Phase I Study of 225Ac-J591 Plus 177Lu-PSMA Small Molecule for Progressive Metastatic Castration Resistant Prostate Cancer

This is a phase I dose-escalation study of 225Ac-J591 administered together with 177Lu-PSMA small molecule. Both drugs are designed to deliver radiation to prostate cancer cells; they are known as radionuclide conjugates (radiation linked to antibodies/molecules that recognize prostate cancer cells). This phase of the study (phase I) will determine the highest dose of the study intervention that can be safely given.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: 68Ga-PSMA-11; Drug: 225Ac-J591; Drug: 177Lu-PSMA-I&T; Drug: 177Lu-PSMA-617

Detailed Description

This clinical trial is for men with progressive metastatic castration-resistant prostate cancer (mCRPC). The two primary objectives of this trial are to determine the highest dose of 225Ac-J591 and 177Lu-PSMA-small molecule that can be administered together (also known as maximum tolerated dose) with the recommended phase II dose and to determine the effectiveness of the drug combination. The two drugs will be co-administered every 8 weeks, for 2 cycles.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: 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 New York Presbyterian

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 95 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
• ECOG performance status of 0-2
• Have serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone bilateral orchiectomy
• Have previously been treated with at least one of the following: Androgen receptor signaling inhibitor (such as enzalutamide), CYP 17 inhibitor (such as abiraterone acetate)
• Have previously received taxane chemotherapy, 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: <1.5 x ULN in the absence of liver metastases; <3 x ULN if due to liver metastases (in both circumstances bilirubin must meet entry criteria)
• Ability to understand, and the willingness to sign, a written informed consent document

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 Treatment visit # 1(Day 1) or current enrollment in investigational oncology drug or device study
• Prior systemic beta-emitting bone-seeking radioisotopes. Prior radium-223 is allowed provided at least 90 days have lapsed since last dose
• For the prior PSMA-TRT-naive cohort, prior PSMA-targeted radionuclide therapy is not allowed (prior PSMA-targeted isotopes used for imaging/diagnostic purposes are allowed, as is prior PSMA-targeted therapy that does not involve therapeutic radionuclides); For the 177Lu-PSMA small molecule exposed cohort, no dose limiting toxicity may have been observed during/after therapy with prior treatment and all other entry criteria must be met
• Known active brain or leptomeningeal metastases
• History of deep vein thrombosis and/or pulmonary embolus within 1 month of Treatment visit #1
• 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 Treatment visit #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 at least 140 days 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
• Prior exposure to PARP inhibitor > 2 weeks

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination of 225Ac-J591 and 177Lu-PSMA-I&T; Participants who received the combination of 225Ac-J591 and 177Lu-PSMA-I&T, along with 68Ga-PSMA-11.	Drug: 68Ga-PSMA-11; [185 ±74 MBq or 5 ±2 mCi] intravenous during screening, 12 weeks, 24 weeks. Imaging agent for PSMA PET/CT.; Other Names: 68Ga-PSMA-HBED-CC; Drug: 225Ac-J591; 30 - 40 KBq/kg (dose-escalation) every 8 weeks, for up to 2 cycles. Administered together with 177Lu-PSMA-617. Intravenous administration.; Drug: 177Lu-PSMA-I&T; 6.8 GBq received every 8 weeks, up to 2 cycles. Administered together with 225Ac-J591. Intravenous administration.
Experimental: Combination of 225Ac-J591 and 177Lu-PSMA-617; Participants will receive the study drugs 225Ac-J591 and 177Lu-PSMA-617, along with 68Ga-PSMA-11.	Drug: 68Ga-PSMA-11; [185 ±74 MBq or 5 ±2 mCi] intravenous during screening, 12 weeks, 24 weeks. Imaging agent for PSMA PET/CT.; Other Names: 68Ga-PSMA-HBED-CC; Drug: 225Ac-J591; 30 - 40 KBq/kg (dose-escalation) every 8 weeks, for up to 2 cycles. Administered together with 177Lu-PSMA-617. Intravenous administration.; Drug: 177Lu-PSMA-617; 6.8 - 7.4 GBq received every 8 weeks, for up to 2 cycles. Administered together with 225Ac-J591. Intravenous administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicity (DLT) of 225Ac-J591 and 177Lu-PSMA small molecule	DLTs will be measured by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	From Cycle 1 Day 1 up to 12 weeks after Cycle 1 Day 1 (each cycle is 8 weeks).
Cumulative maximum tolerated dose (MTD) or recommended phase II dose 225Ac-J591 and 177Lu-PSMA small molecule	The dose that produces an "acceptable" level of toxicity or that, if exceeded, would put subjects at "unacceptable" risk for toxicity. Definition of the MTD usually relies on the sample, as MTD is defined as the dose level at which no more than one patient out of six experienced dose-limiting toxicity (DLT).	From Cycle 1 Day 1 up to 12 weeks after Cycle 1 Day 1 (each cycle is 8 weeks).
Proportion of PSMA+ subjects (by imaging criteria) with >50% PSA decline following treatment with the combination of 225Ac-J591 and 177Lu-PSMA small molecule	Proportion of patients achieving 50% or greater 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.	From Cycle 1 Visit 1 up to end of study, approximately 3 years (each cycle is 8 weeks).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in circulating tumor cells (CTC) count	CTCs will be analyzed through blood specimen collection via CellSearch methodology lab testing	Samples will be collected at screening, week 12, week 24.
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.	Patients will undergo imaging at screening, week 12, and week 24.
Change in 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.	From Cycle 1 Visit 1 up to end of study, approximately 3 years (each cycle is 8 weeks).
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 will be used.	Patients will undergo imaging at screening, week 12, and week 24.
Number of participants with adverse events	National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 is used to grade all adverse events	From Cycle 1 Visit 1 up to end of study, approximately 3 years (each cycle is 8 weeks).
Overall survival following treatment with 225Ac-J591 and 177Lu-PSMA small molecule	Overall survival will be captured through in-clinic or telephone contact with subjects	From Cycle 1 Visit 1 up to end of study, approximately 3 years (each cycle is 8 weeks).

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2021
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: May 11, 2021
• First Submitted That Met QC Criteria: May 13, 2021
• First Posted (Actual): May 14, 2021

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 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; Pluvicto; gallium 68 PSMA-11
• Other Study ID Numbers: 20-08022486

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