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

Prostatic Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02606123
• Other study ID #: EPI-506-CS-0001
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: October 22, 2015
• Last updated: February 27, 2018
• Start date: October 2015
• Est. completion date: December 2017

Study information

• Verified date: February 2018
• Source: ESSA Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 28
• Est. completion date: December 2017
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Genital Diseases, Male
• Genital Neoplasms, Male
• Neoplasms
• Prostatic Diseases
• Prostatic Neoplasms

Intervention

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.

Locations

Country	Name	City	State
Canada	British Columbia Cancer Agency - Vancouver Centre	Vancouver	British Columbia
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Scottsdale Healthcare Hospitals DBA HonorHealth	Scottsdale	Arizona
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
ESSA Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory Objective: Biomarkers	Circulating tumor cells (CTCs) with emphasis on androgen receptor splice variants (AR-V7)	12-24 months
Other	Exploratory Objective: Pain assessments	Assessed by Brief Pain Inventory-Short Form (BPI-SF) instrument	12-24 months
Primary	Part I: Safety and tolerability assessed by vital signs, laboratory measurements, and frequency and severity of treatment-related adverse events		12 weeks
Primary	Part II: Prostate-specific antigen (PSA) response rate		12 weeks
Secondary	Part I: Define the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D)		9 months
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Part I: Food effect on PK	Following a single-dose of EPI-506 on Days 1 and 4 assessed by AUC	6 days
Secondary	Part I: Food effect on PK	Following a single-dose of EPI-506 on Days 1 and 4 assessed by Cmax	6 days
Secondary	Part I: Food effect on PK	Following a single-dose of EPI-506 on Days 1 and 4 assessed by Ctrough	6 days
Secondary	Part I: Food effect on PK	Following a single-dose of EPI-506 on Days 1 and 4 assessed by tmax	6 days
Secondary	Part I: Food effect on PK	Following a single-dose of EPI-506 on Days 1 and 4 assessed by t1/2	6 days
Secondary	Part I: Food effect on PK	Following a single-dose of EPI-506 on Days 1 and 4 assessed by Vz/F	6 days
Secondary	Part I: Food effect on PK	Following a single-dose of EPI-506 on Days 1 and 4 assessed by CL/F	6 days
Secondary	Part I: PSA	Evaluated as a Pharmacodynamic (PD) marker of response	Baseline to Week 12
Secondary	Part II: Safety and tolerability assessed by vital signs, laboratory measurements, and frequency and severity of treatment-related adverse events		12 months
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Part II: Time to PSA progression		12 months
Secondary	Part II: Radiographic progression	Radiographic progression evaluated per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1	12 weeks
Secondary	Part II: Objective response	Radiographic progression evaluation per mRECIST v1.1 in patients with measurable soft tissue disease at baseline	12 weeks