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Prostate CancerPhase 1/2NCT04946370

Phase I/II Trial of Pembrolizumab and Androgen-receptor Inhibitor With or Without 225Ac-J591 for Progressive Metastatic Castration Resistant Prostate Cancer

A Phase 1/2 study testing 225Ac-J591, Pembrolizumab and Androgen receptor inhibitor in people with Prostate Cancer, run by Weill Medical College of Cornell University at 4 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

This is a phase I/II study investigating the combination of 225Ac-J591 (a drug that can deliver radiation to prostate cancer cells) with pembrolizumab (immunotherapy, a drug that increases the immune system's ability to destroy cancer cells). Read more about this study

Who is it for?
Ages 18 years and older, men only
Conditions the study is for
Prostate Cancer
What is being tested?
225Ac-J591, Pembrolizumab and Androgen receptor inhibitor
Could I receive a placebo?
No, everyone receives an active treatment
How many people
52 participants
Where
4 sitesUnited States
Study dates
12 Aug 2021to Dec 2029
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Men only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of prostate adenocarcinoma.
  • A male participant must agree to use a contraception during the treatment period and for at least 4 months after the last dose of study treatment and refrain from donating sperm during this period.
  • 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
  • Evaluable for response with at least one of the following:
  • Measurable disease by RECIST 1.1
  • Detectable (>0) CTC by CellSearch
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  • PSA of at least 2 ng/dL
  • ECOG performance status of 0-1
  • 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 inhibitor (ARI, such as enzalutamide, apalutamide or darolutamide), CYP 17 inhibitor (such as abiraterone acetate). These drugs may have been initiated in the metastatic hormone sensitive (i.e. non-castrate) or non-metastatic (M0) CRPC setting provided they meet criteria for progressive mCRPC at study entry.
  • Age ≥ 18 years
  • Patients must have normal organ and marrow function as defined: Absolute neutrophil count >2,000 cells/mm3, Hemoglobin ≥ 9 g/dL, Platelet count >150 x 10^3/mcL, Serum creatinine <1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 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), Serum internalized normalized ratio (INR) OR prothrombin time (PT) AND activated partial thromboplastin time (aPTT) must be ≤1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • Prior receipt of chemotherapy for castration-resistant prostate cancer. Prior receipt of docetaxel chemotherapy in the hormone sensitive "CHAARTED" setting or for localized disease is acceptable provided at least 6 months has passed since the last dose.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
  • Prior bone-seeking beta-emitting radioisotopes (e.g. Sm-153, Sr-89) or PSMA-targeted radionuclide therapy for metastatic disease; prior radium-223 is allowed provided last dose administered >12 weeks prior to C1D1 on this study
  • Has a history of a second malignancy, unless treatment with curative intent has been completed with no evidence of malignancy for 2 years. Patients with treated localized non-melanoma skin care, non-muscle invasive urothelial carcinoma, or carcinoma in-situ of other site are not excluded.
  • Known history of myelodysplastic syndrome
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  • Has a known history of Human Immunodeficiency Virus (HIV) infection
  • Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
  • Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks or <5 half-lives prior to C1D1.
  • Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
  • Diagnosis of deep vein thrombosis and/or pulmonary embolus within 1 month of C1D1
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has received radiotherapy within 4 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation to non-CNS disease that is not a measurable target lesion.
  • 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. These drugs may be added after week 12 in phase 1 or phase 2.
  • Unless azoospermia is present (whether due to surgery or underlying medical condition), having partners of childbearing potential and not willing to use a method of birth control deemed acceptable by the principal investigator and chairperson during the study and for 4 months after last study drug administration.
  • Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
  • Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines are allowed.
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
  • Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
  • Has an active infection requiring systemic therapy at the time of treatment initiation
  • Has a known history of active TB (Bacillus Tuberculosis)
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Has had an allogenic tissue/solid organ transplant

Trial locations and contacts

4 sites in 1 country. Contact the study team or a site near you to ask about taking part.

GUONC Research Team contact

212-746-1480

guonc@med.cornell.edu

GUCLINIC Research Team contact

guclinic@med.cornell.edu

United States4 sites, 4 recruiting

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

    Himisha Beltran, MD

    Not yet recruiting

  • New York Presbyterian/Brooklyn Methodist Hospital

    Brooklyn, New York, 11215

    Peter Gregos, MD

    Recruiting

  • New York Presbyterian/Weill Cornell Medical Center

    New York, New York, 10021

    GUOnc Research Team, guonc@med.cornell.edu

    Sarah Yuan, 646-962-6040, say7008@med.cornell.edu

    Recruiting

  • Columbia University Irving Cancer Center

    New York, New York, 10032

    Cancer Clinical Trials Research Team, 212-342-5162, cancerclinicaltrials@cumc.columbia.edu

    Mark Stein, MD

    Recruiting

Other trials in United States

About this study

This is a phase I/II study investigating the combination of 225Ac-J591 (a drug that can deliver radiation to prostate cancer cells) with pembrolizumab (immunotherapy, a drug that increases the immune system's ability to destroy cancer cells). This study will assess whether 225Ac-J591 + pembrolizumab + androgen receptor inhibitor (ARI) is more effective against prostate cancer than pembrolizumab + ARI alone.

Read the detailed description

This clinical trial is for men with progressive metastatic castration-resistant prostate cancer (mCRPC). The primary objectives of the study are to determine the optimal dose of 225Ac-J591 when combined with pembrolizumab (phase I) and then to assess whether the combination of 225Ac-J591, pembrolizumab, and androgen receptor inhibitor (ARI) is more effective against prostate cancer than pembrolizumab and ARI alone. 225Ac-J591 is a radionuclide conjugate involving Actinium-225 linked to J591, an antibody that recognizes prostate-specific membrane antigen (PSMA) on the surface of cancer cells; 225Ac-J591 is able to deliver powerful radiation to cancer cells. Pembrolizumab is a drug that strengthens the body's immune response to cancer cells.

In the phase I portion of the study, two cohorts of up to 6 patients each will receive combined therapy: ARI (standard dosing schedule), pembrolizumab (400 mg every 6 weeks), 225Ac-J591 (single dose, either 65 or 80 KBq/kg). Following a minimum of 12 weeks of safety follow-up, the study team will determine which 225Ac-J591 dose is better.

In the phase II portion, patients will be randomized to pembrolizumab + ARI with or without 225Ac-J591. The primary endpoint for phase II will be response - a composite of PSA, circulating tumor cell (CTC) count and imaging changes, comparing baseline and Week 12 measurements. Patients who achieve at least one of the criteria will be considered responders. Imaging (CT scan, bone scan) will occur every 12 weeks. Additionally, participants will undergo 68Ga-PSMA-11 PET/CT scan prior to therapy and at 12 weeks. Patients are able to receive pembrolizumab every 6 weeks for maximum 18 cycles (approximately 2 years).

Conditions
Prostate Cancer
Being tested
225Ac-J591, Pembrolizumab, Androgen receptor inhibitor, 68Ga-PSMA-11
Medical subject headings
Prostatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 225Ac-J591Drug

    Alpha-emitter Actinium-225 conjugated to the anti-PSMA antibody J591.

  • PembrolizumabDrug

    Pembrolizumab will be administered intravenously, 400mg every 6 weeks. Patients may receive maximum 18 cycles of therapy, approximately 2 years.

  • Androgen receptor inhibitorDrug

    Patients will receive an oral androgen receptor inhibitor (ARI). Examples include enzalutamide, apalutamide, darolutamide. Dosing will be the standard dosing, as described by the package insert.

  • 68Ga-PSMA-11Diagnostic test

    Also called 68Ga-PSMA-HBED-CC

    [185 ±74 MBq or 5 ±2 mCi] intravenous during screening and 12 weeks. Imaging agent for PSMA PET/CT.

Study groups in NCT04946370
Study groupRoleWhat they receive
Pembrolizumab + 225Ac-J591 + ARIExperimentalPatients will receive one dose of 225Ac-J591 (single dose, either 65 or 80 Kbq/kg) in combination with pembrolizumab (400mg every 6 weeks) and ARI (standard dose schedule, examples of ARI include enzalutamide, apalutamide, darolutamide).
Receives: Drug: 225Ac-J591; Drug: Pembrolizumab; Drug: Androgen receptor inhibitor; Diagnostic Test: 68Ga-PSMA-11
Pembrolizumab + ARIExperimentalPatients will receive pembrolizumab (400mg every 6 weeks) and ARI (standard dose schedule) without 225Ac-J591.
Receives: Drug: Pembrolizumab; Drug: Androgen receptor inhibitor; Diagnostic Test: 68Ga-PSMA-11

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Proportion of patients with dose-limiting toxicity (DLT) following treatment with pembrolizumab and 225Ac-J591

    Primary outcome for phase I; DLTs will be measured by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. There will be 12 weeks of safety follow-up following visit 1.

    Measured: From visit 1 through 12 weeks on study

  2. Determination of optimal dose of 225Ac-J591 for phase II

    Primary outcome for phase I; following 12 weeks of safety follow-up, the study team will make a determination of the 225Ac-J591 dose for phase II (either 65 or 90 KBq/kg).

    Measured: From visit 1 through 12 weeks on study

  3. Change in composite response rate of pembrolizumab and ARPI with or without 225Ac-J591

    The primary outcome for phase II will be response, a composite of: PSA decline greater than 50% of baseline, measurable disease response by imaging criteria, conversion of circulating tumor cell count to favorable or undetectable.

    Measured: Will be collected at the time of visit 1 and up to 100 months

Secondary outcomes (7)

  1. Change in overall survival following treatment

    Overall survival will be captured through in-clinic or telephone contact with subjects

    Measured: Survival will be collected from Day 1 and up to 100 months

  2. 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.

    Measured: Will be collected at the time of visit 1 and up to 100 months

  3. Change in radiographic progression-free survival

    Response evaluation criteria in solid tumors RECIST (Version 1.1) criteria with prostate cancer working group 3 (PCWG3) modifications will be used.

    Measured: Patients will undergo imaging at screening and then every 12 weeks, for up to 100 months

  4. Change in proportion with 1-year progression-free survival

    By imaging (RECIST 1.1 criteria with prostate cancer working group 3 modifications) or biochemical (PSA) criteria

    Measured: Will be collected at the time of visit 1 through 1 year on study

  5. Change in proportion with >30% PSA decline

    Baseline (pre-treatment) PSA levels will be compared to PSA nadir on study

    Measured: Will be collected at the time of visit 1 and up to 100 months

  6. Change in proportion with >50% PSA decline

    Baseline (pre-treatment) PSA levels will be compared to PSA nadir on study

    Measured: Will be collected at the time of visit 1 and up to 100 months

  7. Change in proportion with >90% PSA decline

    Baseline (pre-treatment) PSA levels will be compared to PSA nadir on study

    Measured: Will be collected at the time of visit 1 and up to 100 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Jun 2021
  2. Study start12 Aug 2021
  3. Primary completionOct 2027 (estimated)
  4. Study completionDec 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
In the phase I portion of the study, patients will receive 225Ac-J591 at either 65 or 80 KBq/kg, in addition to pembrolizumab and ARI. In the subsequent phase II portion of the study, patients will be randomized to receive 225Ac-J591 (at the dose determined in phase I) + ARI and pembrolizumab or ARI and pembrolizumab alone in a 1:1 ratio. Randomization will take into account prior receipt of ARI, baseline PSMA imaging intensity, and presence of visceral metastasis.
Masking
None (open label)
Enrolment
52 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04946370
Sponsor's protocol ID
20-08022500
Status last verified
Apr 2026
First submitted
22 Jun 2021
Last updated
21 Apr 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing 225Ac-J591, Pembrolizumab and Androgen receptor inhibitor in people with Prostate Cancer, run by Weill Medical College of Cornell University at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 21 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact GUONC Research Team (212-746-1480, guonc@med.cornell.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of patients with dose-limiting toxicity (DLT) following treatment with pembrolizumab and 225Ac-J591 (time frame: From visit 1 through 12 weeks on study). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04946370.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Apr 2026.

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