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

Eligibility Criteria

• 1. Male and ≥ 18 years
• 2. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine 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 the following criteria per the investigator in accordance with the Prostate Cancer Working Group 3 (PCWG3) criteria \[Scher et al, 2016\]:
• 1. PSA progression as defined by a minimum of two rising PSA levels at least 1 week apart, ideally three successive measurements
• 2. Soft tissue disease progression defined as \>20% increase in sum of diameters of all target lesions based on sum of diameters since treatment started or the appearance of 1 or more new lesions by RECIST 1.1
• 3. Bone disease progression defined by two or more new lesions on bone scan
• 4. Serum testosterone level \< 50 ng/dL (\< 0.5 ng/mL, \< 1.7 nmol/L). Patients may have ongoing androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) "super-agonist" or antagonist, and/or be surgically or medically castrated.
• 5. Patients must have PSMA positive lesions. These are defined as having Ga 68-PSMA-11 uptake greater than that of liver parenchyma in one or more metastatic lesions of any size in any organ system. PSMA-negative lesions are defined as having PSMA uptake equal to or lower than that of liver parenchyma in any lymph node with a short axis of at 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 1.0 cm in the short axis.
• 6. Patients receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to Day 1
• 7. Patients who have received a taxane or are ineligible or choose not to receive taxane-based chemotherapy based on personal preference or physician opinion. Examples of conditions that could make a patient ineligible or refuse to receive taxane-based chemotherapy include the following:
• 1. Poor performance status
• 2. Prior intolerance to cytotoxic agents
• 3. Other serious medical conditions such as symptomatic peripheral neuropathy Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or higher; or clinically significant cardiovascular disease per the Investigator
• 8. ECOG PS of 0 to 2 for Phase 1 and 0 to 1 for Phase 2a
• 9. Estimated life expectancy of at least 3 months for Phase 1 and 6 months for Phase 2a as determined by the Investigator.
• 10. For patients who have partners of childbearing potential, the partner and/or patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principal investigator during the study and for 3 months after last study drug administration.
• 11. Able and willing to provide signed informed consent and comply with protocol requirements
• 1. Impaired organ function as evidenced by the following laboratory values at Screening:
• 1. Absolute neutrophil count \< 1500/μL
• 2. Platelet count \< 100,000/μL
• 3. Hemoglobin \< 9.0 g/dL Note: the patient cannot have received blood transfusion or growth factor support in the 2 weeks prior to screening laboratory hematology assessments.
• 4. Albumin \< 3.0 g/dL (30 g/L)
• 5. Total bilirubin \> 2 x upper limit of normal (ULN) unless in instances of known or suspected Gilbert's disease
• 6. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 x ULN
• 7. Calculated creatinine clearance \< 60 mL/min (Cockroft-Gault equation), or currently on renal dialysis
• 2. QT interval corrected for heart rate (QTcF) \> 470 msec
• 3. Sjogren's syndrome
• 4. Known or suspected brain metastasis or active leptomeningeal disease
• 5. History of other malignancy within the previous 3 years, except basal cell or squamous cell carcinoma, or non-muscle invasive bladder cancer
• 6. History of active thromboembolism within the last 3 months of Day 1
• 7. Serious persistent infection within 14 days prior to Day 1
• 8. If the patient is known to have a positive polymerase chain reaction (PCR) test for active COVID-19 infection or signs or symptoms consistent with COVID-19, in the absence of a positive PCR test, within 5 days from date of consent
• 9. Patients with any medical condition or other circumstances that, in the opinion of the investigator, compromise obtaining reliable data, achieving study objectives, or completing the study
• 10. History of congestive heart failure New York Heart Association (NYHA) class III or IV, uncontrolled hypertension or evidence of coronary artery disease (including a myocardial infarction) within the previous 6 months from date of consent
• 11. Patients who received any anti-tumor therapy within 4 weeks of Day 1, with the exception of abiraterone, enzalutamide or apalutamide, GnRH therapy and non-radioactive bone-targeted agents
• 12. Superscan as evidenced on baseline bone scan
• 13. Treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 within 6 months prior to Day 1
• 14. Prior hemi-body irradiation
• 15. Prior PSMA-targeted radioligand therapy
• 16. Major surgery within 4 weeks of Day 1
• 17. Prior systemic beta-emitting bone-seeking radioisotopes
• 18. Radiation therapy for treatment of prostate cancer within 4 weeks of Day 1
• 19. Use of anticoagulants within 3 months prior to Day 1 for patients with a history of thromboembolic conditions. Note: Patients receiving anticoagulants for atrial fibrillation are eligible for the study so long as they are on a stable dose of anticoagulants
• 20. Prior use of any herbal products known to decrease PSA levels (e.g., PC-SPES \[prostate cancer hope - dietary supplement\] or saw palmetto) within 30 days prior to Day 1
• 21. Planned initiation of alternative therapy for prostate cancer, investigational therapy, or participation in clinical trials during the study
• 22. Known history of human immunodeficiency virus (HIV) hepatitis B or C infection:
• 1. HIV infected patients who are healthy and have a low risk of Acquired Immune Deficiency Syndrome (AIDS)-related outcomes will be included.
• 2. Patients with a history of hepatitis B or C will be allowed to enrol if hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA are undetectable. At this early stage of development, about the main concern is the potential for re-activation or worsening of HBV or HCV from the effect of radiation on lymphocyte function.
• 23. Vulnerable patients (the investigator involved in the study or his/her family, research staff or students of the investigator involved in the study)
• 24. Implantation of investigational medical device within 4 weeks of Day 1 or current enrolment in oncologic investigational drug or device study
• 25. Use of investigational drugs within 4 weeks or less than 5 half-lives of Day 1
• 26. Patients are excluded if treatment other than the treatment provided in this study is determined more appropriate as determined by the investigator based on the patient and disease characteristics