EPI-7386 in Combination with Enzalutamide Compared with Enzalutamide Alone in Subjects with MCRPC

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.


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.