IONIS-AR-2.5Rx and Enzalutamide in Treating Patients with Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria

• Ability to understand and voluntarily agree to participate by providing written informed consent for the trial
• Histologically confirmed prostate adenocarcinoma cancer, either pure or mixed. Small cell/neuroendocrine differentiation is not allowed
• Castrate levels of serum testosterone (=< 50 ng/dL). Patients must continue androgen deprivation therapy with an luteinizing hormone-releasing hormone (LHRH) analogue or antagonist if they have not undergone bilateral orchiectomy
• Patients must have metastatic disease; either non-measurable disease OR measurable disease per RECIST 1.1
• Progressive disease despite ongoing treatment with androgen deprivation therapy (ADT) based on ANY one of the following: * Progression on axial imaging per treating investigator * PSA evidence for progressive prostate cancer consists of a PSA level of at least 1 ng/ml which has risen on at least 2 successive occasions, at least one week apart. If the confirmatory PSA value is less than the screening PSA value, then an additional test for rising PSA will be required to document progression for the purposes of eligibility * Radionuclide bone scan: At least two new foci consistent with metastatic lesions
• Patients treated with first generation anti-androgen as most recent systemic therapy (e.g. bicalutamide, nilutamide) must have at least 4 weeks elapsed from treatment discontinuation to start of protocol therapy with evidence of disease progression following discontinuation of prior anti-androgen
• Minimum PSA at entry of 1 ng/mL is required
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Absolute neutrophil count (ANC) >= 1,500/uL
• Platelets >= 100,000/uL
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L with or without a red blood cell transfusion within 2 weeks of enrollment
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance >= 30 mL/min for subjects with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl])
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with active liver metastases
• Alkaline phosphatase If > 2.5 x ULN, then liver fraction should be =< 2.5 x ULN
• International normalized ratio (INR) prothrombin time (PT) activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) =< 1.5 x ULN * This can vary if subject is receiving anticoagulant therapy, as long as PT or PTT remains within therapeutic range of the anticoagulant’s intended use
• Subjects must agree to use an adequate method of contraception starting with the time of informed consent through 120 days after the last dose trial therapy

Exclusion Criteria

• Prior chemotherapy and/or enzalutamide for metastatic castration-resistant prostate cancer. Chemotherapy administered in the castration-sensitive setting is allowed provided last dose of chemotherapy was greater than 6 months prior to study entry
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of enrollment
• Has not recovered (i.e., adverse event [AE] =< grade 1 or at baseline) from AEs due to a previously administered agent. Subjects with =< grade 2 neuropathy or =< grade 2 alopecia are an exception to this criterion and are allowed if relevant toxicity is stabilized
• If subjects received major surgery they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting trial therapy
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. At the time of signing informed consent is a known regular user (including "recreational use") of any illicit drug(s) or had a recent history (within the last year) of drug or alcohol abuse
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live virus vaccine within 30 days of planned start of trial therapy
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable brain metastases (stability is normally defined as a period of 1 to 3 months in which there is no evidence of new or enlarging CNS metastases)
• Has symptomatic ascites or pleural effusion; a subject who is clinically stable following treatment for these conditions is eligible
• Has had a prior allogeneic stem cell or bone marrow transplant
• Has known contraindication to aspirin (81 mg)