Background: ²²⁵Ac-lintuzumab consists of a radiometal that emits 4 α-particles linked to an anti-CD33 antibody. A phase I trial showed safety and efficacy of ²²⁵Ac-lintuzumab in relapsed AML. We are conducting a multicenter, phase I trial to determine the maximum tolerated dose (MTD), toxicity, and activity of fractionated-dose ²²⁵Ac-lintuzumab combined with LDAC. Methods: Patients ≥ 60 yrs with untreated AML not suitable for standard induction were eligible. Patients received LDAC 20 mg BID for 10 d every 4-6 wks for up to 12 cycles. During Cycle 1, 2 doses of ²²⁵Ac-lintuzumab were given one week apart, 4-7 d following LDAC. ²²⁵Ac doses were escalated using a 3+3 design. Results: Twelve patients (median age, 77 yrs; range, 68-87 yrs) were treated. Eight (67%) had prior myelodysplastic syndrome, for which 6 (75%) received hypomethylating agents (n = 5) or allogeneic stem cell transplant (n = 1). One (8%) had chronic myeloid leukemia in molecular remission prior to AML. Nine patients (75%) had intermediate-risk and 3 (25%) had poor-risk AML. Median CD33 expression was 74% (range, 45-100%). ²²⁵Ac-lintuzumab was given at 0.5 (n = 3), 1 (n = 6), or 1.5 (n = 3) μCi/kg/fraction. Up to 4 cycles were given, and 2 patients remain on therapy. DLT was seen in one patient at 1 µCi/kg/fraction who had grade 4 thrombocytopenia and marrow aplasia > 6 wks after therapy. Grade 3/4 toxicities included neutropenia (n = 2), thrombocytopenia (n = 3), febrile neutropenia (n = 6), pneumonia (n = 3), bacteremia (n = 1), cellulitis (n = 1), transient creatinine increase (n = 1), hypokalemia (n = 1), rectal hemorrhage (n = 1), and generalized weakness (n = 1). Six of 8 patients (75%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 68%; range, 34-100%). Five patients (63%) had blast reductions of ≥ 50%, but no remissions were observed to date. Median progression-free survival (PFS) was 2.4 mos (range, 1.3+-16.9 mos). Conclusions: Fractionated-dose ²²⁵Ac-linutuzmab can be combined safely with LDAC and has antileukemic activity. Accrual continues to define the MTD. Additional patients will be treated at the MTD to determine response rate, PFS, and OS. Clinical trial information: NCI-2014-01360, NCT01756677.