EValuation of radIOLigand Treatment in mEn With Metastatic Castration-resistant Prostate Cancer With [161Tb]Tb-PSMA-I&T

This prospective, single-centre, single-arm phase I/II trial will assess the safety, efficacy and anti-tumour activity of [161Tb]Tb-PSMA-I&T in patients with mCRPC.

This study aims to assess and establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs) and recommended phase 2 dose (RP2D) of [161Tb]Tb-PSMA-I&T in patients with mCRPC.

42 men with mCRPC who have progressed with at least one line of taxane chemotherapy and at least one second-generation androgen receptor (AR)-targeted agent will be enrolled in this trial in two stages: dose escalation and a dose expansion phase over a period of 24 months.

Inclusion criteria

• Patient has provided written informed consent.
• Male patients must be 18 years of age or older at the time of written informed consent.
• Histologically or cytologically confirmed adenocarcinoma of the prostate, OR unequivocal diagnosis of metastatic prostate cancer (i.e., involving bone or pelvic lymph nodes or para-aortic lymph nodes) with an elevated serum prostate specific antigen (PSA).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Patients must have had prior treatment with at least one line of taxane chemotherapy, unless medically unsuitable.
• Patients must have had prior treatment with at least one second-generation androgen receptor (AR)-targeted agent (e.g., enzalutamide, abiraterone, apalutamide or darolutamide).
• Patients must have progressive disease defined according to The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) as any one of the following:

• PSA progression - minimum of 2 rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement
• Soft tissue progression as per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) criteria
• Bone progression: ≥ 2 new lesions on bone scan
• Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist).
• Serum testosterone levels ≤ 1.75nmol/L (≤ 50ng/dL).
• Significant prostate specific membrane antigen (PSMA) avidity on PSMA positron emission tomography (PET)/computed tomography (CT), defined as a minimum uptake of maximum standardised uptake value (SUVmax) 20 at a site of disease, and SUVmax > 10 at sites of measurable soft tissue disease ≥ 15mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact).
• Patients must have a life expectancy ≥ 6 months.
• Patients must have adequate bone marrow, hepatic and renal function, defined as:

• Haemoglobin ≥ 100g/L independent of transfusions (no red blood cell transfusion in last 4 weeks)
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Platelets ≥ 150 x 10^9/L
• Total bilirubin ≤ 1.5x upper limit of normal (ULN) except for patients with known Gilbert's syndrome, where this applies for the unconjugated bilirubin component
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3x ULN if there is no evidence of liver metastasis or ≤ 5x ULN in the presence of liver metastases
• Adequate renal function: patients must have a creatinine clearance estimated of ≥ 40mL/min using the Cockcroft Gault equation (Appendix 3)
• Sexually active patients are willing to use medically acceptable forms of barrier contraception.
• Willing and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments.
• At least 3 weeks since the completion of surgery or radiotherapy prior to registration.

Exclusion criteria

• Prior treatment with another radioisotope (i.e. PSMA radioligands, radium-223, strontium-89, samarium-153).
• Site(s) of discordant disease on PET imaging (Fluorodeoxyglucose [FDG]-positive and minimal PSMA-uptake).
• Other malignancies (in addition to the prostate cancer being treated on this study) within the previous 2-years prior to registration other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months.
• Symptomatic brain metastases or leptomeningeal metastases.
• Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for more than 4 weeks.
• Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.