Study of Enzalutamide in Patients With Castration-resistant Prostate Cancer
Condition: Metastatic Castration-resistant Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Enzalutamide
Intervention description: Enzalutamide, formerly known as MDV3100, is a rationally-designed second generation AR inhibitor which functions by blocking several steps in the AR signaling cascade. Enzalutamide competitively binds the AR with great potency. Additionally, enzalutamide inhibits nuclear translocation of activated AR and inhibits the association of activated AR with DNA.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 67.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Enzalutamide; Metastatic Castration-resistant Prostate Cancer

Summary:

      This research study is evaluating a drug called enzalutamide in metastatic castration
      resistant prostate cancer. Enzalutamide is already FDA approved for metastatic castration
      resistant prostate cancer after treatment with chemotherapy.

      The purpose of this study is to analyze features of tumor specimens sampled prior to therapy
      and at disease progression to determine why patients respond or stop responding to treatment
      with Enzalutamide.

      Prior chemotherapy is not a requirement of this trial.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must meet the following criteria on screening examination to be eligible
             to participate in the study:

          -  Be a male ≥ 18 years of age.

          -  Participants must have histologically or cytologically confirmed adenocarcinoma of the
             prostate without ≥50% neuroendocrine differentiation or small cell histology.

          -  Participants must have progressive disease as defined by either:

          -  Castrate resistant disease as defined by PCWG. Participants must have a rise in PSA on
             two successive determinations at least one week apart and PSA levels ≥ 2 ng/ml (only
             the screening PSA needs to be ≥ 2 ng/ml) and testosterone levels < 50 ng/dL, OR

          -  Soft tissue progression defined by RECIST 1.1, OR

          -  Bone disease progression defined by PCWG2 with two or more new lesions on bone scan.

          -  CRPC with metastatic disease with at least one site of metastatic disease must be
             amenable to needle biopsy. Soft tissue biopsy sites include: lymph node or visceral
             metastases. Bone sites include lumbar vertebrae, pelvic bones and long bones. Excluded
             sites are thoracic, cervical vertebrae, skull and rib lesions. Biopsy site will be
             selected with guidance of interventional radiologist determining best site to optimize
             balance of obtaining useful tissue for analysis and minimizing risk.

          -  Participants without orchiectomy must be maintained on LHRH agonist/antagonist
             therapy.

          -  Participants may have had any number of previous hormonal therapies (antiandrogens,
             steroids, estrogens, finasteride, dutasteride, ketoconazole, abiraterone) provided
             these were discontinued ≥ 4 weeks before enrollment.

          -  Participants may have had up to two previous cytotoxic therapeutic regimens provided
             these were discontinued ≥ 4 weeks before enrollment.

          -  At least a 4 week interval from previous prostate cancer treatment other than LHRH
             agonist/antagonist therapy or bisphosphonates to enrollment.

          -  Participants receiving bisphosphonates therapy can be maintained on this therapy. If
             participants have not started bisphosphonates, it is recommended that they start
             treatment after the first biopsy.

          -  ECOG performance status < 2 (Karnofsky >60%, see Appendix A).

          -  Participants must have normal organ and marrow function as defined below:

          -  WBC ≥ 3,000/mcL

          -  ANC ≥ 1,500/mcL

          -  Platelets ≥ 100,000/mcL

          -  Hemoglobin ≥ 9 g/dL

          -  Serum albumin ≥ 3.0 g/dL

          -  AST, ALT, and total bilirubin ≤ 1.5 x Institutional ULN

          -  Creatinine ≤ 1.5 Institutional ULN or a calculated creatinine clearance ≥ 50 mL/min
             using the Cockcroft Gault equation

          -  PTT ≤ 60, INR ≤ 1.5 Institutional ULN unless on warfarin therapy (investigator would
             need to determine if safe for participant to stop warfarin prior to biopsy)

          -  Have signed an informed consent document indicating that the subjects understands the
             purpose of and procedures required for the study and are willing to participate in the
             study.

          -  Be willing/able to adhere to the prohibitions and restrictions specified in this
             protocol.

          -  Written Authorization for Use and Release of Health and Research Study Information (US
             sites only) has been obtained.

          -  Able to swallow the study drug whole as a tablet.

          -  Participants who have partners of childbearing potential must be willing to use a
             method of birth control with adequate barrier protection as determined to be
             acceptable by the principal investigator during the treatment period and for 1 week
             after last dose of enzalutamide.

        Exclusion Criteria:

          -  Participants who exhibit any of the following conditions at screening will not be
             eligible for admission into the study.

          -  Uncontrolled illness including, but not limited to ongoing or active infection,
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
             psychiatric illness/social situations that would limit compliance with study
             requirements within 6 months of enrollment.

        Clinically significant heart disease as evidenced by:

          -  Myocardial infarction within 6 months of enrollment.

          -  Uncontrolled angina within 6 months of enrollment.

          -  Congestive heart failure NYHA Class III or IV, or a history of congestive heart
             failure NYHA Class III or IV in the past, unless a screening ECHO or MUGA within 3
             months results in a left ventricular ejection fraction ≥ 45%.

          -  Clinically significant ventricular arrhythmias.

          -  History of Mobitz II second degree or third degree heart block without a permanent
             pacemaker in place.

          -  Bradycardia as indicated by a heart rate < 50 beats per minute at screening visit.

          -  Hypotension as indicated by SBP ≤ 85 on 2 consecutive measurements.

          -  Uncontrolled hypertension as indicated by SBP > 170 mmHg or DBP > 105 mmHg on 2
             consecutive measurements at screening visit.

          -  Thromboembolism within 6 months of enrollment.

          -  History of gastrointestinal disorders (medical disorders or extensive surgery) which
             may interfere with the absorption of the study drug.

          -  History of seizure or any condition or concurrent medication that may predispose to
             seizure.

          -  Individuals with a history of a different malignancy are ineligible except for the
             following circumstances: 1) individuals with a history of other malignancies are
             eligible if they have been disease-free for at least 5 years and are deemed by the
             investigator to be at low risk for recurrence of that malignancy, or 2) individuals
             with the following cancers are eligible if diagnosed and treated within the past 5
             years: superficial bladder cancer, basal cell or squamous cell carcinoma of the skin.

          -  Known brain metastasis. Participants with brain metastasis can only be included if
             they were treated > 4 week prior to enrollment with radiation and the effects of
             treatment have resolved. Subjects with treated brain metastases must have a
             post-treatment brain MRI showing no further progression of prior lesions and no new
             metastatic lesions. Subjects will be ineligible if they have any ongoing symptoms from
             brain metastases or if there continues to be radiographic evidence of cerebral edema.

          -  Have known allergies, hypersensitivity, or intolerance to enzalutamide or their
             excipients.

          -  Surgery or local prostatic intervention within 30 days of the first dose. In addition,
             any clinically relevant issues from the surgery must have resolved prior to
             enrollment.

          -  Major surgery or radiation therapy within 4 weeks of enrollment. Radium-223,
             strontium-89, or samarium-153 therapy within 4 weeks of enrollment. Radiotherapy,
             chemotherapy or immunotherapy within 4 weeks, or single fraction of palliative
             radiotherapy within 14 days of administration of enrollment.

          -  Prior treatment with enzalutamide.

          -  Current enrollment in an investigational drug or device study or participation in such
             a study within 30 days of enrollment.

          -  Concomitant use of medications that may alter pharmacokinetics of enzalutamide. See
             section 5.3.

          -  Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not
             resolved to a NCI CTCAE (version 4) grade of ≤ 1. Chemotherapy induced alopecia and
             grade 2 peripheral neuropathy are allowed.

          -  Condition or situation which, in the investigator's opinion, may put the participant
             at significant risk, may confound the study results, or may interfere significantly
             with participant's participation in the study.

          -  Individuals not willing to comply with the procedural requirements of this protocol.

          -  HIV-positive individuals on combination antiretroviral therapy are ineligible because
             of the potential for pharmacokinetic interactions with enzalutamide. Appropriate
             studies will be undertaken in participants receiving combination antiretroviral
             therapy when indicated.