ZEN-3694, Enzalutamide, and Pembrolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer

NCT04471974 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 20551NCI-2020-04495
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 3

Brief Summary

This phase II trial investigates how well ZEN-3694, enzalutamide, and pembrolizumab work in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). ZEN-3694 blocks the expression of the MYC gene to prevent cellular growth in certain types of tumors, including castrate resistant prostate cancer. Enzalutamide has been shown to block testosterone from reaching prostate cancer cells by binding to a receptor on prostate cancer cells, called androgen receptors. This works similar to a lock and key. When enzalutamide (key) inserts into the androgen receptor (lock) testosterone cannot attach to the androgen receptor, which slows the growth of tumor cells and may cause them to shrink. Pembrolizumab is a monoclonal antibody (proteins that can protect the body from foreign organisms, such as bacteria and viruses) designed to block a specific control switch which may be activated by tumor cells to overcome the body's natural immune system defenses. It also enhances the activity of the body's immune cells against tumor cells. The purpose of this study is to find out the effects ZEN-3694, enzalutamide, and pembrolizumab on patients with metastatic castration-resistant prostate cancer who have previously experienced disease progression.

Conditions

Castration-Resistant Prostate Carcinoma; Metastatic Prostate Adenocarcinoma; Metastatic Prostate Small Cell Carcinoma; Stage IV Prostate Cancer AJCC v8; Stage IVA Prostate Cancer AJCC v8; Stage IVB Prostate Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• Composite Response Rate

  Defined as either objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (complete response (CR), partial response (PR)) or confirmed \>= 50% decline from serum prostate-specific antigen (PSA) at baseline confirmed by repeat measurement performed ≥ 4 weeks later for each study cohort. To be considered evaluable for PSA50 response, patients must have a serum PSA \>=2 ng/mL at baseline. To be considered evaluable for objective response, patients must have measurable soft tissue disease by RECIST 1.1 criteria on baseline scan assessment. The composite response rate along with 95% confidence interval will be reported for participants in each study cohort.

  Up to 3 years

Secondary Outcomes (6)

• Objective Response Rate (ORR)

  Up to 3 years

• Median Duration of Response

  Up to 3 years

• Progression-free survival (PFS)

  Up to 3 years

• PSA50 response proportion

  Up to 3 years

• Overall survival (OS)

  Up to 3 years

Study Arms (3)

Safety Cohort

EXPERIMENTAL

Patients receive 96mg pembrolizumab IV over 30 minutes on day 1, BET bromodomain inhibitor ZEN-3694 PO QD and enzalutamide PO QD on days 1-21. Patients not on enzalutamide prior to study enrollment or have previously discontinued enzalutamide receive BET bromodomain inhibitor ZEN-3694 beginning on day 1 of cycle 2. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: BET Bromodomain Inhibitor ZEN-3694; Drug: Enzalutamide; Biological: Pembrolizumab

Cohort A: Transdifferentiated mCRPC

EXPERIMENTAL

Patients receive pembrolizumab IV over 30 minutes on day 1, BET bromodomain inhibitor ZEN-3694 PO QD and enzalutamide PO QD on days 1-21. Patients not on enzalutamide prior to study enrollment or have previously discontinued enzalutamide receive BET bromodomain inhibitor ZEN-3694 beginning on day 1 of cycle 2. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: BET Bromodomain Inhibitor ZEN-3694; Drug: Enzalutamide; Biological: Pembrolizumab

Cohort B: mCRPC without evidence of transdifferentiation

EXPERIMENTAL

Patients receive pembrolizumab IV over 30 minutes on day 1, BET bromodomain inhibitor ZEN-3694 PO QD and enzalutamide PO QD on days 1-21. Patients not on enzalutamide prior to study enrollment or have previously discontinued enzalutamide receive BET bromodomain inhibitor ZEN-3694 beginning on day 1 of cycle 2. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: BET Bromodomain Inhibitor ZEN-3694; Drug: Enzalutamide; Biological: Pembrolizumab

Interventions

BET Bromodomain Inhibitor ZEN-3694 DRUG

Given PO

Also known as: BETi ZEN-3694, ZEN 3694, ZEN-3694, ZEN003694

Cohort A: Transdifferentiated mCRPC; Cohort B: mCRPC without evidence of transdifferentiation; Safety Cohort

Enzalutamide DRUG

Given PO

Also known as: ASP9785, MDV3100, Xtandi

Cohort A: Transdifferentiated mCRPC; Cohort B: mCRPC without evidence of transdifferentiation; Safety Cohort

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Cohort A: Transdifferentiated mCRPC; Cohort B: mCRPC without evidence of transdifferentiation; Safety Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically confirmed prostate adenocarcinoma at the time of diagnosis, with subsequent development of metastatic castration-resistant prostate cancer. Patients with de novo small cell prostate cancer at the time of diagnosis are excluded from study participation
• Evidence of disease progression by PSA and/or radiographic progression by Prostate Cancer Working Group 3 (PCWG3) criteria at the time of study entry
• Patients must be evaluable for the primary endpoint of composite response, and must have either serum PSA \> 2 ng/mL during Screening and/or measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• Safety lead-in only:
• Metastatic castration resistant prostate cancer with evidence of disease progression by PCWG3 criteria at study entry
• Progression on at least one prior androgen signaling inhibitor (e.g. abiraterone/prednisone, enzalutamide, apalutamide, darolutamide)
• No prior chemotherapy for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Prior chemotherapy administered in the castration-sensitive setting is allowed provided last dose of chemotherapy is \> 6 months prior to cycle 1 day 1 (C1D1)
• Phase 2 Cohort A (transdifferentiated mCRPC) only:
• a. Participants must have clinicogenomic evidence of treatment emergent small cell neuroendocrine prostate cancer as defined by one or more of the following.
• i. Histologic evidence of small cell neuroendocrine prostate cancer on metastatic tumor biopsy and/or
• ii. Presence of loss-of-function mutation or deletion of RB1 on a Clinical Laboratory Improvement Act (CLIA)-approved genomic-sequencing platform and/or
• iii. Low PSA secretors as defined by meeting all of the following criteria during screening period -
• Serum PSA \>=2 ng/mL,
• Radiographic progression by PCWG3 criteria,
• Presence of \> 5 metastases on conventional imaging and/or

You may not qualify if:

• Has participated in a study of an investigational product and received study treatment or used an investigational device other than those specified in the protocol within 2 weeks of C1D1
• Hypersensitivity to ZEN-3694, pembrolizumab, enzalutamide, or any of its excipients
• Has received prior radiotherapy within 2 weeks of C1D1. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=\< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Receipt of prior pembrolizumab or another immune checkpoint inhibitor (e.g. nivolumab, ipilimumab). Prior treatment with sipuleucel-T is allowed
• Receipt of a radiopharmaceutical (e.g. radium-223, 177Lu-prostate-specific membrane antigen (PSMA) within 6 weeks prior to C1D1
• Prior treatment with a bromodomain inhibitor (BETi)
• Individuals with concurrent second malignancy requiring active treatment at study entry. Non-melanoma skin cancer, non-muscle invasive bladder cancer, and other carcinomas-in-situ are allowable exceptions
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Patients on low dose oral weekly methotrexate are allowed. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) or treatment with drugs (e.g. methimazole, neomercazol, carbamazole, etc.) that function to decrease the generation of thyroid hormone by a hyper-functioning thyroid gland (e.g., in Graves' disease) is not considered a form of systemic treatment of an autoimmune disease
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
• Cardiac condition as defined as one or more of the following:
• QT interval by Fridericia (QTcF) \> 480 ms (machine or manual read allowed)
• Uncontrolled supraventricular arrhythmia or ventricular arrhythmia requiring treatment
• New York Heart Association (NYHA) congestive heart failure class III or IV
• History of unstable angina, myocardial infarction, or cerebrovascular accident within 6 months prior to C1D1
• History of seizure or pre-disposing condition (e.g. brain metastases)

Sponsors & Collaborators

• Rahul Aggarwal: lead
• Zenith Epigenetics: collaborator
• Merck Sharp & Dohme LLC: collaborator
• U.S. Army Medical Research and Development Command: collaborator

Study Sites (3)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

University of Chicago

Evergreen Park, Illinois, 60805, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

enzalutamide; pembrolizumab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Rahul R Aggarwal, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 10, 2020
• First Posted: July 15, 2020
• Study Start: January 26, 2021
• Primary Completion (Estimated): May 31, 2028
• Study Completion (Estimated): May 31, 2028
• Last Updated: July 22, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)