This is a Phase II study of the investigational drug opaganib. Patients with metastatic castration resistant prostate cancer (mCRPC) who have experienced disease progression while receiving abiraterone or enzalutamide will receive Opaganib at either 250 mg or 500 mg by mouth twice a day continuously. Patients will continue on study drug until the development of progressive disease, intolerable toxicity, withdrawal of patient consent or other event as outlined in patient discontinuation.

Inclusion Criteria:

1. Patient must have mCRPC. Each patient must have:

   • Tissue diagnosis documented by pathology report, or clinic note attesting to same.
   • Radiographically-demonstrated metastases
   • Patients must have adenocarcinoma, or ductal carcinoma, or combinations of these two entities

2. Voluntary, signed and dated, institutional review board (IRB)-approved informed consent form in accordance with regulatory and institutional guidelines.

3. Documented progression during treatment with enzalutamide or abiraterone, as determined by the enrolling investigator.

4. Testosterone level documented to be less than 50ng/

5. 18 years of age or older.

6. ECOG performance status of 0-2.

7. Acceptable liver function:

   • Bilirubin ≤ 1.5 times upper limit of normal (CTCAE Grade 1 baseline)
   • AST (SGOT) & ALT (SGPT) ≤ 3 x ULN (CTCAE Grade 1 baseline)
   • Subjects with Gilbert's syndrome may be included if the total bilirubin is <3x ULN and the direct bilirubin is within normal limits

8. Acceptable kidney function indicated by serum creatinine ≤ 1.5 X ULN (CTCAE Grade 1 baseline)

9. Acceptable hematologic status:

   • Absolute neutrophil count ≥ 1000 cells/mm3,
   • Platelet count ≥ 75,000 (plt/mm3) (CTCAE Grade 1 baseline)
   • Hemoglobin ≥ 9.0 g/dL.

10. Fasting blood glucose of <165mg/dL

11. Urinalysis: no clinically significant abnormalities

12. International normalized ratio (INR) ≤1.7

13. Well-controlled blood pressure as determined by the treating investigator

14. Patients requiring narcotic analgesics must be on stable doses for at least 2 weeks prior to study entry.

Exclusion Criteria:

1. New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.
2. Underlying psychiatric disorder requiring hospitalization within the last two years.
3. Clinically significant neurological disorder (Parkinson's disease, dementia, multiple sclerosis), as determined by the enrolling investigator.
4. Active, uncontrolled bacterial, viral or fungal infection, requiring systemic therapy.
5. Treatment with radiation therapy, surgery, or investigational therapy within 28 days prior to registration.
6. Unwillingness or inability to comply with procedures required in this protocol.
7. Serious nonmalignant disease that could compromise protocol objectives in the opinion of the Investigator.
8. Patients who are receiving coumadin, apixaban, argatroban or rivaroxaban. Patients who are receiving other drugs that are sensitive substrates of CYP450 1A2, 3A4, 2C9, 2C19 or 2D6, or strong inhibitors or inducers of all major CYP450 isozymes that cannot be stopped at least 7 days or 5 half-lives (whichever is longer) before starting treatment with opaganib may be treated on this study with careful monitoring for toxic effects or loss of efficacy of the relevant drug. A list of commonly used drugs that are sensitive substrates of CYP450 1A2, 3A4, 2C9, 2C19 or 2D6, or strong inhibitors or inducers of all major CYP450 isozymes with the half-life of each drug identified, is included as an Appendix C.
9. Patients who are currently participating in any other clinical trial of an investigational product.
10. Other primary malignancy requiring systemic treatment within past 5 years except carcinoma in situ of the cervix or urinary bladder or non-melanoma skin cancer.
11. Any other mental incapacitation or psychiatric illness that would preclude study participation, as determined by the enrolling investigator.
12. Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.

2 years, 9 months, 23 days