Background: PSMA is overexpressed by most prostate cancers and can be successfully targeted by both antibodies (mAb) and small molecule ligands (SML), each with overlapping and distinct binding sites, kinetics, and biodistributions [Kratochwil Sem Nuc Med 2019]. mAbs are larger, with longer circulating times resulting in greater exposure to bone marrow, but lesser access to PSMA expression on luminal tissue (e.g. salivary glands, small bowel, and kidney). In contrast, SMLs are rapidly excreted via kidneys and readily diffuse to all PSMA-expressing sites. Toxicities of 177Lu vary with these differences in biodistribution (e.g. more hematologic toxicity with mAb, more xerostomia and nausea with SML, p < 0.001)[Niaz AUA 2020]. Alpha emitting isotopes have shorter ranges but high potency compared to beta emitters which have longer ranges, but lower linear energy transfer. In preclinical models, the combination of mAb plus SML has demonstrated additive binding in LNCaP, CWR22Rv1, and PC3/PSMA PC cell lines, and synergistic uptake of 177Lu-mAb plus 177Lu-SML in xenograft models. We developed a phase I/II study to test our hypothesis that concomitant mAb and SML targeting, plus the combination of alpha (225Ac) and beta emitters (177Lu), may offer complementary benefits in a safe and effective manner. Methods: Key eligibility criteria include progressive mCRPC (PCWG3), at least 1 prior AR pathway inhibitor and taxane chemotherapy (or ineligible/refused), and adequate organ function and performance status. PSMA PET/CT must have at least 1 lesion with SUVmax > liver SUV. Prior PSMA-based therapy with radioisotopes is not allowed. 177Lu-PSMA-I&T (PNT2002) will be administered as in the phase III SPLASH study (6.8 GBq q8w for up to 2 doses). The phase I includes up to two dose-escalation cohorts of concurrent 225Ac-J591 (30 & 40 KBq/Kg q8w x2) in a modified 3+3 schema. All subjects undergo 177Lu SPECT on Day 8 after each dose. The primary objective of the Phase I study is to determine the dose-limiting toxicity and recommended phase II dose (RP2D) for this combination. Primary objective of the Phase II study is to assess the proportion of patients with > 50% PSA decline after treatment. Secondary objectives include radiographic response rate (PCWG3-modified RECIST 1.1), biochemical and radiographic progression-free survival, overall survival, safety (CTCAE 5.0), CTC count changes and conversions, and patient-reported outcomes (FACT-P, BPI-SF, EQ-5D). Exploratory objectives include pre- and post-treatment PSMA-based imaging changes, effects of PSMA radionuclides on the microbiome, relationship between genomic alterations and response, and relationship between PSMA PET/CT results and outcome. The phase I was activated at Weill Cornell Medicine in May 2021. Following determination of the RP2D, a multicenter phase II is planned at Prostate Cancer Clinical Trials Consortium (PCCTC) in 2022. Clinical trial information: 04886986.