Fractionated and Multiple Dose 225Ac-J591 for Progressive mCRPC

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma of prostate
2. Documented progressive metastatic CRPC based on Prostate Cancer Working

   Group 3 (PCWG3) criteria, which includes at least one of the following criteria:
   * PSA progression
   * Objective radiographic progression in soft tissue
   * New bone lesions
3. Have serum testosterone \< 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone orchiectomy
4. Have previously been treated with at least one of the following in any disease state:

   * Androgen receptor signaling inhibitor (such as enzalutamide)
   * CYP 17 inhibitor (such as abiraterone acetate)
5. Have previously received taxane chemotherapy (in any disease state), been determined to be ineligible for taxane chemotherapy by their physician, or refused taxane chemotherapy.
6. Age \> 18 years
7. Patients must have normal organ and marrow function as defined below:

   * Absolute neutrophil count \>2,000 cells/mm3
   * Hemoglobin ≥9 g/dL
   * Platelet count \>150,000 x 109/uL
   * Serum creatinine \<1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault
   * Serum total bilirubin \<1.5 x ULN (unless due to Gilbert's Syndrome in which case direct bilirubin must be normal)
   * Serum AST and ALT \<3 x ULN in absence of liver metastases; \< 5x ULN if due to liver metastases (in both circumstances bilirubin must meet entry criteria)
8. ECOG performance status of 0-2
9. Ability to understand and the willingness to sign a written informed consent document
10. For patients enrolled in the post-177Lu-PSMA-RL cohorts, must have previously received either 177Lu-PSMA-617 or 177Lu-PSMA-I\&T

Exclusion Criteria

1. Implantation of investigational medical device ≤4 weeks of Treatment Visit 1 (Day 1) or current enrollment in oncologic investigational drug or device study
2. Use of investigational drugs ≤4 weeks or \<5 half-lives of Cycle 1, Day 1 or current enrollment in investigational oncology drug or device study
3. Prior systemic beta-emitting bone-seeking radioisotopes (e.g. samarium-153, strontium-89)
4. For patients enrolled in the post-177Lu-PSMA-RL cohorts: prior radium-223
5. Untreated hydronephrosis
6. Known active brain metastases or leptomeningeal disease
7. History of deep vein thrombosis and/or pulmonary embolus within 1 month of C1D1
8. Other serious illness(es) involving the cardiac, respiratory, CNS, renal, hepatic or hematological organ systems which might preclude completion of this study or interfere with determination of causality of any adverse effects experienced in this study
9. Radiation therapy for treatment of PC ≤4 weeks of Day 1 Cycle 1
10. Chemotherapy for treatment of PC ≤4 weeks of Day 1 Cycle 1
11. Patients on stable dose of bisphosphonates or denosumab, which have been started no less than 4 weeks prior to treatment start, may continue on this medication, however patients are not allowed to initiate bisphosphonate/Denosumab therapy during the DLT-assessment period of the study
12. Having partners of childbearing potential and not willing to use a method of birth control deemed acceptable by the principle investigator and chairperson during the study and for 1 month after last study drug administration
13. Currently active other malignancy other than non-melanoma skin cancer. Patients are considered not to have "currently active" malignancy if they have completed any necessary therapy and are considered by their physician to be at less than 30% risk of relapse
14. Known history of myelodysplastic syndrome
15. Bone scan with confluent lesions and lack of urinary tracer consistent with a "superscan" as determined by the investigator