EPI-7386 in Combination with Enzalutamide versus Enzalutamide alone in Metastatic Castration-Resistant Prostate Cancer

Prior treatment

• Spinal cord compression as follows: a. Any prior untreated spinal cord compression related to prostate cancer. Note: Treated spinal cord compression related to prostate cancer is allowed. b. Any symptoms of neurologic compromise with radiographic evidence of potential spinal cord compression within 28 days prior to starting study treatment.
• 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.
• Myocardial infarction within 6 months prior to signing informed consent.
• Uncontrolled angina within 3 months prior to signing informed consent.
• Biologic anti-cancer therapy (e.g., sipuleucel-T) within 28 days prior to the start of study treatment.
• Use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) within 14 days prior to start of study drug treatment as this may increase enzalutamide exposure.
• Use of strong inducers of CYP3A (e.g., rifampin) within 28 days prior to start of study drug treatment as this may decrease EPI-7386 and enzalutamide exposure.
• Use of granulocyte colony stimulating factor within 7 days prior to screening laboratories.
• Ongoing participation in another therapeutic trial or use of another investigational agent within 28 days prior to the first dose of study treatment.
• For Phase 2 subjects, prior participation in Phase 1.
• Use of hormonal agents with anti-tumour activity against prostate cancer including 5-alpha reductase inhibitors, androgens (e.g., testosterone), cytoproterone acetate, progestational agents, and oestrogens/diethylstilboestrol 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 (e.g., saw palmetto, PC SPES, PC-HOPE, St. John’s wort, selenium supplements, grape seed extract, etc.) within 28 days of study treatment initiation or plans to initiate treatment with these products/alternative therapies during the entire duration of 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. Note: Palliative radiation for bone pain is allowed.
• 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.

Other illness

• Significant cardiovascular disease including any of the following:
• History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes).
• History of Mobitz II second-degree or third-degree heart block.
• Uncontrolled hypertension as indicated by a resting systolic blood pressure >160 mm Hg or diastolic blood pressure >90 mm Hg at screening.
• 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.
• Known or suspected hypersensitivity to any components of the formulation used for EPI-7386 or enzalutamide, including allergies to sulfonamides.

Lab values

• Congestive heart failure New York Heart Association (NYHA) class III or IV, or a history of congestive heart failure NYHA class III or IV unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months prior to study entry results in a left ventricular ejection fraction that is >45%.
• QT interval corrected by the Fridericia correction formula (QTcF) >480 msec at screening.
• Concurrent disease or any clinically significant abnormality following the Investigator’s review of the screening physical examination findings, 12-lead ECG results, and clinical laboratory tests, which in the judgment of the Investigator and/or sponsor would interfere with the subject’s participation in this study or evaluation of study results.

Other

• Subjects who are not able of give informed consent themselves and are in need of legally authorised representatives to provide informed consent on their behalf.
• Gastrointestinal (GI) issues affecting absorption (e.g., gastrectomy).
• Unwillingness or inability to comply with procedures required in this protocol.
• Not a candidate for enzalutamide treatment, in the opinion of the Investigator.
• Patients with rare hereditary problems of fructose intolerance.

• Independent Ethics Committee (IEC)-approved, written informed consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures being performed.
• 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 as below: a. Absolute neutrophil count >1500/µL, platelet count >100 000/µL; haemoglobin >5.6 mmol/L (9.0 g/dL) at screening. (Note: Subjects must not have received any growth factors within 7 days or blood transfusions within 28 days prior to the hematologic laboratory values obtained at screening). b. TBIL <1.5 × the ULN at screening, except subjects with documented Gilbert’s Syndrome who must have a TBIL <3 mg/dL. c. ALT and AST <2.5 × ULN at screening. d. Creatinine clearance ≥ 45 mL/min and/or estimated glomerular filtration rate ≥ 50. e. Albumin >30 g/L (3.0 g/dL) at screening.
• Subject of child-producing potential agree to use highly effective contraceptive methods (i.e. barrier contraception measures such as a male condom with spermicide during intercourse, vasectomy, female hormonal contraception, bilateral tubal occlusion) and avoid sperm donation during the study treatment and for 3 months after the last dose of study treatment. A man is considered to be of child-producing potential unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v5.0 Grade 1 or less.
• Willing and able to comply with the protocol, including follow-up visits and examinations.
• Males aged ≥18 years.
• Histologically, pathologically, or cytologically confirmed prostate adenocarcinoma without small cell or neuroendocrine features (please note: >10% small cell or neuroendocrine differentiation will be excluded).
• Evidence of castration-resistant prostate cancer (CRPC) defined as PSA levels ≥1 ng/mL while on androgen deprivation therapy (ADT) and documentation of 3 rising PSA levels taken at least 1 week apart during ADT (or surgical castration). This documentation can be from any time while the subject is on ADT.
• 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 or MRI or prostate-specific membrane antigen (PSMA) PET scans. Note: Where available, PSMA PET is an allowed scan modality for documentation of metastatic disease at study entry only. However, baseline bone, CT, or MRI scans are still needed to allow for a longitudinal evaluation of response to treatment following PCWG3 criteria and RECIST 1.1. for nodal and visceral disease. The same modality used at baseline (CT or MRI) is to be used throughout the study for a given subject.
• Naïve to second generation anti-androgens. Previous exposure to docetaxel in the metastatic hormone-sensitive prostate cancer (mHSPC) setting is allowed and will be used as a stratification factor.
• Evidence of progressive disease (PD) defined as 1 or more PCWG3 criteria: • PSA ≥1 ng/mL that has increased on at least 3 successive measurements taken at least 1 week apart. • Nodal or visceral progression as defined by RECIST 1.1 with the current PCWG3 recommendations. • Appearance of 2 or more new lesions in bone scan.
• 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.