Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (²²⁵Ac)-HuM195 (Anti-CD33) in Acute Myeloid Leukemia (AML).

HuM195, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity alone against AML. To increase the antibody’s potency and allow single cell killing, but avoid the nonspecific cytotoxicity associated with β-emitting isotopes, the α-emitter bismuth-213 (²¹³Bi) was initially conjugated to HuM195. In phase I and II trials, ²¹³Bi-HuM195 was capable of inducing remissions in AML after partial cytoreduction with cytarabine. Therapeutic applications of ²¹³Bi, however, are limited by its 46-minute half-life. The isotope generator, ²²⁵Ac, a radiometal which yields 4 α-emitting isotopes and has a 10-day half life, can be conjugated to a variety of antibodies using the bifunctional chelate DOTA-SCN. ²²⁵Ac-containing immunoconjugates can kill in vitro at radioactivity doses 1000 times lower than ²¹³Bi analogs and prolong survival of animals in several xenograft models (McDevitt et al. Science 2001). We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of such an in vivo isotope generator using ²²⁵Ac-HuM195. Seven patients (median age, 61 years; range, 46–77) with relapsed (n=3) or refractory (n=4) AML were treated to date. Three had poor-risk cytogenetics. Patients received a single infusion of ²²⁵Ac-HuM195 at doses of 0.5 (n=3), 1 (n=3), or 2 μCi/kg (n=1). Total administered activities of ²²⁵Ac ranged from 23–170 μCi, and HuM195 doses ranged from 1–1.9 mg. No acute toxicities were seen. One of 2 patients evaluable for neutropenia developed an ANC <500/μL. Grade 4 thrombocytopenia was seen in both patients who were evaluable. Among 4 evaluable patients, resolution of grade 4 leukopenia occurred after a median of 10 days (range, 0–26). Three patients had neutropenic fever. One patient with a prior history of fungal hepatitis developed a grade 3 elevation in alkaline phosphate lasting 6 days after receiving 1 μCi/kg of ²²⁵Ac-HuM195. No other grade 3–4 extramedullary toxicities were observed. No evidence of radiation nephritis has been seen, with follow-up to 10 months. To determine pharmacokinetics over 10 days following treatment, we analyzed plasma by gamma counting at 2 energy windows for 2 of the ²²⁵Ac daughters, francium-221 (²²¹Fr) and ²¹³Bi. Two phase elimination kinetics were seen with mean plasma half-lives t_1/2-α and t_1/2-β of 2.9 and 54 hours, respectively. These results are similar to other HuM195 constructs containing long-lived radioisotopes. Antileukemic effects included elimination of peripheral blood blasts in 3 of 6 evaluable patients and dose-related reductions of >33% of BM blasts in 4 patients at 4 weeks following treatment. One patient had 3% bone marrow blasts after therapy. This is the first study to show that targeted therapy with an in vivo α-particle generator is feasible in humans. ²²⁵Ac-HuM195 appears safe and has antileukemic activity. Accrual to this trial continues.