Study of 225Ac-PSMA-617 in Men With PSMA-positive Prostate Cancer

Inclusion Criteria:

• Patients must have the ability to understand and sign an approved ICF.

• Patients must have the ability to understand and comply with all protocolrequirements.

• Patients must be >=18 years of age.

• Patients must have an ECOG performance status of 0 to 2.

• Patients must have had histological, pathological, and/or cytological confirmationof prostate cancer.

• Patients must have a positive 68Ga-PSMA-11 PET/CT scan performed within 28 days ofstudy entry. If a patient also has soft tissue or visceral disease, it must bePSMA-positive on 68Ga-PSMA-11 PET/CT scan.

• Patients may not participate in the study if their baseline scan shows PSMA-negativedisease (defined as disease that expresses PSMA at a level equal to or less thanliver by visual assessment) in any of the following regions:

A) One or more PSMA negative lymph nodes >2.5 cm on short axis B) Bone metastasis with PSMA-negative soft tissues component > 1 cm in short axis

• Note that PSMA-negative osseous metastases without a soft tissue component >1 cmdoes not exclude the subject C) PSMA-negative solid organ metastases (i.e. lung,liver, adrenal glands, etc) that are PSMA-negative and ≥ 1cm in short axis

• Patients must have recovered or stabilized to =< Grade 2 or baseline from allclinically significant toxicities related to prior prostate cancer therapy.

• Determination of disease progression on treatment prior to enrollment. Progressivedisease for study entry is defined as any one or more of the following:

1. PSA progression: minimum of two rising PSA values from a baseline measurementwith an interval of >= 1 week between each measurement. 2.0 ng/mL is theminimal starting value if PSA rise is only indication of progression.

2. Soft tissue or visceral disease progression as per RECIST 1.1 criteria:increase >= 20% in the sum of the diameter (SOD) (short axis for nodal lesionsand long axis for non-nodal lesions) of all target lesions based on thesmallest SOD since treatment started or the appearance of one or more newlesions.

3. Bone progression: >= 2 new lesions on bone scan.

• Patients must have adequate organ function (bone morrow reserve, hepatic functionand renal function).

• Known HIV-positive patients who are healthy and have a low risk of AIDS-relatedoutcomes are eligible. HIV testing is required.

• For patients who have partners of childbearing potential, patient must use a methodof birth control with adequate barrier protection, deemed acceptable by theprincipal investigator during the study and for 6 months after last study drugadministration.

• Group A Subjects: Patients must have prior orchiectomy and/or ongoingandrogen-deprivation therapy, a castrate level of serum testosterone (< 50 ng/dL or < 1.7 nmol/L) and must have received prior cytotoxic chemotherapy and a novelandrogen axis drug (e.g., abiraterone or enzalutamide). Patients must also be naïveto prior 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T)

• Group B Subjects (South-Africa only): Patients must have ongoing androgendeprivation therapy (ADT) and either prior orchiectomy or be medically castrateusing LHRH agonists/antagonists in order to achieve adequate suppression of serumtestosterone (< 50 ng/dL) but must not have received prior cytotoxic chemotherapy ornovel androgen axis drugs (e.g., abiraterone or enzalutamide). These patients arenaïve to 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T).

• Group C Subjects: Patients must have ongoing androgen deprivation therapy (ADT) andeither prior orchiectomy or be medically castrate using LHRH agonists/antagonists inorder to achieve adequate suppression of serum testosterone (< 50 ng/dL). Patientsmust have been treated with prior 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T) for at least one cycle administered greater than 6 weeks from studyenrollment, and been evaluated for biochemical and radiological response to therapy.Prior exposure to ARPI and/or chemotherapy is not required.

Exclusion Criteria:

• Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188,Radium-223 or hemi-body irradiation.

• Any investigational agents within 28 days of study enrollment.

• Known hypersensitivity to the components of the study therapy or its analogues.

• Other concurrent cytotoxic chemotherapy, targeted therapy, biologic agents,immunotherapy, radioligand therapy, or investigational therapy.

• Transfusion for the sole purpose of eligibility into the study.

• Patients with a history of CNS metastases must have received therapy (surgery,radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and notreceiving corticosteroids for the purposes of maintaining neurologic integrity.Patients with epidural disease, canal disease and prior cord involvement areeligible if those areas have been treated, are stable, and not neurologicallyimpaired.

• Symptomatic cord compression, or clinical or radiologic findings indicative ofimpending cord compression.

• Concurrent serious (as determined by the Principal Investigator) medical conditions,including, but not limited to, uncontrolled infection, active hepatitis B or C, orother significant co-morbid conditions that in the opinion of the investigator wouldimpair study participation or cooperation.

• Diagnosed with other malignancies that are expected to alter life expectancy or mayinterfere with disease assessment. Patients with a prior history of malignancy whohave been disease free for more than 3 years are eligible.

• Participants with an active documented COVID-19 infection (any grade of diseaseseverity) at the time of informed consent may be included only when completelyrecovered (in accordance with local guidance).