177Lu-PSMA-I&T for Metastatic Castration-Resistant Prostate Cancer

Prior treatment

• Prior treatment with radioligand therapy including other lutetium-labeled compounds.
• Prior treatment with radium-223 (Xofigo) within the past 12 weeks.
• Prior chemotherapy treatment for castration-resistant prostate cancer. Prior docetaxel use in the hormone-sensitive setting is permitted, as long as no more than 6 doses were received, the last dose was administered \>1 year prior to consent, and disease progression did not occur during docetaxel treatment.
• Patients with known HRR gene-mutation (BRCA 1/2 encompassing both germline and somatic) who have not been previously treated with olaparib or rucaparib.
• Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.
• Use of an investigational therapeutic drug within the last 4 weeks prior to start of study treatment or scheduled to receive one during the study period.
• Known CNS metastasis unless received therapy, asymptomatic and neurologically stable.
• Patients receiving zoledronic acid for bone-targeted therapy must be on stable dose for 4 weeks prior to randomization.
• Major surgery within 30 days of randomization as determined by the Investigator.
• Previous use of G-CSF for persistent neutropenia after standard of care treatment.
• Participants with active Covid19. Recovered patients may be included when completely recovered (no symptoms at least 28 days before study medication and a negative Covid test within 72 hours).

Other illness

• Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer

Lab values

• Inadequate organ and bone marrow function as evidenced by:
  • Hemoglobin \< 8 g/dL.
  • Absolute neutrophil count \< 1.5 x 109/L.
  • Platelet count \< 100 x 109/L.
  • AST/SGOT and/or ALT/SGPT \> 3.0 x ULN.
  • Total bilirubin \> 2 x ULN unless patient has known Gilbert's syndrome and then may be 3 x ULN.
  • Creatinine clearance (CrCl) \< 50 mL/min based on the Cockcroft-Gault equation.
  • Albumin ≤ 2.75 g/dL
• Patients with active significant cardiac disease defined by any of the following:
  • New York Heart Association class 3 or 4 congestive heart failure within 6 months of signing the ICF unless treated with improvement.
  • Current diagnosis of electrocardiogram abnormalities with significant cardiac arrhythmias
  • History of long QT syndrome or know history of Torsades de Pointe
  • History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months of ICF signature

Other

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2
• Patients who undergo a transfusion for the sole purpose of meeting eligibility for this trial will be excluded.
• Assessment by the Investigator as unable or unwilling to comply with the requirements of the protocol.
• Participants with symptomatic cord compression or clinical/radiological findings indicating impending spinal cord compression
• Patients with a superscan seen on baseline bone scan as determined by investigator.
• Participants who have a pregnant partner or are capable of fathering a child and who are unwilling to take precautions to prevent potential harm to the fetus or prevent pregnancy.

• Male 18 years or older able to understand and provide signed written informed consent.
• Histologically or pathologically confirmed prostate adenocarcinoma without predominant small cell component.
• Progressive disease by one or more of the following criteria:
  • Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week apart with a minimum start value of \>2 ng/mL.
  • Progression of measurable disease (RECIST 1.1) or presence of at least two new bone lesions (PCWG3 criteria).
• Previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g. abiraterone, enzalutamide, apalutamide, darolutamide).
  • Must have received no more than one previous AR-directed therapy.
  • Must have been administered ARAT (abiraterone, enzalutamide, darolutamide, or apalutamide) in the castration-sensitive or castration-resistant setting.
  • Must have progressed while on ARAT.
• PSMA-PET scan (e.g., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by central reader.
• Effective castration with serum testosterone level of \<50 ng/dL and plan to continue with chronic medical or surgical castration.
• Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
• Patients with HIV that are healthy and with a low risk of acquired immune deficiency syndrome related outcomes may participate in the trial at the investigators' discretion.
• Patients with HBV and HCV may also participate if symptoms are sufficiently managed.
• Life expectancy of at least 6 months as assessed by investigator.
• Willing to initiate ARAT therapy determined by investigator.
• For patients who have partners of childbearing potential: The patient and/or partner must use a method of birth control with adequate barrier protection, deemed acceptable by the principal investigator during the study and for 6 months after the last study drug administration.