CML-375: AIM4CML Trial in Progress: A Phase IIIb Study of Asciminib Monotherapy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) with and without T315I Mutations

Context: Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site of BCR-ABL1 are effective treatments for many patients with CML; however, a substantial number of patients experience resistance or intolerance to TKIs. Patients with CML who progress after successive lines of therapy have poor outcomes, and there is a lack of well-defined treatments for patients beyond second-line therapy. Additionally, patients with CML harboring T315I mutations have limited treatment options because this mutation confers resistance to most ATP-binding TKIs. A need remains for an effective CML treatment with a novel mechanism of action. The investigational drug asciminib is a potent first-in-class BCR-ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP). In the phase III ASCEMBL trial, asciminib demonstrated efficacy and tolerability in patients previously treated with ≥2 TKIs (major molecular response [MMR] at 24 weeks: asciminib, 25.5%; bosutinib, 13.2%). Efficacy and safety of asciminib in patients with T315I mutations have been demonstrated as part of a large phase I trial (MMR at 6 months: with T315I, 25%). We present the enrolling phase IIIb Asciminib in Monotherapy 4CML (AIM4CML) trial, designed to further assess asciminib efficacy and safety and explore a once-daily (QD) dosing regimen. Objective: To evaluate the efficacy and safety of asciminib 80 mg QD and 40 mg twice daily (BID) in patients with CML-CP without T315I mutations treated with ≥2 prior TKIs and 200 mg BID in patients with T315I mutations treated with ≥1 prior TKI. Design: This is a multicenter, open-label, phase IIIb study currently enrolling patients in the United States (NCT04666259). Adult patients with CML-CP without or with T315I mutations treated with ≥2 or ≥1 TKIs, respectively, with failure of or intolerance to their most recent therapy and Eastern Cooperative Oncology Group performance status of 0–2 are eligible. Interventions: Patients without detected T315I mutations will be randomized to receive asciminib 80 mg QD or 40 mg BID; patients with T315I mutations will receive asciminib 200 mg BID. Main Outcome Measures: Adverse events (AEs), serious AEs, and laboratory evaluation for 24 weeks are primary endpoints, with additional safety and efficacy secondary endpoints.