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

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