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

Sponsor

Zenith Epigenetics (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04986423

Collaborator

Astellas Pharma Inc (Industry), Newsoara Biopharma Co., Ltd. (Industry)

200

Enrollment

Locations

Arms

35.8

Anticipated Duration (Months)

9.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration-Resistant Prostate Cancer	Drug: ZEN003694 Drug: Enzalutamide	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase 2b Study of ZEN003694 in Combination With Enzalutamide Versus Enzalutamide Monotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

Actual Study Start Date :

Sep 8, 2021

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Sep 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A - ZEN003694 + Enzalutamide Patients will be administered enzalutamide (160 mg) orally once daily for 21 days prior to the initiation of the combination therapy (Lead-in) to reach steady state concentration (Css) prior to Cycle 1. After the Lead-in, ZEN003694 (72 mg) will be administered orally one daily in combination with daily enzalutamide for 28-day cycles.	Drug: ZEN003694 72 mg PO QD Other Names: ZEN-3694 Drug: Enzalutamide 160 mg PO QD Other Names: Xtandi® MDV3100
Active Comparator: Cohort A - Enzalutamide Patients will be administered enzalutamide (160 mg) orally once daily for 21 days prior to Cycle 1 Day 1 (Lead-in). After the Lead-in, patients will be administered enzalutamide 160 mg orally once daily for 28-day cycles. Active control patients will have the option to cross-over to treatment with ZEN003694 in combination with enzalutamide upon confirmed radiographic progression by PCWG3 criteria by independent central review.	Drug: Enzalutamide 160 mg PO QD Other Names: Xtandi® MDV3100
Experimental: Cohort B - ZEN003694 + Enzalutamide Patients will be administered enzalutamide (160 mg) orally once daily for 21 days prior to the initiation of the combination therapy (Lead-in) to reach steady state concentration (Css) prior to Cycle 1. After the Lead-in, ZEN003694 (72 mg) will be administered orally one daily in combination with daily enzalutamide for 28-day cycles.	Drug: ZEN003694 72 mg PO QD Other Names: ZEN-3694 Drug: Enzalutamide 160 mg PO QD Other Names: Xtandi® MDV3100
Active Comparator: Cohort B - Enzalutamide Patients will be administered enzalutamide (160 mg) orally once daily for 21 days prior to Cycle 1 Day 1 (Lead-in). After the Lead-in, patients will be administered enzalutamide 160 mg orally once daily for 28-day cycles. Active control patients will have the option to cross-over to treatment with ZEN003694 in combination with enzalutamide upon confirmed radiographic progression by PCWG3 criteria by independent central review.	Drug: Enzalutamide 160 mg PO QD Other Names: Xtandi® MDV3100

Outcome Measures

Primary Outcome Measures

Cohort A: Radiographic progression-free survival (rPFS) by BICR [Randomization up to 30 months]
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.

Secondary Outcome Measures

Cohorts A + B: Radiographic progression-free survival (rPFS) by BICR [Randomization up to 30 months]
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
Cohort A: Radiographic progression-free survival (rPFS) by investigator assessment [Randomization up to 30 months]
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.
Cohort A + B: Radiographic progression-free survival (rPFS) by investigator assessment [Randomization up to 30 months]
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.
Cohort A: Progression-free survival (PFS) by investigator assessment [Randomization up to 30 months]
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.
Cohort A + B: Progression-free survival (PFS) by investigator assessment [Randomization up to 30 months]
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.
Cohort A: Overall survival (OS) [Randomization up to 30 months]
Time from date of randomization to the date of death from any cause
Cohort A + B: Overall survival (OS) [Randomization up to 30 months]
Time from date of randomization to the date of death from any cause
Cohort A: PSA50 response rate [Randomization up to 30 months]
PSA response is a reduction in serum PSA concentration of ≥50% from baseline.
Cohort A + B: PSA50 response rate [Randomization up to 30 months]
PSA response is a reduction in serum PSA concentration of ≥50% from baseline.
Objective response rate (ORR) [Randomization up to 30 months]
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.
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) [Screening and Day 1 of every 28-day Cycle up to 30 months]
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.
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). [Screening and Day 1 of every 28-day Cycle up to 30 months]
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 to initiation of chemotherapy [Randomization up to 30 months]
Time from date of randomization to the first dose of chemotherapy.
Time to first skeletal related event (SRE) [Randomization up to 30 months]
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.
Measure plasma concentrations of ZEN003694 and the active metabolite ZEN003791 [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]
Plasma concentrations of ZEN003694 and the active metabolite ZEN003791 will be measured.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Males age ≥ 18 years
Metastatic, castration-resistant, histologically confirmed prostate cancer
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
Have progressed on prior abiraterone treatment by PCWG3 criteria
Patients who are not candidates for chemotherapy in the opinion of the investigator or patients who decline chemotherapy
Cohort A only - Patient must meet definition of poor responder to abiraterone by one of the following:
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
Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: < 6 months duration on abiraterone or failure to achieve a PSA50 response
Cohort B only - Patient must meet definition of responder to abiraterone by one of the following:
Abiraterone started in hormone-sensitive prostate cancer (HSPC) disease setting: ≥ 12 months duration on abiraterone and nadir PSA < 0.2 ng/mL
Abiraterone started in castrate-resistant prostate cancer (CRPC) disease setting: ≥ 6 months duration on abiraterone and PSA50 response
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

Any history of brain metastases, prior seizure, conditions predisposing to seizure activity
Have previously received an investigational BET inhibitor (including previous participation in this study or a study of ZEN003694)
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.
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)
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
Have received exogenous administration of testosterone therapy since discontinuation of abiraterone.
Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy (excluding alopecia and neuropathy) prior to study entry
Radiation therapy within 2 weeks of the first administration of study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94158
2	Colorado Urology	Lakewood	Colorado	United States	80228
3	Hematology Oncology Clinic	Baton Rouge	Louisiana	United States	70809
4	University of Michigan Rogel Cancer Center	Ann Arbor	Michigan	United States	48109
5	Weill Cornell Medical College - New York Presbyterian Hospital	New York	New York	United States	10065
6	Messino Cancer Center	Asheville	North Carolina	United States	28806
7	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
8	Anhui Provincial Hospital	Hefei	Anhui	China	230002
9	Chongqing Cancer Hospital	Chongqing	Chongqing	China	400030
10	The First Affiliated Hospital of Xiamen University	Xiamen	Fujian	China	361003
11	Henan Cancer Hospital	Zhengzhou	Henan	China	450000
12	Tongji Hospital of Tongji Medical College, Huazhong University of Science & Technology	Wuhan	Hubei	China	430030
13	Hubei Cancer Hospital	Wuhan	Hubei	China	430079
14	Hunan Cancer Hospital	Changsha	Hunan	China	410006
15	Nanjing Drum Tower Hospital	Nanjing	Jiangsu	China	210008
16	Liaoning Cancer Hospital	Shenyang	Liaoning	China	110042
17	The First Affiliated Hospital of Xi'an Jiaotang University	Xi'an	Shaanxi	China	71000
18	Fudan University Shanghai Cancer Center	Shanghai	Shanghai	China	200032
19	Shanghai Tenth People's Hospital	Shanghai	Shanghai	China	200072
20	First Hospital of Shanxi Medical University	Taiyuan	Shanxi	China	030001
21	Sichuan Provincial People's Hospital	Chengdu	Sichuan	China	610072
22	Zhejiang Provincial People's Hospital	Hangzhou	Zhejiang	China	310014