177Lu-HTK03170 in mCRPC With PSMA Positive Disease

Inclusion Criteria:

Each subject must meet all of the following inclusion criteria to be enrolled in the study:

1. Male subjects ≥ 18 years of age
2. Willing and able to provide consent
3. Life expectancy of \> 6 months
4. Progression on treatment with abiraterone and/or enzalutamide, or similar next generation ARAT therapy, as determined by the investigator. Subjects who have received docetaxel in the castration-resistant setting are also eligible to participate. Prior treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor is permitted.
5. Pathologically confirmed prostate adenocarcinoma
6. Subjects must have evidence of biochemical or imaging progression. Progression is defined as any one of the following:

   1. Prostate-specific antigen progression: two consecutive rising PSA values from a baseline measurement with an interval of ≥ 1 week between measurements. Minimum PSA at screening visit is ≥ 2.0 µg/L.
   2. Soft tissue disease progression on chest, abdomen, pelvis CT or magnetic resonance imaging (MRI; RECIST v1.1)
   3. Bone progression: ≥ 2 new lesions on bone scan
7. Eastern Cooperative Oncology Group (ECOG) performance score ≤2
8. Prior orchiectomy, or if on luteinizing hormone releasing hormone (LHRH) agonist/antagonist, then testosterone \< 1.7 nmol/L or \< 50 ng/dL
9. Adequate organ function:

   a) Marrow i) Absolute neutrophil count ≥ 1.5 × 109 /L ii) Platelet count ≥ 100 ×109 /L iii) Hemoglobin ≥ 90 g/L with no transfusions in the past 2 weeks b) Kidney i) Estimated creatinine clearance ≥40 ml/min according to Cockroft-Gault equation: ((140 - age) × (weight in kg)) / (72 × (serum creatinine)) c) Liver: i) Bilirubin \< 1.0 × upper limit of normal (ULN) (or if bilirubin is between 1.5 to 2 × ULN, must have a normal conjugated bilirubin) ii) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN in the absence of liver metastases, and) ≤ 5.0 × ULN in the presence of liver metastases.
10. Recovery from all previous cancer treatment toxicities to grade ≤ 2 (as per CTCAE 4.03)
11. Able to comply with scheduled visits, treatment plans, laboratory tests, imaging tests, and other procedures required and detailed in the protocol.
12. Must be surgically sterile or use adequate contraception for the duration of the therapy and 6 months after the end of therapy

Exclusion Criteria:

Subjects meeting any of the following exclusion criteria are not to be enrolled in the study.

1. Prior treatment with 225Ac-PSMA-617, 177Lu-PSMA, other radiolabeled therapeutic PSMA-ligands, or radio-immunotherapy
2. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or targeted therapy) within 28 days prior to day of enrollment
3. Radiotherapy to target lesions (measurable disease) ≤ 4 weeks prior to enrolment
4. Known parenchymal brain metastases
5. Active epidural disease (treated epidural disease is permitted)
6. History of risk factors for xerostomia (ie, head and neck radiation, Sjögren's disease) or pre-existing xerostomia Grade ≥1
7. Other concomitant active invasive cancer (except superficial non-melanomatous, non-metastatic skin cancer or non-invasive superficial transitional cell carcinoma \[TCC\])
8. Clinically significant cardiac disease including:

   1. History of unstable angina pectoris, symptomatic pericarditis, or myocardial infarction within 6 months prior to study entry.
   2. History of documented congestive heart failure (New York Heart Association \[NYHA\] functional classification III-IV) or cardiomyopathy.
9. Major surgery within 4 weeks of starting study treatment.
10. Unmanageable urinary tract obstruction or hydronephrosis