Phase I study of <sup>225</sup>Ac-J591 for men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Scott T. Tagawa, Michael Sun, A. Oliver Sartor, Charlene Thomas, Sharon Singh, Mahelia Bissassar, Escarleth Fernandez, Muhammad Junaid Niaz, Benedict Ho, Shankar Vallabhajosula, John Babich, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Joseph Osborne, Neil Harrison Bander
Journal: Journal of Clinical Oncology (2021)

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 &gt;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 &lt; 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 &gt; 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 &gt; 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.