Fractionated and Multiple Dose 225Ac-J591 for Progressive mCRPC
August 17, 2026 updated by: Weill Medical College of Cornell University
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
Intervention / Treatment
- Diagnostic test: 68Ga-PSMA-HBED-CC injection
- Drug: Multiple Dose of 225Ac-J591 at 45 KBq/kg
- Drug: Multiple Dose of 225Ac-J591 at 55 KBq/kg
- Drug: Multiple Dose of 225Ac-J591 at 65 KBq/kg
- Drug: Fractionated Dose of 225Ac-J591 at 45 KBq/kg
- Drug: Fractionated Dose of 225Ac-J591 at 55 KBq/kg
- Drug: Fractionated Dose of 225Ac-J591 at 60 KBq/kg
- Drug: Fractionated Dose of 225Ac-J591 at 65 KBq/kg
- Drug: Fractionated Dose of 225Ac-J591 at 45 KBq/kg (Prior 177Lu-PSMA-RL)
- Drug: Fractionated Dose of 225Ac-J591 at 50 KBq/kg (Prior 177Lu-PSMA-RL)
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 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
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
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 99 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Description
Inclusion Criteria:
- Histologically or cytologically confirmed adenocarcinoma of prostate
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
- 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
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)
- Have previously received taxane chemotherapy (in any disease state), been determined to be ineligible for taxane chemotherapy by their physician, or refused taxane chemotherapy.
- Age > 18 years
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)
- ECOG performance status of 0-2
- Ability to understand and the willingness to sign a written informed consent document
- 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
- Implantation of investigational medical device ≤4 weeks of Treatment Visit 1 (Day 1) or current enrollment in oncologic investigational drug or device study
- 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
- Prior systemic beta-emitting bone-seeking radioisotopes (e.g. samarium-153, strontium-89)
- For patients enrolled in the post-177Lu-PSMA-RL cohorts: prior radium-223
- Untreated hydronephrosis
- Known active brain metastases or leptomeningeal disease
- History of deep vein thrombosis and/or pulmonary embolus within 1 month of C1D1
- 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
- Radiation therapy for treatment of PC ≤4 weeks of Day 1 Cycle 1
- Chemotherapy for treatment of PC ≤4 weeks of Day 1 Cycle 1
- 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
- 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
- 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
- Known history of myelodysplastic syndrome
- Bone scan with confluent lesions and lack of urinary tracer consistent with a "superscan" as determined by the investigator
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Multiple Dose 45 KBq/kg
Participants in this multiple dose cohort received 45 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
|
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Multiple dose of 45 KBq/kg
|
|
Experimental: Multiple Dose 55 KBq/kg
Participants in this multiple dose cohort received 55 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
|
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Multiple dose of 55 KBq/kg in dose-escalation regimen
|
|
Experimental: Multiple Dose 65 KBq/kg
Participants in this multiple dose cohort received 65 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
|
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Multiple dose of 65 KBq/kg in dose-escalation regimen
|
|
Experimental: Fractionated Dose 45 KBq/kg
Participants in this cohort received a single cycle of 45 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
|
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Fractionated dose of 45 KBq/kg in dose-escalation regimen
|
|
Experimental: Fractionated Dose 55 KBq/kg
Participants in this cohort received a single cycle of 55 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
|
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Fractionated dose of 55 KBq/kg in dose-escalation regimen
|
|
Experimental: Fractionated Dose 60 KBq/kg
Participants in this cohort receive a single cycle of 60 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15. This was also the dose level for the expansion cohort of fractionated dose regimen. |
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Fractionated dose of 60 KBq/kg in dose-escalation and dose-expansion regimens
|
|
Experimental: Fractionated Dose 65 KBq/kg
Participant in this cohort receive a single cycle of 65 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
|
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Fractionated dose of 65 KBq/kg in dose-escalation regimen
|
|
Experimental: Fractionated Dose (prior 177Lu-PSMA-RL) 45 KBq/kg
Participants in this cohort, who were previously treated with 177Lu-PSMA-RL, received a single cycle of 45 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
|
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Fractionated dose of 45 KBq/kg for cohort of participants previously treated with 177Lu-PSMA-RL
|
|
Experimental: Fractionated Dose (prior 177Lu-PSMA-RL) 50 KBq/kg
Participants in this cohort, who were previously treated with 177Lu-PSMA-RL, received a single cycle of 50 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
|
68Ga-PSMA-HBED-CC PET/CT before and after treatment
Other Names:
Fractionated dose of 50 KBq/kg for cohort of participants previously treated with 177Lu-PSMA-RL
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Number of Participants With Dose Limiting Toxicity (DLT)
Time Frame: Collected from Day 1 through 6 months
|
DLTs will be measured by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
|
Collected from Day 1 through 6 months
|
|
Maximum Tolerated Dose (MTD)
Time Frame: Collected from Day 1 through 6 months
|
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
Time Frame: Collected from Day 1 through 6 months
|
Collected from Day 1 through 6 months
|
|
|
Number of Participants With PSMA-positive Tumors With >50% PSA Decline Following 225Ac-J591 in Each Cohort Regimen
Time Frame: Collected from Day 1 through 6 months
|
Number 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 |
|---|---|---|
|
Number of Participants With Radiographic Response
Time Frame: Imaging performed at timepoints from Day 1 through study completion, approximately 3 years.
|
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, approximately 3 years.
|
|
Overall Survival Following 225Ac-J591 Treatment
Time Frame: Collected from Day 1 through study completion, approximately 3 years.
|
Overall survival will be captured through in-clinic or telephone contact with participants
|
Collected from Day 1 through study completion, approximately 3 years.
|
|
Change in Disease Assessment With 68Ga-PSMA-11 PET/CT Prior to and Following Investigational Treatment
Time Frame: Scans performed during screening period (within 30 days of Cycle 1 Day 1) and at Day 85 from Cycle 1 Day 1.
|
Change in Maximum SUV (SUVmax) from Baseline 68Ga-PSMA-11 PET/CT to Post-therapy (Week 12) 68Ga-PSMA-11 PET/CT.
68Ga-PSMA-11 PET/CT was utilized as part of the radiographic assessment.
|
Scans performed during screening period (within 30 days of Cycle 1 Day 1) and at Day 85 from Cycle 1 Day 1.
|
|
Number of Participants With Change in Circulating Tumor Cells (CTC) Count at 12 Weeks Following 225Ac-J591
Time Frame: Samples will be collected at Screening and Day 85
|
CTCs will be analyzed through blood specimen collection via CellSearch methodology lab testing.
Number of participants with changes in CTC count.
|
Samples will be collected at Screening and Day 85
|
|
Number of Participants With Adverse Events
Time Frame: Collected from Day 1 through study completion, approximately 3 years
|
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 is used to grade all adverse events
|
Collected from Day 1 through study completion, approximately 3 years
|
|
Assess Biochemical Progression-free Survival
Time Frame: Collected from Day 1 through study completion, approximately 3 years
|
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
|
Collected from Day 1 through study completion, approximately 3 years
|
|
Assess the Proportion With Different Levels of PSA Decline Following 225Ac-J591
Time Frame: Collected from Day 1 through study completion, approximately 3 years
|
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.
|
Collected from Day 1 through study completion, approximately 3 years
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Principal Investigator: Joseph R Osborne, MD, Weill Medical College of Cornell University
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
August 18, 2020
Primary Completion (Actual)
June 1, 2025
Study Completion (Estimated)
December 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)
August 19, 2026
Last Update Submitted That Met QC Criteria
August 17, 2026
Last Verified
August 1, 2026
More Information
Terms related to this study
Additional Relevant MeSH Terms
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
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