[Lu-177]Ludotadipep in Castration-resistant Prostate Cancer(CRPC): Investigation of Drug and Application

Inclusion Criteria: Patients must meet the following criteria in order to be included in both the Phase 1 andPhase 2a parts of the trial:

1. Male and ≥ 18 years
2. Histologically or cytologically confirmed adenocarcinoma of the prostate withoutneuroendocrine differentiation or small cell features at initial diagnosis
3. Disease progression on any one of the following: prior enzalutamide, abiraterone,apalutamide or related agent therapy as defined by meeting at least one of thefollowing criteria per the investigator in accordance with the Prostate Cancer WorkingGroup 3 (PCWG3) criteria [Scher et al, 2016]:
4. PSA progression as defined by a minimum of two rising PSA levels at least 1 weekapart, ideally three successive measurements
5. Soft tissue disease progression defined as >20% increase in sum of diameters ofall target lesions based on sum of diameters since treatment started or theappearance of 1 or more new lesions by RECIST 1.1
6. Bone disease progression defined by two or more new lesions on bone scan
7. Serum testosterone level < 50 ng/dL (< 0.5 ng/mL, < 1.7 nmol/L). Patients may haveongoing androgen deprivation therapy (ADT) with a luteinizing hormone-releasinghormone (LHRH) "super-agonist" or antagonist, and/or be surgically or medicallycastrated.
8. Patients must have PSMA positive lesions. These are defined as having Ga 68-PSMA-11uptake greater than that of liver parenchyma in one or more metastatic lesions of anysize in any organ system. PSMA-negative lesions are defined as having PSMA uptakeequal to or lower than that of liver parenchyma in any lymph node with a short axis ofat least 2.5 cm, in any metastatic solid-organ lesions with a short axis of at least 1.0 cm, or in any metastatic bone lesion with a soft-tissue component of at least 1.0cm in the short axis.
9. Patients receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to Day 1
10. Patients who have received a taxane or are ineligible or choose not to receivetaxane-based chemotherapy based on personal preference or physician opinion. Examplesof conditions that could make a patient ineligible or refuse to receive taxane-basedchemotherapy include the following:
11. Poor performance status
12. Prior intolerance to cytotoxic agents
13. Other serious medical conditions such as symptomatic peripheral neuropathy CommonTerminology Criteria for Adverse Events (CTCAE) Grade 2 or higher; or clinicallysignificant cardiovascular disease per the Investigator
14. ECOG PS of 0 to 2 for Phase 1 and 0 to 1 for Phase 2a
15. Estimated life expectancy of at least 3 months for Phase 1 and 6 months for Phase 2aas determined by the Investigator.
16. For patients who have partners of childbearing potential, the partner and/or patientmust use a method of birth control with adequate barrier protection, deemed acceptableby the principal investigator during the study and for 3 months after last study drugadministration.
17. Able and willing to provide signed informed consent and comply with protocolrequirements

Exclusion Criteria: Patients will be excluded from the study if they meet any of the following criteria (applies to both Phase 1 and Phase 2a):

1. Impaired organ function as evidenced by the following laboratory values at Screening:
2. Absolute neutrophil count < 1500/μL
3. Platelet count < 100,000/μL
4. Hemoglobin < 9.0 g/dL Note: the patient cannot have received blood transfusion orgrowth factor support in the 2 weeks prior to screening laboratory hematologyassessments.
5. Albumin < 3.0 g/dL (30 g/L)
6. Total bilirubin > 2 x upper limit of normal (ULN) unless in instances of known orsuspected Gilbert's disease
7. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN
8. Calculated creatinine clearance < 60 mL/min (Cockroft-Gault equation), orcurrently on renal dialysis
9. QT interval corrected for heart rate (QTcF) > 470 msec
10. Sjogren's syndrome
11. Known or suspected brain metastasis or active leptomeningeal disease
12. History of other malignancy within the previous 3 years, except basal cell or squamouscell carcinoma, or non-muscle invasive bladder cancer
13. History of active thromboembolism within the last 3 months of Day 1
14. Serious persistent infection within 14 days prior to Day 1
15. If the patient is known to have a positive polymerase chain reaction (PCR) test foractive COVID-19 infection or signs or symptoms consistent with COVID-19, in theabsence of a positive PCR test, within 5 days from date of consent
16. Patients with any medical condition or other circumstances that, in the opinion of theinvestigator, compromise obtaining reliable data, achieving study objectives, orcompleting the study
17. History of congestive heart failure New York Heart Association (NYHA) class III or IV,uncontrolled hypertension or evidence of coronary artery disease (including amyocardial infarction) within the previous 6 months from date of consent
18. Patients who received any anti-tumor therapy within 4 weeks of Day 1, with theexception of abiraterone, enzalutamide or apalutamide, GnRH therapy andnon-radioactive bone-targeted agents
19. Superscan as evidenced on baseline bone scan
20. Treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 within 6 months prior to Day 1
21. Prior hemi-body irradiation
22. Prior PSMA-targeted radioligand therapy
23. Major surgery within 4 weeks of Day 1
24. Prior systemic beta-emitting bone-seeking radioisotopes
25. Radiation therapy for treatment of prostate cancer within 4 weeks of Day 1
26. Use of anticoagulants within 3 months prior to Day 1 for patients with a history ofthromboembolic conditions. Note: Patients receiving anticoagulants for atrialfibrillation are eligible for the study so long as they are on a stable dose ofanticoagulants
27. Prior use of any herbal products known to decrease PSA levels (e.g., PC-SPES [prostatecancer hope - dietary supplement] or saw palmetto) within 30 days prior to Day 1
28. Planned initiation of alternative therapy for prostate cancer, investigationaltherapy, or participation in clinical trials during the study
29. Known history of human immunodeficiency virus (HIV) hepatitis B or C infection:
30. HIV infected patients who are healthy and have a low risk of Acquired ImmuneDeficiency Syndrome (AIDS)-related outcomes will be included.
31. Patients with a history of hepatitis B or C will be allowed to enrol if hepatitisB virus (HBV) DNA or hepatitis C virus (HCV) RNA are undetectable. At this earlystage of development, about the main concern is the potential for re-activationor worsening of HBV or HCV from the effect of radiation on lymphocyte function.
32. Vulnerable patients (the investigator involved in the study or his/her family,research staff or students of the investigator involved in the study)
33. Implantation of investigational medical device within 4 weeks of Day 1 or currentenrolment in oncologic investigational drug or device study
34. Use of investigational drugs within 4 weeks or less than 5 half-lives of Day 1
35. Patients are excluded if treatment other than the treatment provided in this study isdetermined more appropriate as determined by the investigator based on the patient anddisease characteristics