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

NCT04946370 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 20-08022500
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 4

Brief 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). This study will assess whether 225Ac-J591 + pembrolizumab + androgen receptor inhibitor (ARI) is more effective against prostate cancer than pembrolizumab + ARI alone.

Conditions

Prostate Cancer

Outcome Measures

Primary Outcomes (3)

• 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.

  From visit 1 through 12 weeks on study

• 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).

  From visit 1 through 12 weeks on study

• 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.

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

Secondary Outcomes (7)

• Change in overall survival following treatment

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

• Change in biochemical progression-free survival

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

• Change in radiographic progression-free survival

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

• Change in proportion with 1-year progression-free survival

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

• Change in proportion with >30% PSA decline

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

Study Arms (2)

Pembrolizumab + 225Ac-J591 + ARI

EXPERIMENTAL

Patients 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).

Drug: 225Ac-J591; Drug: Pembrolizumab; Drug: Androgen receptor inhibitor; Diagnostic Test: 68Ga-PSMA-11

Pembrolizumab + ARI

EXPERIMENTAL

Patients will receive pembrolizumab (400mg every 6 weeks) and ARI (standard dose schedule) without 225Ac-J591.

Drug: Pembrolizumab; Drug: Androgen receptor inhibitor; Diagnostic Test: 68Ga-PSMA-11

Interventions

225Ac-J591 DRUG

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

Pembrolizumab + 225Ac-J591 + ARI

Pembrolizumab DRUG

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

Pembrolizumab + 225Ac-J591 + ARI; Pembrolizumab + ARI

Androgen receptor inhibitor DRUG

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.

Pembrolizumab + 225Ac-J591 + ARI; Pembrolizumab + ARI

68Ga-PSMA-11 DIAGNOSTIC_TEST

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

Also known as: 68Ga-PSMA-HBED-CC

Pembrolizumab + 225Ac-J591 + ARI; Pembrolizumab + ARI

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Metastatic Castrate Resistant Prostate Cancer
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• United States Department of Defense: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (4)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

NOT YET RECRUITING

New York Presbyterian/Brooklyn Methodist Hospital

Brooklyn, New York, 11215, United States

RECRUITING

New York Presbyterian/Weill Cornell Medical Center

New York, New York, 10021, United States

RECRUITING

Columbia University Irving Cancer Center

New York, New York, 10032, United States

RECRUITING

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

pembrolizumab; Androgen Receptor Antagonists

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Androgen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Scott Tagawa, MD, MS

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

GUONC Research Team

CONTACT

212-746-1480; guonc@med.cornell.edu

GUCLINIC Research Team

CONTACT

guclinic@med.cornell.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 22, 2021
• First Posted: June 30, 2021
• Study Start: August 12, 2021
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): December 1, 2029
• Last Updated: April 21, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)