Testing the Anti-cancer Drug DSP-5336 (Enzomenib) in Prostate Cancer

A Phase II Study of Enzomenib in Metastatic Castration-Resistant Prostate Cancer

This phase II trial tests how well enzomenib works in treating patients with prostate cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and has continued to grow or spread despite androgen deprivation therapy (castration-resistant). The growth and survival of prostate tumor cells often depends on testosterone. Androgen deprivation therapy blocks the use of testosterone by the tumor cells. Although most tumors respond to androgen deprivation therapy at first, nearly all eventually progress to a castration-resistant state. Enzomenib, a menin inhibitor, targets and blocks menin, a protein that plays a role in the survival and growth of tumor cells.

Study Overview

• Status: Not yet recruiting
• Conditions: Stage IVB Prostate Cancer AJCC v8; Metastatic Castration-Resistant Prostate Adenocarcinoma
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Bone Scan; Procedure: Biopsy Procedure; Other: Fludeoxyglucose F-18; Procedure: FDG-Positron Emission Tomography; Drug: Antiandrogen Therapy; Procedure: Computed Tomography; Drug: Enzomenib; Procedure: PSMA PET Scan

Detailed Description

PRIMARY OBJECTIVE:

I. To assess the efficacy of DSP-5336 (enzomenib) as measured by fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolic response rate, in patients with advanced treatment-refractory prostate cancer.

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of DSP-5336 (enzomenib) in patients with advanced treatment-refractory prostate cancer.

II. To determine the activity of DSP-5336 (enzomenib) in patients with advanced treatment-refractory prostate cancer.

III To assess the pharmacodynamics of DSP-5336 (enzomenib) in patients with advanced treatment-refractory prostate cancer.

IV. To assess the pharmacokinetics of DSP-5336 (enzomenib) in patients with advanced treatment-refractory prostate cancer.

EXPLORATORY OBJECTIVES:

I. To identify molecular subpopulations associated with response. II. To evaluate circulating tumor deoxyribonucleic acid (DNA) (ctDNA) as a predictor for response.

III. To evaluate differential metabolic responses between prostate-specific membrane antigen (PSMA)-positive and PSMA-negative lesions.

OUTLINE:

Patients continue to receive usual androgen deprivation therapy per standard of care. Patients receive enzomenib orally (PO) twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, FDG PET/computed tomography (CT), PSMA PET/CT, CT, bone scan and tissue biopsy throughout the study.

After completion of study treatment, patients are followed up at 30 days then every 3 months for up to 12 months.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• At the time of informed consent, be ≥ 18 years of age. Because no dosing or adverse event data are currently available on the use of DSP-5336 (enzomenib) in patients < 18 years of age, and because prostate cancer is an adult malignancy, pediatric patients are not part of the target disease population, therefore children are excluded from this study

• Histologically confirmed prostate adenocarcinoma

• Metastatic disease documented by conventional imaging, including cross-sectional imaging (CT or magnetic resonance imaging [MRI]) and bone scan. Advanced imaging, including PSMA PET/CT or FDG PET/CT, may be used as supportive documentation but is not sufficient as the sole evidence of metastatic disease for eligibility

• Patients with treated, stable brain metastases are eligible if neurologically stable for ≥ 4 weeks and not requiring corticosteroids for central nervous system (CNS) disease for at least 7 days prior to registration. Routine screening for asymptomatic CNS metastases is not required

• Participants with documented progressive metastatic castration-resistant prostate cancer (mCRPC), as assessed by the treating physician based on at least 1 of the following criteria:

  • Prostate specific antigen (PSA) progression may be used for study eligibility, either alone or with radiographic progression. PSA progression is defined as a rise in PSA that is both ≥ 25% and ≥ 2.0 ng/mL above the lowest PSA value since the start of the most recent systemic therapy, or above the pre-treatment baseline PSA if there was no PSA decline. The rise must be confirmed by a second PSA value obtained at least 3 weeks/21 days later. The reference PSA must be ≥ 1.0 ng/mL. Radiographic disease progression in soft tissue based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • Radiographic disease progression in bone, defined as appearance of 2 or more new bone lesions on bone scan

• Participants must have received prior systemic therapy for advanced or metastatic prostate cancer, including both of the following:

  • At least one androgen receptor pathway inhibitor, such as abiraterone, enzalutamide, apalutamide, or darolutamide. Androgen receptor pathway inhibitor (ARPI) exposure in the metastatic castration-sensitive, non-metastatic castration-resistant, or metastatic castration-resistant setting may satisfy this requirement and
  • At least one prior taxane chemotherapy regimen, such as docetaxel or cabazitaxel, and/or PSMA-targeted radioligand therapy. At least one therapy satisfying this second requirement must have been administered in the metastatic castration-resistant setting

• Prior poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapy, immunotherapy, radium-223, or other standard therapies are permitted but are not required to satisfy eligibility

• Therapy administered solely in the localized, neoadjuvant, adjuvant, or locally advanced setting does not count toward the required prior therapy history. Docetaxel administered solely in the metastatic castration-sensitive setting does not satisfy the required mCRPC therapy criterion

• Prior orchiectomy or medical castration, with castrate levels of serum testosterone defined as testosterone ≤ 50 ng/dL documented prior to initiation of study treatment. Participants receiving medical castration with a gonadotrophin releasing hormone (GnRH) agonist or antagonist must continue androgen deprivation therapy throughout the treatment phase

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

• Absolute neutrophil count ≥ 1,000/mcL

• Platelets ≥ 75,000/mcL

• Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN), except in patients with Gilbert syndrome, who may enroll if total bilirubin is ≤ 3 x institutional ULN and direct bilirubin is ≤ 1.5 x institutional ULN

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotranferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN

• Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m^2

• Participants must be willing to undergo baseline and on-treatment tumor biopsies and must have a lesion considered safely accessible for biopsy by the procedural team. Biopsies may be obtained from soft tissue or bone lesions, although soft tissue biopsy is preferred when feasible

• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

• Patients must have disease evaluable for the primary FDG PET metabolic response endpoint, defined as at least one FDG-avid lesion evaluable on baseline FDG PET/CT. The baseline FDG PET/CT must be performed during screening, and the presence of at least one FDG-avid, evaluable lesion must be confirmed prior to registration. RECIST 1.1 measurable disease is not required for eligibility. Patients with RECIST 1.1 measurable disease will be evaluable for RECIST-based secondary response assessments

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better. Participants must have Fridericia's formula-corrected QT interval (QTcF) ≤ 480 msec based on screening electrocardiogram

• The effects of DSP-5336 (enzomenib) on the developing human fetus are unknown. For this reason and because menin inhibitors agents are known to be teratogenic, men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of DSP-5336 (enzomenib) administration. Participants should not donate sperm for the duration of study participation, and 6 months after completion of the last dose of study drug

Exclusion Criteria:

• Prior treatment with a menin inhibitor (any investigational compound targeting the menin-MLL complex)
• Untreated, symptomatic, active, or progressive CNS metastases
• Inability or unwillingness to undergo FDG and PSMA PET/CT imaging, including inability to lie flat for > 30 minutes. Patients with uncontrolled diabetes mellitus are not eligible if fasting blood glucose cannot be controlled to ≤ 200 mg/dL, or to the institutional threshold required for interpretable FDG PET/CT imaging, despite appropriate medical management
• Known hypersensitivity to DSP-5336 (enzomenib) or any of its excipients
• Patients who have received systemic anticancer therapy, including oral anticancer therapy, chemotherapy, radioligand therapy, immunotherapy, targeted therapy, investigational anticancer agents, or other investigational agents, within 5 half-lives or 14 days, whichever is shorter, prior to initiation of study treatment. Longer washout may be required when clinically appropriate based on unresolved toxicity or prolonged expected pharmacodynamic effect. Patients who have received external beam radiation therapy within 2 weeks prior to initiation of study treatment are not eligible. Routine concomitant medications are permitted unless otherwise prohibited by the protocol. Ongoing androgen deprivation therapy with a GnRH agonist or antagonist is permitted
• Concomitant use of medications known to cause QT prolongation that cannot be safely discontinued or substituted prior to initiation of study treatment
• Patients with uncontrolled intercurrent illness or any other significant condition(s), including active infection requiring intravenous systemic therapy, that would make participation in this protocol unreasonably hazardous

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (androgen deprivation therapy, enzomenib); Patients continue to receive usual androgen deprivation therapy per standard of care. Patients receive enzomenib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, FDG PET/CT, PSMA PET/CT, CT, bone scan and tissue biopsy throughout the study.

Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Bone Scan; Undergo bone scan; Other Names: Bone Scintigraphy; Procedure: Biopsy Procedure; Undergo tissue biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Other: Fludeoxyglucose F-18; Given FDG; Other Names: 18FDG; FDG; fludeoxyglucose F 18; Fludeoxyglucose (18F); Fludeoxyglucose F18; Fluorine-18 2-Fluoro-2-deoxy-D-Glucose; Fluorodeoxyglucose F18; Procedure: FDG-Positron Emission Tomography; Undergo FDG PET/CT; Other Names: FDG; FDG-PET; FDG-PET Imaging; Drug: Antiandrogen Therapy; Given usual androgen deprivation therapy; Other Names: ADT; Androgen Deprivation Therapy; Anti-androgen Therapy; Anti-androgen Treatment; Antiandrogen Treatment; Hormone Deprivation Therapy; Hormone-Deprivation Therapy; Androgen Deprivation Therapy (ADT); Procedure: Computed Tomography; Undergo CT, FDG PET/CT, and PSMA PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Enzomenib; Given PO; Other Names: DSP 5336; DSP-5336; DSP5336; Menin Inhibitor DSP-5336; Menin-MLL Interaction Inhibitor DSP-5336; Procedure: PSMA PET Scan; Undergo PSMA PET/CT; Other Names: PSMA PET; Prostate-specific Membrane Antigen PET; PSMA-Positron emission tomography

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fluorodeoxyglucose (FDG) positron emission tomography metabolic response rate	Will be defined as the proportion of patients achieving a ≥ 30% reduction from baseline in total FDG uptake (standardized uptake value [SUVtotal]) across all FDG-avid lesions. The response rate will be estimated along with its exact 95% confidence interval (CI).	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Will be graded according to current Cancer Therapy Evaluation Program-required Common Terminology Criteria for Adverse Events version. Will be summarized by type, grade, seriousness, attribution, and relationship to study treatment.	Up to 30 days after last dose of study treatment
Overall response rate	Will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Working Group 3 (PCWG3). Will be reported with exact 95% CI where applicable. Will be summarized using Kaplan-Meier methods when appropriate.	Up to 12 months
Radiographic progression-free survival (PFS)	Will be summarized using Kaplan-Meier methods when appropriate.	Up to 12 months
Prostate specific antigen (PSA)-PFS	Will be summarized using Kaplan-Meier methods when appropriate.	Up to 12 months
Duration of response (DOR)	Kaplan-Meier estimates of median DOR and 95% CIs will be provided.	From first documented response to radiographic or clinical progression, or death, assessed up to 12 months
Time to PSA progression	Progression will be assessed using PCWG3. Will be summarized using Kaplan-Meier methods.	From treatment initiation to confirmed PSA progression, will be assessed up to 12 months
Overall survival (OS)	Will be summarized using Kaplan-Meier estimates, including median OS and 95% CIs.	From treatment initiation to death from any cause, assessed up to 12 months
Tumor response signatures	Bulk ribonucleic sequencing will be evaluated for transcriptome changes. Will be summarized using Kaplan-Meier methods when appropriate.	Up to 12 months
DSP-5336 (enzomenib) pharmacokinetics (PK)	PK parameters will be summarized descriptively, and exploratory exposure-safety and exposure-response relationships may be evaluated.	Up to 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor signatures	Mutations identified by whole exome sequencing (WES) will focus on the PI3K/AKT/mTOR pathway and common alterations associated with prostate cancer, lineage plasticity, and therapeutic resistance. Paired baseline and on-treatment tumor samples will be used to assess pharmacodynamic changes in transcriptional programs and AKT pathway signaling. Baseline tumor WES with matched germline deoxyribonucleic acid (DNA) will be used to characterize genomic alterations in the enrolled population.	Up to 12 months
Change in variant allele frequencies of tumor mutations in circulating tumor DNA (ctDNA)	Will be compared to pretreatment. Serial ctDNA dynamics will be explored for association with metabolic response, radiographic response/progression, and clinical outcomes. Given the sample size, correlative analyses will be hypothesis-generating.	At cycle 3 (cycle length = 28 days)
Change in FDG uptake (SUVtotal) in prostate-specific membrane antigen (PSMA)-positive and PSMA-negative lesions	Exploratory imaging analyses will evaluate metabolic response globally and, when feasible, by lesion phenotype, including PSMA-positive and PSMA-negative lesions. Lesion-level analyses will be descriptive and exploratory, with attention to within-patient heterogeneity.	Up to 12 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Adel Mandl, JHU Sidney Kimmel Comprehensive Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Estimated): February 26, 2027
• Primary Completion (Estimated): January 4, 2029
• Study Completion (Estimated): January 4, 2029

Study Registration Dates

• First Submitted: October 31, 2026
• First Submitted That Met QC Criteria: October 31, 2026
• First Posted (Actual): November 4, 2026

Study Record Updates

• Last Update Posted (Actual): November 4, 2026
• Last Update Submitted That Met QC Criteria: October 31, 2026
• Last Verified: October 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Pharmacologic Actions; Chemical Actions and Uses; Carbohydrates; Hydrolases; Enzymes; Enzymes and Coenzymes; Diagnostic Techniques, Surgical; Deoxyglucose; Deoxy Sugars; Peptide Hydrolases; Metalloproteases; Carboxypeptidases; Exopeptidases; Metalloexopeptidases; Fluorodeoxyglucose F18; Androgen Antagonists; Biopsy; Specimen Handling; Glutamate Carboxypeptidase II
• Other Study ID Numbers: NCI-2026-07869; UM1CA186691 (U.S. NIH Grant/Contract); NCI-2026-07869 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10790 (Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO); 10790 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No