A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With Enzalutamide
Condition: Metastatic Castration-resistant Prostate Cancer (mCRPC)
MeSH terms: Prostatic Neoplasms; Seizures
Intervention: Enzalutamide
Intervention description: Participants received 4 capsules (40 mg each) of enzalutamide orally once a day, for a total daily dose of 160 mg. Treatment was given with or without food and as close as possible to the same time each day.
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 424.0
Sex: Male
Healthy volunteers: No
Keywords: enzalutamide; Xtandi; seizure; Central Nervous System; MDV3100; metastatic castration-resistant prostate cancer (mCRPC)

Summary:

      The objective of this study was to evaluate the incidence of seizures and monitor the safety
      of enzalutamide treatment in participants with metastatic castration-resistant prostate
      cancer (mCRPC) known to have risk factor(s) for seizure.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject has histologically confirmed metastatic adenocarcinoma of the prostate.

          -  Subject has ongoing androgen deprivation therapy with a Gonadotropin-releasing hormone
             (GnRH) analogue (agonist or antagonist) or bilateral orchiectomy (i.e., surgical or
             medical castration).

          -  Subject has disease progression by at least one of the following:

               1. Prostate-Specific Antigen (PSA) progression defined by a minimum of 2 rising PSA
                  levels with an interval of at least 1 week between each draw;

               2. Bone disease progression as defined by Prostate Cancer Working Group 2 guidelines
                  (at least 2 new lesions) on bone scan; or

               3. Soft tissue disease progression as defined by RECIST 1.1

          -  For subjects who have not had an orchiectomy, there must be a plan to maintain
             effective GnRH-analogue therapy for the duration of the study.

          -  Subject must have failed at least one course of androgen deprivation therapy (ADT),
             i.e., treatment with GnRH analogues.

          -  Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          -  Subject has been evaluated by a local neurologist prior to study entry who has
             determined the subject has at least one risk factor for seizure including:

               1. past history of seizure due to any cause except a single febrile seizure in
                  childhood. Patients with a history of seizures should not have had a seizure
                  within 12 months of Screening and must have had no anticonvulsants for 12 months
                  prior to Screening,

               2. history of cerebrovascular accident (CVA) or transient ischemic attack (TIA),

               3. history of traumatic brain or head injury with loss of consciousness

               4. unexplained loss of consciousness within the last 12 months,

               5. presence of a space occupying lesion in the brain including previously treated
                  brain metastasis(es) or primary central nervous system (CNS) tumor,

               6. history of arteriovenous malformations of the brain,

               7. history of brain infection (i.e., abscess, meningitis, or encephalitis),

               8. current use of medication that may lower seizure threshold

               9. presence of Alzheimer's disease, meningioma, leptomeningeal disease from prostate
                  cancer.

          -  Subject is able to swallow the study drug and comply with study requirements.

          -  Subject agrees not to participate in another interventional study while on treatment.

          -  Male subject and his female partner who is of childbearing potential must use two
             acceptable methods of birth control (one of which must include a condom as a barrier
             method of contraception) starting at Screening and continuing throughout the study
             period and for 3 months after final study drug administration.

             1. Two acceptable forms of birth control include:

               1. Condom (barrier method of contraception), AND

               2. One of the following acceptable forms of contraception is required:

                    1. Established use of oral, injected or implanted hormonal methods of
                       contraception.

                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).

                    3. Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault
                       caps) with spermicidal foam/gel/film/cream/suppository).

                    4. Vasectomy or surgical castration at least 6 months prior to Screening.

          -  Male subject must use a condom, if having sex with a pregnant woman.

          -  Male subject must not donate sperm starting at Screening and throughout the study
             period and for at least 3 months after final drug administration.

        Exclusion Criteria:

          -  Subject with a history of exposure to enzalutamide.

          -  Subject has severe concurrent disease, infection, or co-morbidity that, in the
             judgment of the Investigator, would make the subject inappropriate for enrollment.

          -  Subject is currently being treated with anti-epileptics.

          -  Subject has a history of seizure within the past 12 months of Screening as assessed by
             neurology examination and history.

          -  Subject with rapidly progressing visceral disease who has not received and is thought
             to be able to tolerate cytotoxic chemotherapy. (However, subject who has previously
             received cytotoxic chemotherapy is permitted).

          -  Subject has clinical signs suggestive of high or imminent risks for pathological
             fracture, spinal cord compression and/or cauda equina syndrome.

          -  Subject's absolute neutrophil count is < 1500/microliter (µL), platelet count is <
             100,000/µL) or hemoglobin is < 5.6 millimoles(mmol)/liter (L) (9 grams (g)/deciliter
             (dL) at Screening.

          -  Subject's total bilirubin is ≥ 1.5 x upper limit of normal (ULN) (except for subjects
             with documented Gilbert's disease) or alanine aminotransferase (ALT) or aspartate
             aminotransferase (AST) is ≥ 2.5x upper limit of normal (ULN) at Screening.

          -  Subject's estimated creatinine clearance (Cer) is less than 30 milliliter (mL)/minute
             (min) by the Cockcroft and Gault formula (Creatinine Clearance (mL/min) = (140 -
             age)(weight (wt) kilogram (kg) / 72 x serum creatinine (milligram (mg)/100 mL)
             [Cockcroft, 1976] at Screening.

          -  Subject has uncontrolled hypertension as indicated by a resting systolic blood
             pressure > 160 millimeter of mercury (mmHg) or diastolic blood pressure > 100
             millimeter of mercury (mmHg) at Screening.

          -  Subject has received an investigational agent within 4 weeks or 5 half lives whichever
             is longer prior to Day 1.

          -  Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient
             or any of the capsule components, including Labrasol, butylated hydroxyanisole, and
             butylated hydroxytoluene.