Targeted Radionuclide Therapy in Metastatic Prostate Cancer Using a New PSMA Ligand Radiolabelled With Terbium-161 (161Tb-SibuDAB) - Dose Identification/Escalation Phase Ia/b Study

Researchers will test a new treatment for prostate cancer. This treatment uses an antibody tagged with a small amount of radioactive material. Researchers believe the new antibody might work better than those used before. In the first part of the study researchers will compare the new treatment to the old one on prostate cancer patients using very low doses, not strong enough to treat nor to cause strong adverse reactions. Each patient will eventually receive both treatments, but one at a time. The aim of the second part of the study is to find the best dose of the new treatment for patients. This means finding the dose that offers the most benefits with the fewest side effects. The performance of different prostate cancer diagnostic methods is also in scope of the study.

Radioligand therapy (RLT) has emerged as an effective treatment of metastatic, castration resistant prostate cancer (mCRPC) for those patients having, prostate-specific membrane antigen (PSMA)-positive disease. This led to the FDA approval of 177Lu-PSMA-617 (PluvictoTM), a PSMA ligand radiolabelled with the β--particle emitter lutetium-177(177Lu). Despite the success of this treatment modality, the therapeutic response after RLT with 177Lu-based PSMA radioligands is limited and disease relapse inevitable. In addition, approximately 1/3 of the patients does not respond to 177Lu-based RLT despite PSMA-positive mCRPC. It has been hypothesized that the insufficient absorbed dose delivery to macroscopic tumours and, in particular, to microscopic metastases with currently used 177Lu-based PSMA radioligands is the reason for the treatment failure in these patients. SibuDAB, a novel long-circulating PSMA ligand, was successfully tested in the preclinical setting in combination with terbium-161 (161Tb) that emits not only β--particles but also conversion and Auger electrons and, hence, delivers 2-4 times higher absorbed doses to microscopic tumours than 177Lu. The researchers, therefore, propose to enhance the efficacy of PSMA-targeting RLT by using the long-circulating ligand (SibuDAB) labelled with 161Tb. The researchers expect 161Tb-SibuDAB to exhibit increased and/or prolonged tumour uptake with a higher deposition of energy (due to short ranged Auger electrons) resulting in a high linear energy transfer (LET) and, hence, relative biological effectiveness. 161Tb-SibuDAB should not only deliver the absorbed dose to the cellular nucleus (via β-- radiation) but also to the cell membrane and organelles (through the emission of conversion and Auger electrons) which, in mathematical models, leads to a 3-4-fold increased absorbed dose to single cancer cells compared to standard RLT.