EPI-7386 in Combination With Enzalutamide Compared With Enzalutamide Alone in Subjects With mCRPC

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1/2 study of EPI-7386 orally administered in combination with enzalutamide in subjects with mCRPC. Phase 1 of the study will be a single-arm dose escalation study of EPI-7386 in combination with a fixed dose of enzalutamide. This portion of the study will primarily evaluate the safety and tolerability of the drug combination and establish the RP2CDs for EPI-7386 and enzalutamide when dosed in combination. In addition, blood sampling will be conducted for PK evaluation to assess the potential DDI between the two drugs. Once the RP2CD for each drug has been established, Phase 2 of the study will commence. Phase 2 is a two-arm, randomized (2:1), open-label study. Approximately 120 subjects will be randomized 2:1 to: Group 1: EPI-7386 at the RP2CD + enzalutamide(depending on the results of the Phase 1) (n=80) Group 2: Enzalutamide single agent (n=40) The planned dose of enzalutamide and EPI-7386 for the combination arm will be those determined in the Phase 1 of this study based on safety and exposure data. Subjects may remain on study treatment as long as they are tolerating treatment without disease progression based on RECIST v1.1 and/or PCWG3.

Official Title
-----------------
A Phase 1/2 Study of EPI-7386 in Combination With Enzalutamide Compared With Enzalutamide Alone in Subjects With Metastatic Castration-Resistant Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Enzalutamide
* Drug: EPI-7386 with Enzalutamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males ≥18 years. Histologically, pathologically, or cytologically confirmed prostate adenocarcinoma. Evidence of castration-resistant prostate cancer (CRPC). Presence of metastatic disease at study entry documented by 1 or more bone lesions on bone scan or by soft tissue disease observed by CT/MRI. Naïve to second generation anti-androgens. Evidence of progressive disease defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy or history of bilateral orchiectomy, with castrate level testosterone. Serum testosterone ≤1.73 nmol/L (50 ng/dL). Subjects receiving bisphosphonates or other approved bone-targeting therapy (e.g., denosumab) must be on a stable dose for at least 28 days prior to the start of study treatment. Demonstrate adequate organ function. Exclusion Criteria: Biologic anti-cancer therapy within 28 days prior to the start of study treatment. Use of hormonal agents with anti-tumor activity against prostate cancer within 28 days prior to the start of study treatment. Use of herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity within 28 days prior to the start of study treatment or plans to initiate during the study. Intervention with any chemotherapy, investigational agents, or other anti-cancer drugs within 28 days of the first dose of study treatment. Use of radium-223 dichloride or other radioligand/radiopharmaceutical within 28 days prior to the start of study treatment. Received limited-field palliative bone radiotherapy >5 fractions and/or any radiotherapy within 2 weeks prior to the start of study treatment. Received a blood transfusion within 28 days of hematologic screening labs. Known intra-cerebral disease or brain metastasis unless adequately treated and stable for the last 28 days before signing of informed consent. Spinal cord compression. Diagnosis of another clinically significant malignancy within the previous 3 years other than curatively treated non-melanomatous skin cancer or superficial urothelial carcinoma and other in situ or non-invasive malignancies. Gastrointestinal issues affecting absorption. Significant cardiovascular disease. Known history of seizure or conditions that may pre-dispose them to seizure, including brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Concurrent disease or any clinically significant abnormality. Known or suspected hypersensitivity to any components of the formulation used for EPI-7386 or enzalutamide. Use of strong inhibitors of CYP2C8. Use of strong inducers of CYP3A. Use of narrow therapeutic index sensitive CYP2C8 or sensitive substrates for CYP3A and CYP2B6. Use of granulocyte colony stimulating factor within 7 days prior to screening laboratories. Not a candidate for enzalutamide treatment. Patients with rare hereditary problems of fructose intolerance.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: Phase 1 Cohort 1<br>600 mg QD EPI-7386 in combination of Enzalutamide120 mg | Drug: EPI-7386 with Enzalutamide<br>* Daily oral dose of EPI-7386 in combination of enzalutamide<br>|
| Experimental: Phase 1 Cohort 2<br>800 mg QD EPI-7386 in combination of Enzalutamide120 mg | Drug: EPI-7386 with Enzalutamide<br>* Daily oral dose of EPI-7386 in combination of enzalutamide<br>|
| Experimental: Phase 1 Cohort 3<br>600 mg BID EPI-7386 in combination of Enzalutamide120 mg | Drug: EPI-7386 with Enzalutamide<br>* Daily oral dose of EPI-7386 in combination of enzalutamide<br>|
| Experimental: Phase 1 Cohort 4<br>RP2D mg EPI-7386 in combination of Enzalutamide160 mg | Drug: EPI-7386 with Enzalutamide<br>* Daily oral dose of EPI-7386 in combination of enzalutamide<br>|
| Experimental: Phase 2 Enzalutamide + EPI-7386 (Randomized 2:1)<br>RP2D mg EPI-7386 in combination of Enzalutamide RP2D mg | Drug: EPI-7386 with Enzalutamide<br>* Daily oral dose of EPI-7386 in combination of enzalutamide<br>|
| Active Comparator: Phase 2 Enzalutamide single agent<br>Enzalutamide 160 mg | Drug: Enzalutamide<br>* Daily oral dose of enzalutamide<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Incidence of Dose Limiting Toxicities | Characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for AEs [NCI CTCAE version 5.0]), timing in relation to study treatment administration, seriousness, and relationship to study treatment. | Baseline to End of Cycle 1 (each cycle is 28 days) | 
| Phase 1: Incidence of treatment emergent adverse events | Characterized by type, frequency, severity, timing, seriousness, and relationship to study treatment. | Baseline to 30 days after last dose of study drug | 
| Phase 1: Incidence of laboratory abnormalities as a measure of safety and tolerability of EPI-7386 | Characterized by type, frequency, severity, timing, seriousness, and relationship to study treatment. | Baseline to 30 days after last dose of study drug | 
| Phase 1: Changes in ECOG performance status |  | Baseline to 30 days after last dose of study drug | 
| Phase 2: Proportion of subjects with a prostate-specific antigen decline of >50% (PSA50) at Week 12 |  | Baseline to Week 12 |