPI-506 on Days 1 and 4 assessed by tmax
20. Part I: Food effect on PK [ Time Frame: 6 days ]
    Following a single-dose of EPI-506 on Days 1 and 4 assessed by t1/2
21. Part I: Food effect on PK [ Time Frame: 6 days ]
    Following a single-dose of EPI-506 on Days 1 and 4 assessed by Vz/F
22. Part I: Food effect on PK [ Time Frame: 6 days ]
    Following a single-dose of EPI-506 on Days 1 and 4 assessed by CL/F
23. Part I: PSA [ Time Frame: Baseline to Week 12 ]
    Evaluated as a Pharmacodynamic (PD) marker of response
24. Part II: Safety and tolerability assessed by vital signs, laboratory measurements, and frequency and severity of treatment-related adverse events [ Time Frame: 12 months ]
25. Part II: To evaluate the PK of EPI-506 [ Time Frame: 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. ]
    Assessed by AUC
26. Part II: To evaluate the PK of EPI-506 [ Time Frame: 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. ]
    Assessed by Cmax
27. Part II: To evaluate the PK of EPI-506 [ Time Frame: 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. ]
    Assessed by Ctrough
28. Part II: To evaluate the PK of EPI-506 [ Time Frame: 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. ]
    Assessed by tmax
29. Part II: To evaluate the PK of EPI-506 [ Time Frame: 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. ]
    Assessed by t1/2
30. Part II: To evaluate the PK of EPI-506 [ Time Frame: 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. ]
    Assessed by Vz/F
31. Part II: To evaluate the PK of EPI-506 [ Time Frame: 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. ]
    Assessed by CL/F
32. Part II: To evaluate the PK of EPI-002 [ Time Frame: 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. ]
    Assessed by AUC
33. Part II: To evaluate the PK of EPI-002 [ Time Frame: 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. ]
    Assessed by Cmax
34. Part II: To evaluate the PK of EPI-002 [ Time Frame: 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. ]
    Assessed by Ctrough
35. Part II: To evaluate the PK of EPI-002 [ Time Frame: 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. ]
    Assessed by tmax
36. Part II: To evaluate the PK of EPI-002 [ Time Frame: 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. ]
    Assessed by t1/2
37. Part II: To evaluate the PK of EPI-002 [ Time Frame: 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. ]
    Assessed by Vz/F
38. Part II: To evaluate the PK of EPI-002 [ Time Frame: 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. ]
    Assessed by CL/F
39. Part II: Time to PSA progression [ Time Frame: 12 months ]
40. Part II: Radiographic progression [ Time Frame: 12 weeks ]
    Radiographic progression evaluated per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1
41. Part II: Objective response [ Time Frame: 12 weeks ]
    Radiographic progression evaluation per mRECIST v1.1 in patients with measurable soft tissue disease at baseline

Other Outcome Measures:

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Scottsdale Healthcare Hospitals DBA HonorHealth

Scottsdale, Arizona, United States, 85258

United States, Michigan

University of Michigan Health System

Ann Arbor, Michigan, United States, 48109

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98109

Canada, British Columbia

British Columbia Cancer Agency - Vancouver Centre

Vancouver, British Columbia, Canada, V5Z 4E6

Sponsors and Collaborators

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

More Information

• Responsible Party: ESSA Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02606123
• Other Study ID Numbers: EPI-506-CS-0001
• First Posted: November 17, 2015
• Last Update Posted: March 1, 2018
• Last Verified: February 2018

Keywords provided by ESSA Pharmaceuticals:

Prostate Cancer; Metastatic castration-resistant prostate cancer

Additional relevant MeSH terms:

Prostatic Neoplasms; Neoplasms; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Neoplasms; Neoplasms by Site