Final results of a first-in-human study of the MC1R-targeting radiopharmaceutical ²²⁵ actinium MTI-201 ( ²²⁵ Ac-MTI-201) in metastatic uveal melanoma (mUM).

3099 Background: Prognosis in mUM is poor with limited efficacy of currently available therapies. The melanocortin-1 receptor (MC1R) is an attractive target for radiopharmaceutical therapy given high expression in UM. 225 Ac-MTI-201 is a novel alpha particle emitting MC1R bound radiopharmaceutical with high biostability, affinity, and MC1R-specific cytotoxicity with defined dosimetry and pharmacokinetics in pre-clinical studies. Methods: In this first-in-human study (NCT05496686) of a single IV dose of 225 Ac-MTI-201, we enrolled mUM patients (pts) who had disease progression on at least 1 prior therapy. Pts had adequate organ and functional status; prior radiotherapy to >25% of bone marrow was exclusionary. The primary objective was safety and toxicity of 225 Ac-MTI-201 with secondary endpoints of pharmacokinetics (PK) and clearance of 225 Ac-MTI-201, response rate, progression-free survival (PFS), and overall survival (OS). Up to 12 dose levels [from 4.7 microcurie (µCi) to 1327 µCi] for 225 Ac-MTI-201 were planned per a modified continual re-assessment method (CRM) with a cohort size of one based on dose limiting toxicity (DLT) assessment within 28 days of drug administration using CTCAE v5.0. Response was assessed by RECIST 1.1. Results: Sixteen pts (8 male, 8 female), median age 63 years (43, 84) have been treated. Median number of prior systemic regimens was 2 (0,4), 8 pts had prior liver directed treatment. Dose of 225 Ac-MTI-201 was escalated to level 6 (152 µCi) when one DLT (G4 thrombocytopenia and G4 neutropenia) was observed requiring de-escalation per CRM. A second DLT (G4 neutropenia) at level 5 (76 µCi) required expansions at levels 4 (38 µCi; n=5) and 5 (n=6) where all remaining pts were treated without further DLT with 1 pt currently pending final DLT assessment. Adverse events (AEs) were mostly G1-2 including leucopenia, lymphopenia, neutropenia, thrombocytopenia, anemia, nausea, fatigue and ↑ AST. Reversible myelosuppression [lymphopenia (7), neutropenia (5), thrombocytopenia (2)] was the most common > G3 AE. No non-hematological DLT was seen. Best response was stable disease (4/15; 27%); seen at dose levels 4 and 5. The median PFS was 2.30 months (95% CI: 1.84, 3.65); 6-month PFS was 0.07 (95% CI: 0.0, 0.26) and 12-month OS was 0.39 (95% CI: 0.13, 0.64). Median distribution phase half-life (n=15) was 6.19 minutes followed by a slower median elimination phase half-life of 74.06 minutes with significant positive correlation between fast and slow half-lives (Spearman = 0.696, p= 0.0039), independent of dose level. Conclusions: Single dose administration of 225 Ac-MTI-201 with dose escalation to 76 µCi appears safe and feasible in mUM. Disease stability in this difficult to treat population is encouraging and a multi-dose study of 225 Ac-MTI-201 in mUM is planned pending final pt DLT assessment. 225 Ac-MTI-201 has Orphan Drug designation for mUM. Clinical trial information: NCT05496686 .