CUPID ( ⁶⁴ Cu-TLX592 phase I PK, biodistribution and dosimetry): A proof-of-concept study of TLX592-targeted alpha therapy in prostate cancer.

177 Background: Antibody-based PSMA-targeting therapies have potential to overcome limitations of small molecule approaches such as undesirable off-target side effects. TLX592 utilizes RADmAb technology engineered to optimize clearance rates while retaining advantages of antibody-based approaches including high target selectivity & rapid internalization. 225 Ac is a high energy emitter with a short path length. 225 Ac-PSMA-RADmAb is a "next generation" targeted alpha therapy for patients with prostate cancer (PC) who progress after 177 Lu-based therapy. We report preliminary results from an open-label, first-in-human mass dose escalation study of TLX592 in patients with advanced PC. To demonstrate proof-of-targeting, copper-64 ( 64 Cu), detectable by PET, was used as a surrogate for 225 Ac. Methods: 11 patients with PC confirmed with PSMA imaging as either oligometastatic (≤5 metastatic lesions; Groups 1-3, dose escalation) or higher tumor burden (≥10 metastatic lesions; Group 4) were assigned to the following: 1) 300 MBq, 2mg 64 Cu-TLX592 (n=3); 2) 300 MBq, 2mg 64 Cu-TLX592+8mg unlabeled TLX592 (10mg mass dose; n=3); 3) 300 MBq, 2mg 64 Cu-TLX592+18mg unlabeled TLX592 (20mg mass dose; n=2); or 4) 300 MBq, 2mg 64 Cu-TLX592+18mg unlabeled TLX592 (20mg mass dose, based on dose escalation results; n=3). PET/CT scans were performed 1h±5, 4±0.5h, & 20±4h after infusion for Groups 1-3 & 4h±0.5h, 20±3h & 48±4h after infusion for Group 4. Blood samples were collected before each imaging period, & vital signs were collected before infusion, after infusion, 1h after infusion, & prior to each imaging period. The primary endpoint was tumor-to-healthy tissue SUV & residence times. Secondary endpoints included safety assessments & absorbed radiation doses. Results: TLX592 blood clearance was more rapid than TLX591 (T ½ =19.86+1.96, T ½ =33.65+11.04h, resp.) with similar organ uptake. TLX592 circulating levels increased with mass dose. Whole-body effective dose (mean±SD mSv/MBq) was 0.043±0.007 & 0.042±0.002 in Groups 3 & 4, resp. Residence times for Groups 3 & 4 are shown (Table). At 20h, TLX592 uptake in bone lesions in Group 4 correlated with 68 Ga-PSMA-11 uptake (r=.756, P =.003). No serious adverse events were observed. Conclusions: Preliminary results demonstrate successful proof-of-concept of RADmAb technology, intended for use with therapeutic alpha-emitting radionuclides. Rapid antibody clearance has potential to minimize radiation exposure & augment the safety & tolerability profile of antibody-based therapies. Clinical trial information: NCT04726033 . Residence times (mean±SD) MBq.hr.MBq -1 . Source Organ Group 3 Group 4 Kidneys 0.305±0.059 0.370±0.064 Liver 5.440±1.188 5.443±0.771 Lungs 0.890±0.139 1.227±0.184 Salivary glands 0.005±0.001 0.006±0.003 Bone/red marrow 0.576±0.424 0.513±0.218 Spleen 0.444±0.104 0.470±0.201 Remainder of body 7.615±0.049 9.990±0.448