This phase II trials studies the side effects and how well ESK981 works in treating patients with castration-resistant prostate cancer that has spread to other places in the body. ESK981 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the PSA >= 50% response rate (PSA50) from baseline using the Prostate Cancer Working Group 3 (PCWG3) criteria to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981) as a single agent in men with castration-resistant prostate cancer (CRPC) who have progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor).

II. To assess the safety and tolerability of ESK981 as a single agent.

SECONDARY OBJECTIVES:

I. To determine the time to PSA response to ESK981 in metastatic CRPC patients. II. To determine the duration of PSA response to ESK981 in metastatic CRPC patients.

III. To determine PSA progression rates and PSA progression free survival (PFS), as defined by the PCWG3 criteria.

TERTIARY OBJECTIVES:

I. To assess exploratory biomarkers from blood and tumor biopsies.

OUTLINE:

Patients receive pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 orally (PO) once daily (QD) for 5 days (Monday-Friday). Treatment repeats for up to 8 weeks in the absence of disease progression or unacceptable toxicity. If treatment is successful after 8 weeks, patients may receive up to 6 months of pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

• Have signed an informed consent document indicating that the subject 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
• Eastern Cooperative Group (ECOG) performance status =< 1
• Patient must have evidence of castrate resistant prostate cancer as evidenced by a confirmed rising PSA (per PCWG3 criteria) and a castrate serum testosterone level (i.e. =< 50 mg/dL)
• Documented histologically confirmed adenocarcinoma of the prostate
• Metastatic prostate cancer (M1) as documented by appropriate medical imaging (i.e. computed tomography [CT]-scan, positron emission tomography [PET] scan or bone scan)
• Treatment failure of either abiraterone and/or enzalutamide as evidenced by a confirmed rising PSA (per PCWG3 criteria) and a castrate serum testosterone level (i.e. =< 50 mg/dL) while receiving treatment with either abiraterone and/or enzalutamide
• Willingness to use contraception by a method that is deemed effective by the Investigator throughout the treatment period and for at least 30 days following the last dose of therapy
• Willingness and ability to comply with study procedures and follow-up examination
• Able to swallow and retain oral medication

Exclusion Criteria:

• Current systemic therapy (other than a gonadotrophin releasing hormone [GnRH] agonist/antagonist) for CRPC including:

  • CYP-17 inhibitors (e.g. ketoconazole, abiraterone)
  • Antiandrogens (e.g. bicalutamide, nilutamide)
  • Second generation antiandrogens (e.g. enzalutamide, ARN-509, Galeterone)
  • Immunotherapy (e.g. sipuleucel-T, ipilimumab)
  • Chemotherapy (e.g. docetaxel, cabazitaxel)

• Greater than 2 lines of prior systemic therapy for CRPC

• Prior chemotherapy (e.g. docetaxel, cabazitaxel) for CRPC; prior docetaxel administered in the castrate-sensitive space is allowed

• Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153, etc.) within the past year

• Have any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements

• Absolute neutrophil count (ANC) less than 1500/mm^3

• Platelet count less than 100000/mm^3

• Hemoglobin less than 9 g/dL

• Bilirubin greater than 1.5 times the upper limit of normal (ULN)

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2.0 times the ULN in the absence of known hepatic metastases, or ALT or AST greater than 3.0 times the ULN in the presence of known hepatic metastases

• The patient has a serum creatinine value greater than 1.5 mg/dL

• The patient has active brain metastases

• The patient is currently on warfarin or heparin therapy

• The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria, or gastrointestinal bleeding, and a history of a clinically significant cardiovascular or cerebrovascular event within 12 months prior to study entry

• The patient has uncontrolled hypertension defined as a blood pressure measurement greater than 150 mm Hg systolic or 90 mm Hg diastolic with medication

• The patient has received any investigational drug within the past 4 weeks

• The patient has previously been enrolled in the study or received ESK981

• The patient has known hypersensitivity to gelatin or lactose monohydrate

• The patient has taken a medication known to be a potent inducer of CYP1A2, CYP2C8, or CYP3A4 within 4 weeks prior to the first dose of study drug

• The patient has taken a medication known to be a potent inhibitor of CYP1A2, CYP2C8, or CYP3A4 within 2 weeks prior to the first dose of study drug