Re-treatment 225Ac-J591 for mCRPC

Pilot Study of PSMA-TRT Re-treatment Utilizing 225Ac-J591

The purpose of this study is to find out if re-treatment with 225Ac-J591 can be given without severe side effects.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: 225Ac-J591

Detailed Description

This is an open-label, pilot study designed to determine the safety of PSMA-TRT re-treatment with 225Ac-J591, which will be given in a single dose on D1, in men with progressive mCRPC. If the patient responds and tolerates this dose, another may be given upon progression, provided at least 12 weeks after the initial dose.

This research study is being done because the standard treatments for prostate cancer that has spread beyond the prostate gland are intended to minimize the adverse effects of the disease and make men live longer. These treatments, however, are not curative so additional treatments are needed. 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 some 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. This drug used currently is not FDA approved for any indication and is considered experimental.

In the first part of the study, a small group of subjects will receive a dose of 225Ac-J591 based upon a prior study. If that dose does not lead to severe side effects in many subjects, an additional small group will be treated. If the initial dose leads to too many severe side effects, another group will receive a lower dose. If it is determined by a physician that a subject's tumor has responded favorably to treatment, did not experience severe side effects and subject in agreement, then the subject will be allowed to receive one additional dose of the study drug 225Ac-J591, provided that at least 3 months have passed since the initial dose. For subjects receiving re-treatment, they will also participate in the same study procedures and followed for treatment including short-term and long-term follow up.

All treatment visits and all visits involving investigational PSMA PET imaging are required to be performed at the Weill Cornell Medicine - NewYork Presbyterian site located in the upper east side of Manhattan.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Brooklyn, New York, United States, 11215
      • Brooklyn Methodist Hospital - New York Presbyterian
    • New York, New York, United States, 10065
      • Weill Cornell Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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. ECOG performance status of 0-2
4. 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

5. 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)
6. Have previously received taxane chemotherapy (in any disease state), been determined to be ineligible for taxane chemotherapy by their physician, or refused taxane chemotherapy
7. Age ≥ 18 years

8. 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 x 10^3/ microliter
   • Serum creatinine: ≤1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min/1.73 m^2 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)
9. Ability to understand and the willingness to sign a written informed consent document
10. In the opinion of the investigator, history of clinical benefit with treatment using PSMA-TRT and no dose-limiting toxicity. Clinical benefit might be assessed by PSA changes, CTC changes, radiographic changes, and/or symptomatic improvement

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 bone-seeking beta-emitting radioisotopes. Prior radium-223 is allowed provided last dose was at least 12 weeks prior to C1D1 on this protocol
4. History of deep vein thrombosis and/or pulmonary embolus within 1 month of C1D1
5. 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
6. Radiation therapy ≤4 weeks of Day 1 Cycle 1
7. 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
8. 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
9. Known history of known myelodysplastic syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Heavily Exposed	Drug: 225Ac-J591; In this study, subject enrollment will be done in a re-treatment design. A single dose of 225Ac-J591 given at the specified dose per cohort. The initial planned dose level will be determined based upon prior radioactivity exposure level. Those with moderate exposure (up to 30 GBq of 177Lu) will start with 65 KBq/Kg and those with heavy prior exposure (more than 30 Gbq of 177Lu or any 225Ac) will start with 50 KBq/Kg.; Other Names: 68Ga-PSMA-HBED-CC injection for PET/CT Scan at screening, week 12 and week 24
Experimental: Moderately Exposed	Drug: 225Ac-J591; In this study, subject enrollment will be done in a re-treatment design. A single dose of 225Ac-J591 given at the specified dose per cohort. The initial planned dose level will be determined based upon prior radioactivity exposure level. Those with moderate exposure (up to 30 GBq of 177Lu) will start with 65 KBq/Kg and those with heavy prior exposure (more than 30 Gbq of 177Lu or any 225Ac) will start with 50 KBq/Kg.; Other Names: 68Ga-PSMA-HBED-CC injection for PET/CT Scan at screening, week 12 and week 24

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the proportion of subjects in assessing safety of 225Ac-J591 in those previously treated with PSMA-TRT.	Proportion of subjects with dose-limiting toxicity (DLT) from treatment cycle 1 to the end of the safety evaluation period at the end of the study. Acceptable safety is determined if no more than 2 (33%) of the subjects in a cohort experience DLT.	Will be collected at the time of visit 1 through end of study or 100 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the number of subject with Prostate Specific Antigen (PSA) decline following 225Ac-J591 administration	PSA will be analyzed through blood specimen collection	Will be collected at the time of visit 1 through end of study or 100 months
Change in adverse event rate response	National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 is used to grade all adverse events	Will be collected at the time of visit 1 through end of study or 100 months
Change in the number of subjects with dose limiting toxicity (DLT)	DLTs will be measured by the recommended phase I fractionated dose and multiple dose regimens of 225Ac-J591 dose by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Will be collected at the time of visit 1 through end of study or 100 months
Change in radiographic response rate	Radiographic response rate will be captured through radiographic scans such as MRI, CT and bone scans. Response evaluation criteria in solid tumors (RECIST) criteria with Prostate Cancer Working Group 3 (PCWG3) modifications	Will be collected at the time of visit 1 through end of study or 100 months
Change in circulating tumor cells (CTC) response	CTCs will be analyzed through blood specimen collection via CellSearch methodology lab testing	Will be collected at the time of visit 1 through end of study or 100 months
Change in progression-free survival following re-treatment doses of 225Ac-J591		Will be collected at the time of visit 1 through end of study or 100 months
Change in Overall Survival Following re-Treatment Doses of 225Ac-J591	Overall survival will be captured through in-clinic or telephone contact with subjects	Survival will be collected at the time of visit 1 through end of study or 100 months

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Investigators: Principal Investigator: Scott Tagawa, MD, Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2020
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): May 31, 2024

Study Registration Dates

• First Submitted: September 24, 2020
• First Submitted That Met QC Criteria: September 30, 2020
• First Posted (Actual): October 6, 2020

Study Record Updates

• Last Update Posted (Estimated): August 28, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; gallium 68 PSMA-11
• Other Study ID Numbers: 20-01021286

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No