This multi-center prospective Phase 1 study is designed to evaluate the safety, tolerability, biodistribution and dosimetry of 177Lu-DOTA-TLX591 administered to patients together with best SoC with metastatic castration-resistant prostate cancer (mCRPC) that expresses PSMA and has progressed despite prior treatment with a novel androgen axis drug (NAAD).~PSMA positivity will be defined by 68Ga-PSMA-11 or [18F]DCFPyL PET/CT where at least one site of metastatic disease has an intensity of tracer uptake significantly greater than normal liver (i.e., standardized uptake value [SUV]max at least 1.5 times SUV of normal liver.~Approximately 25-50 eligible patients will be enrolled and evaluated for safety and tolerability as well as undergo imaging to allow determination of the biodistribution and dosimetry 177Lu-DOTA-TLX591. All patients will receive two single intravenous (IV) infusions of 76 mCi each (equivalent to 45 mCi/m2 in a standard 1.7m2 individual) of 177Lu-DOTA-TLX591, given notionally 14 days apart, plus best SoC.~Twenty-five patients will also be enrolled in a biodistribution and dosimetry sub-study, involving the collection of quantitative single-photon emission computerized tomography (SPECT) or single-photon emission computerized tomography/computerized tomography (SPECT/CT) data in a subset of patients.~SPECT/CT scans will be performed after administration of the drug, at the following timepoints: i) 4h ± 5 min, ii) 24 ± 4h, iii) 96 ± 4h, iv) Day 7± 4h and v) Day 13± 4h. These SPECT/CT scans will be conducted to further support safety monitoring and to understand exposure of tumour and healthy tissue to 177Lu-DOTA-TLX591.~Imaging data from the first five patients enrolled in the biodistribution study will be analysed and, if appropriate, the number of imaging timepoints will be reduced to three for subsequent patients. Qualitative comparison of 68Ga-PSMA-PET/CT images and 177Lu-DOTA-TLX591 images will also be undertaken for patients undergoing the biodistribution study to ensure equivalence of radiopharmaceutical localization to tumour sites and equivalent off-target localization.~Blood samples for pharmacokinetic analysis will be performed at 15 min ± 5 min before administration of the drug, and at the following timepoints after dosing: i) end of infusion ± 5min, ii) 60 min ± 5 min, ii) 4h ± 5 min, iii) 24 ± 4h, v) 48 ± 4h, vi) 96 ± 4h, vii) Day 7± 4h and viii) Day 13± 4h.~Collection of information on prior and concomitant medications and adverse events (AEs), as well as the review of temporary contra-indications and conditions for withdrawal, will occur at every patient interaction.
This is a Phase 1 trial of TLX591, a monoclonal antibody HuX591 conjugated with a DOTA chelator and radiolabelled with 177Lu (177Lu-DOTA-TLX591). TLX591 is being developed as a PSMA-targeting antibody to be radiolabelled with a therapeutic radiosotope for the treatment of PSMA-expressing tumours, therefore this study has been designed to assess the safety and tolerability, pharmacokinetics, whole body biodistribution and radiation dosimetry of 177Lu-DOTA-TLX591.