NeoAdjuvant Theranostic Lutetium Study: The Nautilus Trial

Inclusion Criteria:

1. Men ≥18 years of age

2. Histologically documented prostatic adenocarcinoma with an NCCN risk group ofhigh-risk or very high-risk. NCCN High Risk and Very High-Risk criteria shown below. (Network, N.C.C. (2021). Prostate Cancer (Version 02.2021). High Risk:

• Has no very-high-risk features and has exactly one high-risk feature:

• cT3a

• Grade Group 4 or Grade Group 5

• PSA >20 ng/mL Very high:

• Has at least one of the following:

• cT3b-cT4

• Primary Gleason pattern 5

• 2 or 3 high-risk features

• >4 cores with Grade Group 4 or 5

3. Prostate biopsy within 90 days prior to randomization is allowed for entryrequirements. Prostate biopsy must be reviewed at MD Anderson Cancer Center.Patients with small cell, neuroendocrine, or transitional cell carcinomas are noteligible

4. ECOG performance status (PS) grade 1

5. No evidence of metastatic disease or clinically positive lymph nodes as documentedby technetium99m (99mTc) bone scan and by computed tomography (CT) or magneticresonance imaging (MRI) scans. Imaging may be obtained up to 60 days prior torandomization

6. Minimum prostate tumor volume of 1.5 cm3 or greater as measured on prostate MRIwithin 60 days prior to randomization

7. Distant metastatic disease or clinically positive lymph nodes not identified byconventional imaging including by technetium-99m (99mTc) bone scan and by computedtomography (CT) or magnetic resonance imaging (MRI) scans but identified PSMA PET isallowed based on provider discretion

8. PSMA expression within the primary tumor with a minimum SUVmax of the primary tumorof at least 8

9. Localized or locally advanced disease deemed by the surgeon to be resectable.Patients must be appropriate candidates for and plan to undergo radicalprostatectomy and pelvic lymph node dissection

10. No prior treatment for prostate cancer including prior surgery (excludingtransurethral resection of the prostate [TURP]), cryoablation, pelvic lymph nodedissection, radiation therapy, hormonal therapy or chemotherapy

11. Adequate bone marrow function documented by:

• Hemoglobin ≥11 g/dL

• Absolute neutrophil count ≥1.5 x 109/L

• Platelet count ≥150 x 109/L

12. Adequate renal function defined as creatinine <1.5 x ULN or estimated glomerularfiltration rate >60 mL/min/1.73 m2 using BSA with CKD-EPI

13. Adequate hepatic function documented by:

• Total bilirubin ≤1.5 x ULN

• AST ≤2.5 x ULN

• ALT ≤2.5 x ULN

• Alkaline Phosphatase (ALP) ≤2.5 x ULN Patients with Gilbert's syndrome do not need to meet total bilirubin requirementsprovided their total bilirubin is not greater than their historical level. Gilbert'ssyndrome must be documented appropriately as past medical history

14. Consents to providing whole blood samples for correlative PSMA evaluation ofcirculating tumor cells and extra cellular vesicles

15. Willing and able to comply with clinic visits and study-related procedures

16. Provide informed consent signed by study patient

17. To avoid risk of drug exposure through the ejaculate (even men with vasectomies),subjects must use a condom during sexual activity while on study drug and for 6months following the last dose of study drug. If the subject is engaged in sexualactivity with a woman of childbearing potential, a condom is required along withanother effective contraceptive method consistent with local regulations regardingthe use of birth control methods for subjects participating in clinical studies andtheir partners. Donation of sperm is not allowed while on study drug and for 3months following the last dose of study drug.

Exclusion Criteria:

1. Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens,ketoconazole, or estrogens (5-α reductase inhibitors allowed), or LHRHagonists/antagonists

2. Currently enrolled in another interventional study

3. Concurrent treatment with systemic corticosteroids (prednisone dose >10 mg per dayor equivalent) or other immunosuppressive drugs <14 days prior to treatmentinitiation Steroids that are topical, inhaled, nasal (spray), or ophthalmic solutionare permitted.

4. Known evidence of an active infection requiring systemic therapy such asuncontrolled human immunodeficiency virus (HIV), active hepatitis, or fungalinfection. Uncomplicated urinary tract infection (UTI) does not qualify as anexcluding infection.

• Patients with HIV must be on an effective anti-retroviral regimen atleast fourweeks prior to enrollment, HIV viral load less than 400 copies/mL and CD4+ Tcell counts greater than 350 cell/uL.

• Patients with HIV must agree to adhere to anti-retroviral therapy for theentirety of their participation in the protocol unless dictated by treatmenttoxicities.

• Patients on Tenofovir will be excluded as there is a known risk of proximalrenal tubule dysfunction leading to renal toxicity. Given that PSMA isexpressed on the proximal tubule there is a theoretical risk of overlappingtoxicity.

5. History of clinically significant cardiovascular disease including, but not limitedto:

• Myocardial infarction or unstable angina ≤6 months prior to treatmentinitiation

• Clinically significant cardiac arrhythmia

• Deep vein thrombosis, pulmonary embolism, stroke ≤6 months prior to treatmentinitiation

• Congestive heart failure (New York Heart Association class III-IV)

• Pericarditis/clinically significant pericardial effusion

• Myocarditis

• Endocarditis

6. History of major implant(s) or device(s), including but not limited to:

• Prosthetic heart valve(s)

• Current or prior history of infection or other clinically significant adverseevent associated with an exogenous implant or device that cannot be removed

7. Other prior malignancy (exceptions: adequately treated basal cell or squamous cellskin cancer, superficial bladder cancer, or any other cancer in situ currently incomplete remission) ≤2 years prior to enrollment

8. Has received major surgery within 90 days of first administration of study drug

9. Prior allogeneic stem cell transplantation or recipients of organ transplants orautologous stem cell transplantation at any time MD Anderson Protocol Number: 2022-0500 2022-0500 Version Date 8/29/2023 26

10. Any medical, psychological or social condition that in the opinion of theinvestigator, would preclude participation in this study

11. Previously received external beam irradiation to the pelvis or to a field thatincludes more than 30% of the bone marrow or kidneys

12. Previous treatment with any of the following: PSMA-targeted radionuclide therapy,Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-bodyirradiation

13. Transfusion of blood products for the sole purpose of meeting the eligibilitycriteria for this clinical trial

14. Patient has a functionally or anatomically solitary kidney.

15. Patients with Hydronephrosis and a Mag3 Lasix Renogram that demonstrates objectiveurinary obstruction.