Study of SX-682 Plus Enzalutamide in Men With Abiraterone-Resistant Metastatic Castration Resistant Prostate Cancer

Inclusion Criteria:

1. Signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form prior to beginning study and undergoingprocedures.

2. Diagnosis of mCRPC with (a) any histology and (b) currently on or previously onabiraterone/prednisone (or abiraterone/dexamethasone) with documented progression ineither the mCRPC or mHSPC settings, and with:

• rising PSA (a rising PSA requires at least 3 measurements obtained at least 1week apart showing increase from nadir with the last level above 2 ng/mL bylocal testing); or

• progression of new or existing bone or soft tissue metastatic lesions by CT,MRI or bone scan; no abiraterone washout necessary.

3. Availability of archival tumor tissue for pathologic review and correlative studies.Tumor tissue (localized or metastatic) does not need to be received but ratheridentified and available (slides and blocks) upon later request for futurepathologic review and possible correlative studies.

4. Castrate levels of serum total testosterone (<50 ng/dl) OR ongoing documented ADT.

5. Karnofsky performance status of 70 or higher.

6. ≥ 18 years of age

7. Life expectancy of ≥ 6 months

8. Recovered to ≤ Grade 2 toxicity from prior therapy (per CTCAE Version 5.0)

9. Adequate bone marrow function:

• Absolute neutrophil count (ANC) ≥ 1.2 × 10^9/L without any growth factors inprior 7 days

• Hemoglobin ≥ 9.0 g/dL with no blood transfusion in the prior 14 days

• Platelet count ≥ 75 × 10^9/L with no platelet transfusion in the prior 7 days Adequate hepatic function:

• Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for Gilbert's syndrome)

• AST (serum glutamic oxaloacetic transaminase [SGOT]) / ALT (serum glutamicpyruvate transaminase [SGPT]) ≤ 3 × institutional ULN Adequate renal function:

• Creatinine clearance per Cockcroft-Gault equation (or institutional equivalent)of ≥ 50 mL/min

10. Willingness of patients who are not surgically sterile or with partners who are notpostmenopausal to use medically acceptable methods of birth control for the durationof the study treatment, including 90 days after the last dose of study drug.

11. Willing and able to provide written informed consent and HIPAA authorization for therelease of personal health information.

Exclusion Criteria:

1. Prior systemic anticancer treatment:

• Prior treatment with docetaxel or marketed antibody within 4 weeks of firstdose of study treatment

• Prior radium-223 therapy within 6 weeks

• Prior PSMA-Lu177-617 therapy within 4 weeks

2. Prior receipt of (a) ketoconazole or any second-generation AR antagonist (e.g.,enzalutamide, apalutamide, darolutamide), (b) 2 or more chemotherapy regimens withdocetaxel or (c) any chemotherapy other than docetaxel.

3. Current presence of liver metastases on imaging.

4. Has received prior radiotherapy within 2 weeks of start of study intervention.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

5. Major surgery requiring general anesthesia within 3 weeks of starting studytreatment (limited biopsy or line placement is acceptable)

6. Has received a live vaccine within 30 days prior to the first dose of study drug.Examples of live vaccines include, but are not limited to, the following: measles,mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BacillusCalmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed; however, intranasalinfluenza vaccines (e.g., FluMist®) are live attenuated vaccines and are notallowed.

7. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study intervention.

8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

9. Congestive heart failure (New York Heart Association Class III or IV) or unstableangina pectoris; previous history of myocardial infarction within one year prior tostudy entry, uncontrolled hypertension, or uncontrolled arrhythmias.

10. Has a history of a second malignancy, unless potentially curative treatment has beencompleted with no evidence of malignancy for 2 years.

11. Has known active untreated CNS metastases and/or carcinomatous meningitis.Participants with previously treated brain metastases may participate provided theyare radiologically stable, i.e., without evidence of progression for at least 4weeks by repeat imaging (note that the repeat imaging should be performed duringstudy screening), clinically stable and without requirement of steroid treatmentgreater than prednisone 10 mg daily (or equivalent) for at least 14 days prior tofirst dose of study intervention.

12. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed.

13. Has a history of (non-infectious) pneumonitis that required steroids or has currentpneumonitis.

14. Has an active infection requiring systemic therapy.

15. Has a known uncontrolled Human Immunodeficiency Virus (HIV) infection based ondetectable HIV viral load and abnormal CD4 count of <350/mm^3.

16. Has a known active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] isdetected) infection.

17. Has a known active TB (Bacillus Tuberculosis) infection.

18. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

19. Has known current psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

20. Has had an allogenic tissue/solid organ transplant.

21. Concomitant medication(s) known to be (a) a strong inhibitor or inducer of CYP3A4,or (b) QT prolonging as defined in the drug's approved label, with the exception ofdrugs that are considered absolutely essential for the care of the subject or if theInvestigator believes that beginning therapy with such medication is vital to anindividual subject's care while on study, and in either case, there is noalternative drug (if exceptions apply contact Syntrix medical monitor prior toenrollment).

22. ECG demonstrating a QTcF interval > 470 msec or patients with congenital long QTsyndrome.

23. Coronary artery bypass, angioplasty, vascular stent, myocardial infarction, anginaor congestive heart failure in the last 6 months.