ZEN003694 and Enzalutamide Versus Enzalutamide Monotherapy in Metastatic Castration-Resistant Prostate Cancer

Phase 2RecruitingNCT04986423

Zenith Epigenetics200 enrolled

Overview

This is an open-label, randomized, Phase 2b study of ZEN003694 in combination with enzalutamide vs. enzalutamide monotherapy in patients with mCRPC who have progressed on prior abiraterone by PCWG3 criteria. Disease must have progressed on only abiraterone by PCWG3 criteria prior to study entry. The patient population will be separated into two cohorts: Cohort A: Patients with poor response to prior abiraterone defined as: * Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: \< 12 months duration on abiraterone or failure to achieve PSA nadir of 0.2 ng/mL while taking abiraterone, or; * Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: \< 6 months duration on abiraterone or failure to achieve PSA50 response while on abiraterone Cohort B: Patients with response to prior abiraterone, defined as: * Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: ≥ 12 months duration on abiraterone and nadir PSA \< 0.2 ng/mL, or; * Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: ≥ 6 months duration on abiraterone and confirmed PSA50 response

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

200

Conditions

Metastatic Castration-Resistant Prostate Cancer

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Males age ≥ 18 years 2. Metastatic, castration-resistant, histologically confirmed prostate cancer 3. Surgical castration or continuous medical castration for ≥ 8 weeks prior to screening; serum testosterone \< 50 ng/dL confirmed within 4 weeks of first administration of study drug 4. Have progressed on prior abiraterone treatment by PCWG3 criteria 5. Patients who are not candidates for chemotherapy in the opinion of the investigator or patients who decline chemotherapy 6. Cohort A only - Patient must meet definition of poor responder to abiraterone by one of the following: 1. Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: \< 12 months duration on abiraterone or failure to achieve PSA nadir of 0.2 ng/mL while taking abiraterone 2. Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: \< 6 months duration on abiraterone or failure to achieve a PSA50 response 7. Cohort B only - Patient must meet definition of responder to abiraterone by one of the following: 1. Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: ≥ 12 months duration on abiraterone and nadir PSA \< 0.2 ng/mL 2. Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: ≥ 6 months duration on abiraterone and PSA50 response 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Exclusion Criteria: 1. Any history of brain metastases, prior seizure, conditions predisposing to seizure activity 2. Have previously received an investigational BET inhibitor (including previous participation in this study or a study of ZEN003694) 3. Receipt of prior second-generation androgen receptor inhibitors (e.g. enzalutamide, apalutamide, darolutamide, proxalutamide). Receipt of first-generation AR antagonists (e.g. bicalutamide, nilutamide, flutamide) does not count towards this limit. 4. Have received prior chemotherapy in the metastatic castration-resistant setting (prior chemotherapy in the hormone-sensitive setting is allowed provided last dose was at least 6 months prior to first dose of study drug) 5. Have received prior systemic anti-cancer therapy within 2 weeks or five half-lives, whichever is shorter, prior to the first administration of study drug 6. Have received exogenous administration of testosterone therapy since discontinuation of abiraterone. 7. Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy (excluding alopecia and neuropathy) prior to study entry 8. Radiation therapy within 2 weeks of the first administration of study drug

Outcomes

Primary Outcomes

Cohort A: Radiographic progression-free survival (rPFS) by BICR

Time from date of randomization to the date of first disease radiographic progression or death for any reason. Radiographic progression disease will be evaluated by RECIST 1.1 and PCWG3.

Time frame: Randomization up to 30 months

Secondary Outcomes

Cohorts A + B: Radiographic progression-free survival (rPFS) by BICR

Time from date of randomization to the date of first disease radiographic progression or death for any reason. Radiographic progression disease will be evaluated by RECIST 1.1 and PCWG3

Time frame: Randomization up to 30 months

Cohort A: Radiographic progression-free survival (rPFS) by investigator assessment

Time from date of randomization to the date of first disease radiographic progression or death for any reason. Radiographic progression disease will be evaluated by RECIST 1.1 and PCWG3.

Time frame: Randomization up to 30 months

Cohort A + B: Radiographic progression-free survival (rPFS) by investigator assessment

Time from date of randomization to the date of first disease radiographic progression or death for any reason. Radiographic progression disease will be evaluated by RECIST 1.1 and PCWG3.

Time frame: Randomization up to 30 months

Cohort A: Progression-free survival (PFS) by investigator assessment

Time from date of randomization to the date of first disease radiographic progression, clinical progression, or death for any reason. Radiographic progression of disease will be evaluated by RECIST 1.1 and PCWG3 by investigator assessment. Clinical progression is significant pain increase or clinical deterioration that requires initiating another line of treatment.

Time frame: Randomization up to 30 months

Cohort A + B: Progression-free survival (PFS) by investigator assessment

Time frame: Randomization up to 30 months

Cohort A: Overall survival (OS)

Time from date of randomization to the date of death from any cause

Time frame: Randomization up to 30 months

Cohort A + B: Overall survival (OS)

Time from date of randomization to the date of death from any cause

Time frame: Randomization up to 30 months

Cohort A: PSA50 response rate

PSA response is a reduction in serum PSA concentration of ≥50% from baseline.

Time frame: Randomization up to 30 months

Cohort A + B: PSA50 response rate

PSA response is a reduction in serum PSA concentration of ≥50% from baseline.

Time frame: Randomization up to 30 months

Cohort A: Assess efficacy endpoints for patients enrolled in the USA

Time frame: Randomization up to 30 months

Cohort A + B: Assess efficacy endpoints for patients enrolled in the USA

Time frame: Randomization up to 30 months

Objective response rate (ORR)

Proportion of the patients who have either a complete response (CR) or partial response (PR) by RECIST 1.1 criteria who have measurable disease at baseline.

Time frame: Randomization up to 30 months

Patient-reported health status and quality of life (QoL) measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)

EORTC QLQ-C30: cancer-specific instrument with 30 questions to assess the participant QoL. First 28 questions used to evaluate 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, nausea and vomiting, pain) and other single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Each question assessed on a 4-point scale (1= not at all, 2= a little, 3= quite a bit, 4= very much); functional scales: higher score = better level of functioning; symptom scale: higher score = more severe symptoms; for single items: higher score= more severe problem. Last 2 questions used to evaluate global health status (GHS)/QoL. Each question was assessed on 7-point scale (1= very poor to 7= excellent). Scores averaged, transformed to 0-100 scale; higher score=better quality of life/better level of functioning.

Time frame: Screening and Day 1 of every 28-day Cycle up to 30 months

Patient-reported health status and quality of life (QoL) measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Module (EORTC QLQ-PR25).

EORTC QLQ-PR25: prostate cancer specific instrument with 25 questions used in conjunction with EORTC QLQ-C30 to assess the participant QoL. Used to evaluate 5 multi-item scales (urinary, bowel, and hormonal treatment-related symptoms, sexual activity, and sexual functioning) and one single item (problems due to incontinence aid use). Each question assessed on a 4-point scale (1= not at all, 2= a little, 3= quite a bit, 4= very much). Scores averaged, transformed to 0-100 scale; higher score=better quality of life/better level of functioning.

Time frame: Screening and Day 1 of every 28-day Cycle up to 30 months

Time to initiation of chemotherapy

Time from date of randomization to the first dose of chemotherapy.

Time frame: Randomization up to 30 months

Time to first skeletal related event (SRE)

Time from date of randomization to the first SRE such as pathological fracture, surgery/radiotherapy for pain/prevention of fracture, hypercalcemia, and spinal cord compression.

Time frame: Randomization up to 30 months

Measure plasma concentrations of ZEN003694 and the active metabolite ZEN003791

Plasma concentrations of ZEN003694 and the active metabolite ZEN003791 will be measured.

Time frame: Cycle 1 Day 1: Pre-dose, 1 hour, 2 hours, and 4 hours post-dose; Cycle 2 Day1: Pre-dose, 1 hour, 2 hours, and 4 hours post-dose

ZEN003694 and Enzalutamide Versus Enzalutamide Monotherapy in Metastatic Castration-Resistant Prostate Cancer

Overview

Conditions

Interventions

Eligibility

Locations (31)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts