177^Lu-PSMA-617 in Combination With Sipuleucel-T for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Assent, when appropriate, will be obtained per institutional guidelines

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies

• If unavailable, exceptions may be granted with study principal investigator (PI) approval

• Age: ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) ≤ 1

• Male

• Progressive castration-resistant metastatic prostate cancer with pathologicallyconfirmed adenocarcinoma of the prostate without small cell features

• Patients must have either:

• Measurable disease

• For extranodal (visceral) lesions (e.g. lung, liver, etc.) to beconsidered measurable, they must be ≥ 10 mm in one dimension, using spiralCT

• For lymph nodes to be considered measurable (i.e., target or evaluablelesions), they must be ≥ 20 mm in at least one dimension, using spiral CT

• OR non-measurable disease

• All other lesions, including small lesions (longest diameter < 20 mm withconventional techniques or < 10 mm with spiral CT scan) and trulynon-measurable lesions

• Lesions that are considered non-measurable include bone lesions (only).Progression on first generation ADT

• Patients must have been on androgen deprivation therapy with a gonadotrophinreleasing hormone (GnRH) analogue, antagonist, or bilateral orchiectomy (i.e.,surgical or medical castration) for at least 3 months prior to study entry andmaintain castrate levels of serum testosterone < 50 ng/dL throughout studyparticipation unless intolerant

• Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prioranti-cancer therapy

• Absolute neutrophil count (ANC) ≥ 1,500/mm^3 (within 10 days prior to day 1 ofprotocol therapy)

• White blood cell (WBC) counts > 2500/uL (within 10 days prior to day 1 of protocoltherapy)

• Lymphocyte count ≥ 300/uL (within 10 days prior to day 1 of protocol therapy)

• Platelets ≥ 100,000/mm^3 (within 10 days prior to day 1 of protocol therapy)

• Hemoglobin ≥ 9g/dL (within 10 days prior to day 1 of protocol therapy)

• NOTE: Red blood cell transfusions are not permitted within 14 days ofhemoglobin assessment unless cytopenia is secondary to disease involvement

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 10 days prior to day 1of protocol therapy) (unless has Gilbert's disease, serum bilirubin level ≤ 3 x ULN)

• Aspartate aminotransferase (AST) ≤ 2.5 x ULN (within 10 days prior to day 1 ofprotocol therapy)

• Alanine aminotransferase (ALT) ≤ 3.0 x ULN (within 10 days prior to day 1 ofprotocol therapy)

• Alkaline phosphatase ≤ 3 x ULN (within 10 days prior to day 1 of protocol therapy) (Patients with documented bone metastases, alkaline phosphatase [ALP] ≤ 5 x ULN)

• Serum creatinine ≤ 1.5 x ULN or creatinine clearance of ≥ 50 mL/min perCockcroft-Gault formula (within 10 days prior to day 1 of protocol therapy)

• If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN (within 10 days prior to day 1 of protocol therapy)

• If on anticoagulant therapy: PT must be within therapeutic range of intended use ofanticoagulants (within 10 days prior to day 1 of protocol therapy)

• If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.3x ULN (within 10 days prior to day 1 of protocol therapy)

• If on anticoagulant therapy: aPTT must be within therapeutic range of intended useof anticoagulants (within 10 days prior to day 1 of protocol therapy)

• Seronegative for HIV antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV),active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapidplasma reagin [RPR]) (within 10 days prior to day 1 of protocol therapy)

• If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed.OR

• If seropositive for HIV, HCV or HBV, nucleic acid quantitation must beperformed. Viral load must be undetectable

• Meets other institutional and federal requirements for infectious disease titerrequirements

• Note Infectious disease testing to be performed within 28 days prior to day 1of protocol therapy

• For male patients with partners of childbearing potential, agreement (by patientand/or partner) to use highly effective form(s) of contraception or abstain fromheterosexual activity for the course of the study through at least 4 months afterthe last dose of protocol therapy

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Any approved or investigational anticancer therapy, including chemotherapy, hormonaltherapy (e.g., androgen receptor [AR] antagonists, 5 alpha reductase inhibitor,estrogen), or radiotherapy, within 4 weeks prior to initiation of study treatment

• Treatment with any of the following medications or interventions within 28 daysof registration:

• External beam radiation therapy or surgery

• Chrysanthemum morifolium/Ganoderma lucidum/Glycyrrhiza glabra/Isatisindigotica/Panax pseudoginseng/Rabdosia rubescens/Scutellariabaicalensis/Serona repens supplement (PC-SPES) (or PC-SPEC) or sawpalmetto

• Systemic corticosteroids. Use of inhaled, intranasal, and topical steroidsis acceptable

• Megestrol acetate (Megace®), diethyl stilbestrol (DES), or cyproteroneacetate

• Ketoconazole

• 5-alpha-reductase inhibitors (e.g., finasteride [Proscar®], dutasteride [Avodart®])

• High dose calcitriol (1,25[OH]2 vitamin [Vit]D) (i.e., > 7.0 ug/week)

• Prior treatment with 177^Lu-PSMA-617 and/or sipuleucel-T

• Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment

• Known clinically significant liver disease, including active viral, alcoholic, orother hepatitis; cirrhosis; fatty liver; and inherited liver disease

• Treatment with any investigational vaccine within 2 years of registration ortreatment with any other investigational product within 28 days of registration

• Patients with acute leukemias, accelerated/blast-phase chronic myelogenous leukemia,chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, ornon-secretory myeloma

• Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases

• Inability to comply with study and follow-up procedures

• Any other active malignancy at time of first dose of study treatment or diagnosis ofanother malignancy within 3 years prior to first dose of study treatment thatrequires active treatment, except for locally curable cancers that have beenapparently cured, such as basal or squamous cell skin cancer, superficial bladdercancer, or carcinoma in situ of the prostate, cervix, or breast

• Any other condition that would, in the investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)