Enzalutamide and Niraparib in the Treatment of Metastatic Castrate-Resistant Prostate Cancer (CRPC)
Condition: Metastatic Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Enzalutamide; Niraparib
Intervention description: Following completion of 28-day lead-in cycle, enzalutamide 160 mg PO daily will continue to be administered in 28-day cycles until documented progression, unmanageable toxicity, or decision to discontinue for any reason.; Niraparib will be administered daily in three dose-escalation cohorts of 6 subjects per dose levels of 100mg PO, 200mg PO or 300mg PO in 28-day cycles until documented progression, unmanageable toxicity, or decision to discontinue for any reason.
Intervention MeSH terms: Niraparib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Enzalutamide; Niraparib; PARP-1 inhibitor; PARP-2 inhibitor; Castrate-Resistant Prostate Cancer

Summary:

      This is a phase I study to determine the safety and feasibility of the combination of
      enzalutamide and niraparib in subjects with metastatic castration-resistant prostate cancer
      (CRPC).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent and Health Insurance Portability and Accountability Act
             (HIPAA) authorization for release of personal health information. NOTE: HIPAA
             authorization may be included in the informed consent or obtained separately.

          -  Age ≥ 18 years at the time of consent.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 14 days
             prior to registration.

          -  Men who are not surgically sterile (vasectomy) must agree to use an acceptable method
             of contraception. Male subjects with female sexual partners who are pregnant, possibly
             pregnant, or who could become pregnant during the study must agree to use condoms from
             the first dose of study drug through at least 120 days after the last dose of study
             drug. Total abstinence for the same study period is an acceptable alternative.

          -  Documented histologically or cytologically confirmed adenocarcinoma of the prostate.

          -  Ongoing androgen deprivation therapy with a Gonadotropin Releasing Hormone (GnRH)
             analogue or bilateral orchiectomy. Subjects who have not undergone orchiectomy must
             plan to continue GnRH analogue therapy for the duration of the trial.

          -  All subjects on oral anti-androgen therapy must have been off therapy for at least 4
             weeks prior to registration (6 weeks for bicalutamide) to exclude an anti-androgen
             withdrawal response. Patients who received secondary anti-androgen therapy and did not
             exhibit a >50% PSA decline, or subjects with any rise in PSA, objective or symptomatic
             progression following anti-androgen withdrawal will not be required to meet this
             withdrawal requirement.

          -  Documented metastatic disease with prostate-specific antigen (PSA) progression,
             radiographic progression, or both, despite receiving luteinizing hormone releasing
             hormone (LHRH) analogue therapy or orchiectomy with a serum testosterone level of 50
             ng/dL or less.

               -  PSA progression is defined as three successive rising PSA values with an interval
                  of at least one week between determinations.

               -  Radiographic progression is defined by Response Evaluation Criteria in Solid
                  Tumors (RECIST) 1.1 criteria or at least two new lesions on bone scan.

          -  At screening the serum testosterone must be 50 ng/dL or less and the PSA must be
             greater or equal to 2 ng/mL.

          -  Estimated life expectancy > 6 months

          -  Prior treatment of CRPC, including docetaxel, cabazitaxel, sipuleucel-T, or Radium-223
             is allowed.

          -  Prior therapy with abiraterone allowed for a maximum of 9 subjects.

          -  Prior chemotherapy must be completed at least 28 days prior to registration and the
             participant subject must have recovered from the acute toxic effects.

        Exclusion Criteria:

          -  Prior enzalutamide or other next-generation androgen receptor- (AR) targeting therapy.

          -  Prior PARP-inhibitor therapy.

          -  History of or active central nervous system (CNS) metastases. Subjects with
             neurological symptoms must undergo a head computed tomography (CT) scan or brain
             magnetic resonance imaging (MRI) to exclude brain metastasis.

          -  Radioisotope or external beam radiation exposure in the last 4 weeks. Exposure to
             strontium, regardless of when exposure occurred.

          -  Prior radiation to 25% or more of the bone marrow.

          -  Treatment with any investigational agent within 28 days prior to registration.

          -  Known significant immunodeficiency as determined by the site investigator.

          -  Prior malignancy except for adequately treated basal cell or squamous cell skin
             cancer, or other cancer for which the subject has been disease-free or stable for at
             least one year.

          -  Prolonged QTc over 470 ms.

          -  History of seizure.

          -  Clinically significant active infections on systemic therapy as judged by the site
             investigator.