Phase 1/2 Evaluation of EPI-7386 and Enzalutamide Combination Versus Enzalutamide Monotherapy in Metastatic Castration-Resistant Prostate Cancer

Trial ID: 2023-509336-25-00
Protocol: EPI-7386-CS-010
Sponsor: Essa Pharma Inc.

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Diseases & Conditions

Hormone-refractory prostate cancer

Objectives

The primary objectives of this Phase 1/2 study are to assess the **safety** and tolerability, determine the maximum tolerated dose (MTD), and establish the recommended Phase 2 combination dose (RP2CD) of **EPI-7386** when administered with a fixed dose of **enzalutamide** in subjects with metastatic castration-resistant prostate cancer (mCRPC) who are naïve to second-generation anti-androgens. Additionally, the study aims to evaluate the anti-tumor activity and safety of EPI-7386 in combination with enzalutamide compared to enzalutamide alone in this patient population. These objectives are clinically relevant as they aim to optimize treatment regimens for mCRPC, potentially improving patient outcomes by enhancing therapeutic efficacy and minimizing adverse effects.

Secondary objectives include evaluating the pharmacokinetics (PK) of EPI-7386 and enzalutamide when administered alone and in combination during Phase 1, as well as assessing the PK of these agents in combination during Phase 2. Understanding the PK profiles is crucial for determining the appropriate dosing and ensuring effective drug delivery in the target population.

Participants

The clinical trial involves a total of **88 male participants** diagnosed with **metastatic castration-resistant prostate cancer**. The study population consists of males aged **18 years and older**, with no female participants included. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of prostate adenocarcinoma without small cell or neuroendocrine features, evidence of castration-resistant prostate cancer, and the presence of metastatic disease. The trial excludes individuals with more than 10% small cell or neuroendocrine differentiation. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not involve a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified, but participants must demonstrate adequate organ function and agree to use effective contraceptive methods if of child-producing potential. The trial population is naïve to second-generation anti-androgens, although previous exposure to docetaxel in the metastatic hormone-sensitive prostate cancer setting is permitted. The sponsor has not provided additional information regarding lifestyle factors or other demographic details.

Plans and Procedures

The clinical trial is designed to evaluate the safety, tolerability, and efficacy of **EPI-7386** in combination with **enzalutamide** compared to enzalutamide alone in subjects with metastatic castration-resistant prostate cancer (mCRPC). This study is structured as a randomized, double-blind, controlled trial, encompassing both Phase 1 and Phase 2 components. The trial is expected to commence recruitment on May 15, 2024, and conclude by September 30, 2026. Participants will be involved in the study for a duration that includes initial screening, treatment, and follow-up visits, with the total involvement period varying based on individual response and progression.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as serum testosterone levels, organ function, and evidence of mCRPC. Following successful screening, participants will undergo regular follow-up visits to monitor safety, tolerability, and treatment efficacy. These visits will include assessments of prostate-specific antigen (PSA) levels, imaging studies, and evaluations of any adverse events. The end-of-study visit will occur after the completion of the treatment phase, where final assessments will be conducted to evaluate the overall outcomes of the trial.

Participants are expected to remain in the study unless they experience unacceptable toxicity, disease progression, or choose to withdraw consent. Conditions that may lead to early termination include non-compliance with the protocol, adverse events that compromise safety, or any other medical reasons deemed significant by the investigator. The trial aims to establish the recommended Phase 2 combination dose (RP2CD) and assess the anti-tumor activity of the combination therapy, with primary endpoints focusing on dose-limiting toxicities (DLTs) and PSA decline. The study will adhere to ethical guidelines, ensuring informed consent and privacy protection for all participants.

Treatment

The clinical trial involves the administration of **EPI-7386**, an investigational medication, in combination with **enzalutamide**. **EPI-7386** is a small molecule pharmaceutical product developed by ESSA Pharmaceutical, Inc. It is formulated as a **film-coated tablet** and is intended for **oral use**. The active substance in **EPI-7386** is **masofaniten**, a chemical compound with the synonym N-{4-[(4-{2-[3-chloro-4-(2-chloroethoxy)-5-cyanophenyl]propan-2-yl}phenoxy)methyl]pyrimidin-2-yl}methanesulfonamide. The dosage, frequency, and specific administration schedule of **EPI-7386** are determined based on the study protocol, with the aim to establish the maximum tolerated dose (MTD) and recommended Phase 2 combination dose (RP2CD) in subjects with metastatic castration-resistant prostate cancer (mCRPC) who are naïve to second-generation anti-androgens.

**Enzalutamide**, marketed under the name Xtandi, is used as a comparator treatment in this study. It is provided in the form of **40 mg soft capsules** and is also administered **orally**. Enzalutamide is a well-established anti-androgen therapy, and its role in the trial is to serve as a standard-of-care therapy against which the combination with **EPI-7386** is evaluated. The fixed dose of enzalutamide is administered according to the standard dosing regimen for patients with mCRPC. The trial aims to assess the safety and anti-tumor activity of the combination therapy compared to enzalutamide alone.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The study is designed to evaluate both the safety profile and the therapeutic efficacy of the combination treatment, with a focus on determining the optimal dosing strategy for future clinical applications.

Efficacy

The efficacy of the clinical trial will be assessed through a series of primary endpoints designed to evaluate the therapeutic impact of EPI-7386 in combination with enzalutamide compared to enzalutamide alone in subjects with metastatic castration-resistant prostate cancer (mCRPC). In Phase 2 of the study, the primary efficacy endpoint is the proportion of subjects achieving a prostate-specific antigen decline of greater than 90% (PSA90). This endpoint will provide a quantitative measure of the anti-tumor activity of the treatment regimen.

Data collection for efficacy assessment will involve regular monitoring of prostate-specific antigen (PSA) levels, with specific timepoints for measurement not explicitly detailed. The analysis will focus on the percentage of subjects who achieve the defined PSA90 threshold, indicating a significant reduction in PSA levels, which is a marker of disease activity in prostate cancer. The results will be analyzed to determine the comparative efficacy of the combination therapy versus monotherapy with enzalutamide.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.
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.
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.

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Exclusion Criteria

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.
Biologic anti-cancer therapy (e.g., sipuleucel-T) within 28 days prior to the start of study treatment.
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.
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.
Gastrointestinal (GI) issues affecting absorption (e.g., gastrectomy).
Significant cardiovascular disease including any of the following:
Myocardial infarction within 6 months prior to signing informed consent.
Uncontrolled angina within 3 months prior to signing informed consent.
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.
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.
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.
Known or suspected hypersensitivity to any components of the formulation used for EPI-7386 or enzalutamide, including allergies to sulfonamides.
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.
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.