AMG 208 Tumor Microenvironment in Metastatic Castration Resistant Prostate Cancer (mCRPC)

Inclusion Criteria: 1. Histologically or cytologically confirmed adenocarcinoma of the prostate. 2. Presence of metastatic disease to the bone. 3. Patients must have a castrate level of testosterone (\</= 50 ng/dL) at the screening visit, medical or surgically induced. For patients who are medically castrated, gonadotropin releasing hormone antagonist or analog must continue to maintain testicular suppression. 4. Evidence of progressive disease prior to enrolment based on AT LEAST one of the following criteria: a) Rising PSA: PSA progression defined by a minimum of two rising PSA levels with an interval of \>/= 1 week between each determination. The PSA value at the Screening visit should be \>/= 2 ng/mL; b) Non-measurable (evaluable) disease: 2 (two) or more new metastatic bone lesions by radionuclide bone scan or plain bone films (x-rays); c) Measurable disease (RECIST 1.1) by transaxial imaging: patients must show evidence of new or progressive disease on CT or MRI scans. 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 6. For patients who received combined androgen blockade (a GnRH antagonist, analog or orchiectomy in combination with continuous antiandrogen not including enzalutamide), disease progression must have been determined after antiandrogen discontinuation as defined below: a) For patients receiving flutamide: at least one of the PSA values must be obtained 4 weeks or more after flutamide discontinuation.; b) For patients receiving bicalutamide or nilutamide: at least one of the PSA values must be obtained 6 weeks or more after antiandrogen discontinuation.; However, in patients who did not respond to combined androgen blockade or who showed a decline in PSA for 3 months or less after an antiandrogen was administered as a second-line or later intervention, no withdrawal response will be expected and therefore disease progression will be determined provided at least one rising PSA value is obtained 2 weeks or more after antiandrogen discontinuation. 7. Patients who received any other hormonal therapy, including megestrol acetate, finasteride, ketoconazole, abiraterone, enzalutamide, diethylstilbestrol or any systemic corticosteroids, must have discontinued such agent for at least 2 weeks prior to enrollment. Progressive disease must be documented after discontinuation of such therapy. Low dose maintenance steroids (prednisone \</=10 mg/d or hydrocortisone \</= 30 mg/d equivalents) are permitted. 8. No more than two prior cytotoxic chemotherapies for metastatic prostate cancer. 9. Relative to Day 1 visit, at least 3 weeks since radiation therapy (2 weeks if single fraction), at least 4 weeks since major surgery or investigational therapy, and at least 8 weeks since radioisotope therapy. 10. Resolution of all acute toxic effects of prior therapy or surgical procedure to Grade \</=1 at baseline. 11. Adequate organ function as defined: serum aspartate transaminase (AST) and serum alanine transaminase (ALT) \</= 3 x upper limit of normal (ULN) if no metastatic liver involvement, or \</= 5 if liver involvement; total serum bilirubin \</= 1.5 x ULN; absolute neutrophil count (ANC) \>/= 1500/uL; platelets \>/= 100,000/uL; hemoglobin \>/= 9.0 g/dL; serum albumin \>/=3.0 g/dL; serum creatinine \< 2.0 mg/dL or calculated creatinine clearance \>/=60 ml/min; PT (or INR) or PTT \</=1.5 x ULN. Subject may not have received any growth factors or blood transfusions within 7 days of the hematologic laboratory values obtained at the Screening visit. 12. Able to swallow the study drug and comply with study requirements. 13. Agree to use a double-barrier method of contraception, which involves the use of a condom in combination with one of the following: contraceptive sponge, diaphragm, or cervical ring with spermicidal gel or foam, if having sex with a woman of child-bearing potential during the length of the study and for at least one month after AMG 208 is discontinued. 14. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment. Exclusion Criteria: 1. Small cell or other variant histology. 2. Brain metastases or active epidural disease. Patients with treated epidural disease are eligible if stable for at least 4 weeks. 3. Diagnosis of any second malignancy within the last 2 years, except basal cell carcinoma, squamous cell skin cancer, or in situ carcinoma that has been adequately treated with no evidence of recurrent disease for 12 months. 4. Impending complication from bone metastasis (fracture and/or cord compression). Any bone fracture must be healed. 5. Presence of acute urinary obstruction. 6. Prior anti-c-Met or c-Met/VEGR-2 inhibitor. 7. Patients on stable doses of bisphosphonates or denosumab showing subsequent tumor progression may continue on this therapy; however, patients are not allowed to initiate bisphosphonate therapy in at least 4 weeks prior to or during the study. 8. Ongoing treatment with therapeutic doses (with therapeutic INR levels) of coumarin derivatives or oral anti-vitamin K agents. Therapeutic doses of low molecular weight heparins are allowed. 9. Concurrent or prior (within 14 days of study day 1) use of strong CYP3A4 inhibitors (including, but not limited to, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). 10. Concurrent or prior (within 7 days of study day 1) grapefruit products and other foods that are known to inhibit CYP3A4. 11. Concurrent or prior (within 28 days of study day 1) use of strong CYP3A4 inducers (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Subjects should not take St John's Wort. 12. Concurrent or prior (within 28 days of study day 1) use of strong P-glycoprotein and Breast Cancer Receptor Protein inhibitors (including, but not limited to elacridar and valspodar). 13. Clinically significant cardiovascular disease including: a) Myocardial infarction within 6 months of Screening visit; b) Uncontrolled angina within 3 months of Screening visit; c) Current or past history of congestive heart failure NYHA class III or IV or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months results in a left ventricular ejection fraction (LVEF) that is \>/= 50%; d) History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes), grade \>/= 2 cardiac dysrhythmias, atrial fibrillation of any grade, or QTcF interval \> 470 msec on the screening Electrocardiogram (ECG); e) History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place; 14. (Continued from Exclusion #13) f) Hypertension that cannot be controlled by medications (\> 140 mmHg systolic OR \> 90 diastolic despite optimal medical therapy). 15. Seizure disorder not controlled with standard medical therapy, or cerebrovascular accident or transient ischemic attack within 6 months of Screening visit. 16. Patients must not have clinical history of coagulopathy or bleeding diathesis, or arterial or venous thrombosis within 1 year of Screening visit. 17. Gastrointestinal abnormalities such as inability to take oral medication; requirement for intravenous alimentation; prior surgical procedures affecting absorption including total gastric resection; treatment for active peptic ulcer disease in the past 6 months; active gastrointestinal bleeding as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy; malabsorption syndromes. 18. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drugs administration, or which, in the judgment of the investigator would make the patient inappropriate for entry into the trial. 19. Current treatment on another therapeutic clinical trial. 20. Patients with known HIV, or active HBV or HCV infection 21. Concurrent medications that prolong QTc (e.g. levofloxacin, diphenhydramine, fluconazole) (Appendix F)