Phase I study of 225Ac-J591 for men with metastatic castration-resistant prostate cancer (mCRPC).

5015 Background: Antibodies and small molecule ligands target PSMA with different kinetics and biodistribution, with certain sites of PSMA expression such as salivary/lacrimal glands, kidneys, and small bowel less accessible to large antibodies. Alpha emitters such as 225 Ac have high potency, but short range. We report dose-escalation plus expansion cohort results of a first in human study of 225 Ac-J591. Methods: Men with progressive mCRPC following at least 1 potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and chemo (or unfit/refuse chemo) without limit of # prior therapies (including Ra-223 or prior 177 Lu-PSMA) provided adequate organ function were eligible. Baseline 68 Ga-PSMA11 PET was performed, but not used for eligibility. Dose-escalation was in single-subjects x4 followed by 3+3 with a single infusion of 225 Ac-J591 (13.3 KBq/kg with planned escalation up to 93.3 KBq/kg). Dose-limiting toxicity (DLT) was defined as attributable grade (Gr) 4 heme toxicity or Gr 3/4 non-heme tox. Imaging, genomic, patient-reported outcomes (PRO), and immune correlates embedded. Results: 32 men were treated with a single dose of 225 Ac-J591 on 7 dose levels with expansion at the highest dose level (n = 16). Median age 69.5 (range 52-89), PSA 149.1 (4.8-7168.4); 75% with >2 prior ARPI, 62.5% chemo, 28% Ra-223, 43.7% 177 Lu-PSMA. One (3.1%) CALGB (Halabi) good prognostic risk, 8 (25%) intermediate, and 23 (71.9%) poor risk. While PSMA uptake was not a prerequisite for treatment, of 28 with pre-treatment PSMA PET, none had tumor SUVmax < liver, 5 (17.8%) with tumor SUVmax 1-2.5x liver, 2 (7.2%) with tumor SUVmax 2.5-5x liver, and 21 (75%) with tumor SUVmax > 5x liver SUVmean. 1 of 6 in cohort 6 (80 KBq/kg) had DLT (Gr 4 anemia and platelets) with 0 of 6 at the highest dose level (93.3 KBq/Kg) and this dose was expanded. High Gr AEs were restricted to hematologic: In addition to DLT, 4 (12.5%) Gr 3 platelets and 2 (6.2%) with Gr 3 neutropenia. Non-heme AE’s were restricted to Gr 1/2 and included: 10 (31.2%) fatigue, 5 (15.6%) pain flare, 14 (43.7%) nausea, 8 (25%) with Gr 1 xerostomia (of which 5 received prior 177 Lu-PSMA), 12 (37.5%) AST elevation. Despite prior treatment including 177 Lu-PSMA and no selection for PSMA expression, 22 (68.7%) with any PSA decline, 12 (37.5%) with > 50% PSA decline. Of 21 with paired baseline and 12-wk CTC counts, 12 declined (5 converting from unfavorable to favorable and 5 converting detectable to 0), 5 remained 0, 4 increased. In the subset with PRO data, pain scores by BPI-SF tended to improve by wk 12. Following a single dose of 225 Ac-J591, median PFS 7.2 months [95% CI 4.6-NR], median OS 10.9 months [7.6-21.1]. Conclusions: PSMA-targeted alpha-emitter 225 Ac utilizing intact antibody J591 is tolerable with early evidence of clinical activity. Based upon these results, a follow up study [NCT04506567] testing multiple and fractionated dosing of 225 Ac-J591 is underway. Clinical trial information: NCT03276572.