Fractionated and Multiple Dose 225Ac-J591 for Progressive mCRPC

Phase I/II Dose-escalation Study of Fractionated and Multiple Dose 225Ac-J591 for 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, that can be given without severe side effects. The purpose of the second (phase II) portion of the study is to determine the proportion of those with PSMA-positive tumors with >50% PSA decline following 225Ac-J591 treatment in two regimens.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Diagnostic test: 68Ga-PSMA-HBED-CC injection; Drug: Fractionated dose of 225Ac-J591; Drug: Multiple single doses of 225Ac-J591

Detailed Description

This clinical trial is for men with progressive metastatic castration resistant prostate cancer. The purpose of this study is to find the highest dose level of the study drug, 225Ac-J591, that can be given without severe side effects. The 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. These treatments, however, are not curative.

Patients who choose to participate in this study will have a screening visit to determine whether or not they are eligible to participate in the study. There are two different regimens for men with progressive mCRPC with and without prior 177Lu-PSMA-RL treatment.

The fractionated dose regimen is a single cycle of study drug administered on Day 1 and Day 15. The dose-limiting toxicity assessment period is 8 weeks for the fractionated dose regimen (starting from Cycle 1 Day 1).

The multiple dose regimen is a single dose of 225Ac-J591 per cycle, with each cycle administered every 6 weeks up to 4 cycles. The dose-limiting toxicity assessment period is up to 9 weeks past the 2nd dose of 225Ac-J591. Following treatment, short-term follow up is planned until radiographic progression, expected to be 6 months.

The study medication is called 225Ac-J591, and is administered as a single fractionated cycle day 1 and day 15 in the fractionated dose regimen and as a single dose per cycle repeated every 6 weeks in the multiple dose regimen. Upon completion of investigational treatment with 225Ac-J591, participants will undergo 68Ga-PSMA-HBED-CC injection and same day PET/CT to document treatment response. 68Ga-PSMA-HBED-CC is comprised of gallium-68, which is a positron-emitting radionuclide linked to PSMA-HBED-CC (aka PSMA11), which is a small molecule targeting PSMA. 68Ga-PSMA-HBED-CC will be administered intravenously prior to PET/CT at screening and at follow up imaging x2. Subsequent survival data and additional treatment(s) information will be captured from their routine standard of care (SOC) visits. During the other study visits, participants will undergo routine tests and procedures, such as physical examinations, and blood tests. Some blood tests will be done for research purposes only. After completion of therapy, participants may be contacted on a periodic basis to see how they are doing.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; 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. 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

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fractionated Dose Regimen without prior 177Lu-PSMA-RL; Patients without prior 177Lu-PSMA-RL exposure receive a single cycle of 225Ac-J591, administered as a fractionated dose on days 1 and 15.	Diagnostic test: 68Ga-PSMA-HBED-CC injection; 68Ga-PSMA-HBED-CC PET/CT before and after treatment; Other Names: 68Ga-PSMA-11; Drug: Fractionated dose of 225Ac-J591; Single cycle of fractionated dose of 225Ac-J591
Experimental: Multiple Dose Regimen; Patients enrolled in this multiple dose regimen cohort receive 225Ac-J591 every 6 weeks, up to 4 cycles.	Diagnostic test: 68Ga-PSMA-HBED-CC injection; 68Ga-PSMA-HBED-CC PET/CT before and after treatment; Other Names: 68Ga-PSMA-11; Drug: Multiple single doses of 225Ac-J591; Single dose of 225Ac-J591 every 6 weeks up to 4 cycles
Experimental: Fractionated Dose Regimen with prior 177Lu-PSMA-RL; Patients who were previously treated with 177Lu-PSMA-RL receive a single cycle of 225Ac-J591, administered as a fractionated dose on days 1 and 15.	Diagnostic test: 68Ga-PSMA-HBED-CC injection; 68Ga-PSMA-HBED-CC PET/CT before and after treatment; Other Names: 68Ga-PSMA-11; Drug: Fractionated dose of 225Ac-J591; Single cycle of fractionated dose of 225Ac-J591

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with dose limiting toxicity (DLT)	DLTs will be measured by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Collected from Day 1 through 6 months
Cumulative maximum tolerated dose (MTD)	The dose that produces an "acceptable" level of toxicity or that, if exceeded, would put subjects at "unacceptable" risk for toxicity. MTD is defined as the dose level at which no more than two patients out of six experienced dose-limiting toxicity (DLT).	Collected from Day 1 through 6 months
Recommended phase II dose (RP2D) of 225Ac-J591 in fractionated dose and multiple dose regimens both pre- and post-treatment with 177Lu-PSMA-RL		Collected from Day 1 through 6 months
Proportion of participants with PSMA-positive tumors with >50% PSA decline following 225Ac-J591 in two regimens both pre- and post- treatment with 177Lu-PSMA-RL	Proportion of participants achieving greater than 50% PSA decline (relative to baseline/pre-treatment PSA). Response may occur at any time following treatment initiation and prior to going off study or initiation of new therapy.	Collected from Day 1 through 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in disease assessment with 68Ga-PSMA-11 PET/CT prior to and following investigational treatment	68Ga-PSMA-11 PET/CT will be utilized as part of the radiographic assessment.	Scans will be performed at screening, day 85 and day 168
Change in circulating tumor cells (CTC) and the rate of favorable and undetectable CTC count at 12 weeks following 225Ac-J591	CTCs will be analyzed through blood specimen collection via CellSearch methodology lab testing	Samples will be collected at screening, day 1, day 85 and at disease progression
Safety of treatment and adverse event rate	National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 is used to grade all adverse events	Will be collected from Day 1 through study completion up to 3 years
Assess biochemical progression-free survival	PSA progression will be defined as a rise of > 25% above either the pretreatment level or the nadir PSA level (whichever is lowest). PSA must increase by > 2 ng/ml to be considered progression	Will be collected from Day 1 through study completion up to 3 years
Assess the proportion with different levels of PSA decline following 225Ac-J591	PSA will be monitored through serial blood draws. Response may occur at any time following treatment initiation and prior to going off study or initiation of new therapy.	Will be collected from Day 1 through study completion up to 3 years
Number of participants with radiographic response	Response evaluation criteria in solid tumors RECIST (Version 1.1) criteria with prostate cancer working group 3 (PCWG3) modifications to be used.	Imaging performed at timepoints from Day 1 through study completion up to 3 years
Overall survival following 225Ac-J591 treatment	Overall survival will be captured through in-clinic or telephone contact with participants	Collected from Day 1 through study completion up to 3 years

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Investigators: Principal Investigator: Joseph R Osborne, MD, Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2020
• Primary Completion (Actual): June 1, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: August 6, 2020
• First Submitted That Met QC Criteria: August 6, 2020
• First Posted (Actual): August 10, 2020

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: February 12, 2026
• Last Verified: February 1, 2026

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: 20-01021288

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