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 pathway inhibitor (ARPI) is
more effective against prostate cancer than pembrolizumab and ARPI 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: ARPI (standard dosing schedule),
pembrolizumab (400 mg every 6 weeks), 225Ac-J591 (single dose, either 65 or 90 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 + ARPI 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.
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).
- 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
- 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
- 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). These drugs may have been initiated in the metastatic hormone
sensitive 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 >150,000 x 109/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.
- Prior receipt of chemotherapy for castration-resistant prostate cancer. Prior receipt
of docetaxel chemotherapy in the hormone sensitive setting or for localized disease is
- 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 investigational
PSMA-targeted therapy; 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 potentially curative treatment has been
completed with no evidence of malignancy for 2 years.
- 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
- 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
- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks or <5 half-lives prior to enrollment.
- 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 (≤2 weeks of radiotherapy) to non-CNS disease.
- 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.
- 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
- Has received a live vaccine within 30 days. Examples of live vaccines include, but are
not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken
pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines and are
allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated
vaccines and are not allowed.
- Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
- Has a history of (non-infectious) pneumonitis that required steroids or has current
- 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