Abstract CT122: Phase I dose-escalation study of prostate-specific membrane antigen (PSMA)-targeted alpha emitter 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC)
Authors: Tagawa Scott T. , Osborne Joseph , Thomas Charlene , Fernandez Escarleth , Niaz Muhammad J. , Vallabhajosula Shankar , Vlachostergios Panagiotis , Molina Ana M. , Sternberg Cora , Singh Sharon , Patel Amie , Tan Angela , Babich John , Nanus David M. , Ballman Karla , Bander Neil H. 
Published: September 2020

Abstract
Background: PSMA may be targeted by antibodies or small molecule ligands labeled with potent alpha emitters. Certain sites of PSMA expression such as salivary/lacrimal glands, kidneys, and small bowel are not accessible to antibodies such as J591. Following binding, immunoreactivity, and xenograft studies, we performed a first in human study of 225Ac-J591.
Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abiraterone/enzalutamide) and taxane chemotherapy (or unfit/refuse chemo) without limit of # prior therapies (including radium-223 or prior PSMA therapy) provided adequate organ function were eligible. Baseline 68Ga-PSMA11 PET was performed, but not used for eligibility. Initially single-subject cohorts were treated until transition to 3+3 with dose level 5 (the dose level predicted by historical J591 dosimetry to have moderate toxicity) with a single infusion of 225Ac-J591 (13.3 KBq/kg with planned escalation up to 93.3 KBq/kg). Dose-limiting toxicity (DLT) was defined as attributable grade 4 hematologic toxicity or grade 3/4 non-heme toxicity. Imaging, genomic, patient-reported outcomes, and immune correlates are included.
Results: In the dose-escalation phase, 22 men were treated on 7 dose levels; median age 72.5 (range 58-89), PSA 146.5 (4.8-7168.4); 82% with at least 2 prior potent AR pathway inhibitors, 64% chemo, 23% radium-223, 55% prior 177Lu-PSMA. 1 (4.5%) CALGB (Halabi) good prognostic risk, 10 (20.7%) intermediate, and 11 (50%) poor prognostic risk category. One of 6 subjects in cohort 6 (80 KBq/kg) had DLT (grade 4 anemia and platelets); no other subjects had any attributable grade &gt;2 non-hematologic or grade &gt;3 heme AE (including 0 of 6 at the highest dose level 93.3 KBq/Kg). Low grade temporary AE's include: 17 (77%) with fatigue, 11 (50%) pain flare, 11 (50%) nausea, 6 (27%) with Gr 1 xerostomia (5 of 6 with prior 177Lu-PSMA), 4 (18%) AST elevation. Despite the heavily pre-treated population including the majority with prior PSMA-TRT and no selection for PSMA expression, 14 (63.6%) with any PSA decline, 9 (40.9%) with &gt;50% PSA decline. Interestingly, 15 (68%) had initial PSA increase followed by subsequent decline from peak (delayed effect). With follow up ongoing 2 with response &gt; 1 year despite prior 177Lu-PSMA with correlative assays in process. Of 15 with paired baseline and 12-week CTC counts (CellSearch), 8 declined (45-100% decline), 4 remained undetectable, 3 increased.
Conclusions: PSMA-targeted alpha-emitter 225Ac utilizing intact antibody J591 is tolerable with early evidence of clinical activity including long-term responders in a pre-treated population. Correlative studies are in progress and enrollment into a Simon 2-stage expansion cohort has been initiated. Clinicaltrials.gov NCT03276572
Citation Format: Scott T. Tagawa, Joseph Osborne, Charlene Thomas, Escarleth Fernandez, Muhammad J. Niaz, Shankar Vallabhajosula, Panagiotis Vlachostergios, Ana M. Molina, Cora Sternberg, Sharon Singh, Amie Patel, Angela Tan, John Babich, David M. Nanus, Karla Ballman, Neil H. Bander. Phase I dose-escalation study of prostate-specific membrane antigen (PSMA)-targeted alpha emitter 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT122.