Overview
This study is a phase I dose escalation clinical trial aims to evaluate 161Tb-PSMA-I\&T, a new generation prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) using Terbium-161 to replace Lutetium-177, its safety, dosimetry, biodistribution, pharmacokinetics, and preliminary efficacy in Taiwanese men with metastatic castration-resistant prostate cancer, and to inform future clinical trials.
Description
Metastatic castration-resistant prostate cancer (mCRPC) represents the most advanced and treatment-refractory form of prostate cancer, where disease progression continues despite hormone-suppressing therapies and multiple lines of systemic treatment. Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) has emerged as a promising treatment strategy, delivering targeted radiation to cancer cells using PSMA-binding ligands labeled with therapeutic radioisotopes. While Lutetium-177 (177Lu)-labeled compounds such as 177Lu-PSMA-617 have demonstrated meaningful clinical benefit, their effectiveness may be limited in cases of micrometastatic disease or heterogeneous PSMA expression, due to the physical characteristics of longer-range β particle radiation.
Terbium-161 (161Tb) is a next-generation radionuclide that emits not only β particles but also short-range, high-linear energy transfer Auger electrons. This dual emission profile enables more effective cell killing in small or poorly perfused tumor sites, with potentially enhanced tumor-to-normal tissue selectivity. Preclinical studies and early case reports suggest that 161Tb-labeled PSMA agents may offer superior tumor dosimetry and cytotoxicity compared to 177Lu analogs. Most notably, the recently published VIOLET Phase I/II trial-the largest clinical experience with 161Tb-PSMA-I\&T to date-demonstrated favorable safety across escalating doses (up to 7.4 GBq) and promising therapeutic activity. These findings confirm that 161Tb-PSMA RLT is both safe and clinically active, even in patients previously treated with 177Lu-based agents.
Building on this foundation, our study aims to establish a standardized GMP-grade production process for 161Tb-PSMA-I\&T and to evaluate its pharmacokinetics, biodistribution, and radiation dosimetry in a small cohort of Taiwanese patients with mCRPC. These pilot data will generate critical clinical insight and infrastructure, directly informing the design of future Phase Ib/II trials and accelerating national readiness for next-generation PSMA-targeted therapies, especially emphasizing on three specific aims: (1) to establish a GMP-compliant manufacturing process for clinical-grade 161Tb-PSMA-I\&T suitable for clinical application in Taiwan; (2) to characterize 161Tb-PSMA-I\&T focusing on its pharmacokinetics, biodistribution, and radiation dosimetry; (3) to explore preliminary safety data of 161Tb-PSMA-I\&T using potential treatment doses in Asian population.
Eligibility
Inclusion Criteria:
- Age ≥ 20 years, ability to understand and willingness to sign informed consent, cooperate with all study-related procedures and assessments including blood tests and imaging
- Histologically confirmed adenocarcinoma of the prostate with evidence of metastatic castration-resistant prostate cancer (mCRPC)
- Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone analog, with a serum testosterone level \<50 ng/dL (castrate range)
- Prior treated with at least one line of taxane-based chemotherapy unless medically unsuitable, and at least one line of androgen receptor pathway inhibitor (e.g., abiraterone, enzalutamide, apalutamide, or darolutamide)
- Prior treated with 177Lu-labeled PSMA RLT unless medically unsuitable or declined by the patient
- Progressive disease defined according to Prostate Cancer Clinical Trials Working Group 3: Either a PSA progression of more than 2 rising PSA values from baseline with intervals ≥ 1 week, or a soft-tissue progression on images per RECIST 1.1 criteria, or a bone progression on images with more than 2 new lesions
- Evidence of significant PSMA-avid lesions on 68Ga- or 18F-labeled PSMA PET/CT within 12 weeks prior to screening, which defined as 68Ga-PSMA or 18F-PSMA uptake greater than that of liver or spleen parenchyma (depend on the tracer used) in at least one metastatic lesion of any size in any organ system
- A life expectancy of ≥ 6 months and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Adequate bone marrow and organ functions 9.1 Hemoglobin ≥ 10 g/dL without RBC transfusion within 4 weeks 9.2 Absolute neutrophil count ≥ 1.5 × 109/L 9.3 Platelet count ≥ 150 × 109/L 9.4 Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault) 9.5 AST and ALT ≤ 3 × ULN, total bilirubin ≤ 1.5 × ULN
- Willingness to comply with the use of medically acceptable forms of barrier contraception if sexually active
Exclusion Criteria:
- History of allergic reaction to PSMA-targeted compounds or radiometals
- Prior radioligand therapy with 223Ra or 177Lu-PSMA within 6 months
- Prior surgery or radiotherapy within 4 weeks prior to first investigational dose
- Prior systemic therapies against prostate cancer within 4 weeks, including androgen receptor pathway inhibitor, chemotherapy, targeted therapy such as PARP inhibitors (PARPi)
- Discordant disease on PET images: FDG-positive disease with minimal PSMA expression
- Urinary tract obstruction causing hydronephrosis unless appropriately treated beforehand
- Known symptomatic brain metastases or leptomeningeal disease, symptomatic or impending cord compression unless appropriately treated beforehand
- Other active malignancy requiring systemic treatment
- Significant cardiovascular disease (e.g., recent myocardial infarction, unstable angina)
- Concurrent severe uncontrolled illness that may jeopardize patient safety, including uncontrolled infections
