This is a clinical trial for adult men with progressive metastatic castration resistant prostate cancer.
   
The purpose of the initial phase I portion of this study is to find a dose level and administration schedule of the study drug, 225Ac-J591 plus 177Lu-PSMA-I&T that can be given without severe side effects. Following selection of the proper dose for each treatment regimen, the purpose of the phase II portion of the study is to test if the regimen of 225Ac-J591 plus 177Lu-PSMA-I&T leads to treatment response. 
   
Prostate-specific membrane antigen (PSMA) is a protein that is on the surface of most prostate cancer cells. It is absent from most other normal places in the body but is present to a lower degree in the kidney, small intestine, salivary glands, and brain. J591 is a monoclonal antibody (an engineered protein) which recognizes PSMA. Actinium-225 (225Ac) is a small radioactive particle that emits alpha-particles (damaging/ionizing radiation). 
   
225Ac-J591 is the combination compound that has the radioactive particle linked to J591. It is designed so that J591 will recognize PSMA and drags the radioactive particle 225Ac with it wherever it goes.
   
PSMA-I&T is a small molecule that also recognizes PSMA. It is linked to and carries the radioactive particle, Lutetium-177 (177Lu). The combination compound is called 177Lu-PSMA-I&T. 
   
Both 225Ac-J591 and 177Lu-PSMA-I&T are not yet approved by the United States Food and Drug Administration (FDA) approved and are considered experimental drugs. 
   
Before participants start study treatment and during the study, they will have radiographic assessments of their cancer by Computed Tomography (CT) Scan (a computerized series of x-rays) or Magnetic Resonance Imaging (MRI, body pictures created by using magnetic energy rather than x-ray energy), a whole-body bone scan, and 68Ga-PSMA11 or 18F-DCFPyL Positron Emission Tomography (PET, which detects energy coming from tumors). Patients are eligible for the treatment portion of this study if their 68Ga-or 18F-DCFPyL PSMA PET is determined to be positive (if the tumors “light up”).

68Ga−PSMA−HBED−CC (aka PSMA11) Positron Emission Tomography (PET) imaging involves linking an energy-emitting particle to a small molecule that recognizes PSMA. This allows for tumors to be detected on imaging. 68Ga−PSMA−HBED−CC PET is not FDA approved and is considered investigational. 
   
Participants may receive up to two intravenous treatments with 225Ac-J591 plus 177Lu-PSMA-I&T. The treatment portion of the study will last approximately 2-6 months. Short term follow up will continue until there is confirmed cancer growth on scans. Participants will then enter the long-term follow-up period.