Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia

Lintuzumab-Ac255 is an humanized anti-CD33 antibody linked to Actinium-225 that delivers high-energy alpha-particles to tumor cells, leading to double-strand DNA breaks and cell death. This phase 1 study assessed the safety and efficacy of lintuzumab-Ac225 after CLAG-M salvage therapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Primary objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and safety profile. Using a 3+3 dose-escalation design, 21 patients were enrolled sequentially into 4 cohorts to receive a lintuzumab-Ac225 infusion (0.25-1.0 µCi/kg) 7 (+2) days after CLAG-M (days 1-6); 5 additional patients received the RP2D. Of 23 efficacy-evaluable patients, 86.7% had high-risk disease. The MTD was 1.0 µCi/kg; the RP2D was 0.75 µCi/kg. The most common grade 3/4 adverse events were febrile neutropenia (65.4%), decreased white blood cells (50%), and decreased neutrophil count (42.3%). The composite complete remission rates (CR/CR with incomplete count recovery) were 56.6% overall, 50% in patients with mutated TP53 , and 38.5% in prior venetoclax-treated patients. Measurable residual disease (MRD)-negativity occurred in 75% of 12 evaluable patients. Lintuzumab-Ac225 plus CLAG-M was well tolerated with expected, manageable toxicities, while yielding deep responses characterized by high rates of MRD-negativity including in high-risk R/R AML populations.