Crizotinib and Enzalutamide in Treating Patients with Metastatic Hormone-Resistant Prostate Cancer

Inclusion Criteria

• The patient has pathologically confirmed adenocarcinoma of the prostate
• The subject must have castration-resistant prostate cancer (CRPC) with castrate levels of serum testosterone less than 50 ng/dL; Note: subjects must maintain a castrate state; if they have not had an orchiectomy must continue to receive luteinizing-hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists unless intolerant
• Evidence of metastatic disease by radiographic imaging (bone scan or other nodal or visceral lesions on computed tomography [CT] or magnetic resonance imaging [MRI])
• Prostate cancer progression since or on last prior therapy documented by prostate-specific antigen (PSA) according to Prostate Cancer Working Group 2 (PCWG2) or radiographic progression according to modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1
• No limit on number or type of prior therapies * Prior treatment with docetaxel is permitted but not required * Prior treatment with ketoconazole, estrogens, abiraterone or novel antiandrogens allowed, including past enzalutamide * Require at least a 6 week withdrawal period from the last dose of bicalutamide, or nilutamide or 4 weeks from last flutamide or enzalutamide dose ** Must have a documented PSA rise after stopping the antiandrogen * Will require a 2 week washout period from last dose of ketoconazole, chemotherapy, radiation (including radium-223), or prior investigational systemic agents
• Prior radiation is allowed
• Eastern Cooperative Oncology Group (ECOG) performance status < 2
• Life expectancy of greater than 6 months
• Absolute neutrophil count >= 1,500/mcL
• Hemoglobin >= 8 g/dL * Transfusions and erythropoietin supplementation permitted
• Platelets >= 100,000/mcL
• Total bilirubin within normal institutional limits (unless known Gilbert’s syndrome)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal or =< 5 x if presence of liver metastases * For patients with documented bone metastases, AST can be > 2.5 x upper limit of normal (ULN) if the investigator can provide evidence of no underlying liver dysfunction and thus, it is likely that the AST is originating from bone source
• Creatinine clearance >= 30 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
• Able to swallow the study drug as a whole tablet
• Diabetics on insulin or antihyperglycemics must be on a stable dose (i.e., no titrations within the last 2 weeks) at the time of study entry
• The effects of crizotinib and enzalutamide on the developing human fetus are unknown. For this reason and because investigational agents as well as other standard antiandrogen agents used in this trial may be teratogenic, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of crizotinib administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Pathology consistent with small cell carcinoma of the prostate
• Prior treatment with c-Met inhibitors
• Persistent grade > 1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.0) adverse events (AEs) due to investigational drugs that were administered more than 14 days before study enrollment with the exception of alopecia
• Participants with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction or seizures that would confound the evaluation of neurologic and other adverse events
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to crizotinib or enzalutamide
• History of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke or significant brain trauma, history of loss of consciousness or transient ischemic attack within 12 months of study entry); diabetics on a stable dose of insulin or antihyperglycemic regimen are allowed if they have had no prior seizures and no history of loss of consciousness due to hypoglycemia
• Concomitant use of medications that may alter pharmacokinetics of crizotinib or enzalutamide; would exclude the use of strong cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) inhibitors, strong or moderate CYP3A inducers, CYP2C8, cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) and cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) substrates with narrow therapeutic indices
• Uncontrolled intercurrent 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
• Clinically significant heart disease defined as: * Myocardial infarction within 6 months of screening visit * Uncontrolled angina within 3 months of screening visit * Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months of the screening visit results in a left ventricular ejection fraction that is >= 45% * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes) * Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiogram (ECG) > 470 msec * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place * Hypotension (systolic blood pressure < 86 mmHg) or bradycardia with a heart rate of < 50 beats per minute on the screening ECG, unless pharmaceutically induced and thus reversible (i.e. beta blockers) or known, chronic asymptomatic baseline heart rate * Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the screening visit
• Thrombosis or vascular ischemic events within the last six months, such as deep venous thrombosis, pulmonary embolism, transient ischemic attack, cerebral infarction, or myocardial infarction
• Pregnant women are excluded from this study
• No defined washout period from major or minor surgery is required but incisions must be fully healed
• Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with crizotinib or enzalutamide. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
• Inability to comply with study and/or follow-up procedures