CML-427 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 the T315I Mutation

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/intolerance to TKIs. Patients with CML who progress after successive lines of therapy have poor outcomes, and well-defined treatments for patients beyond second-line therapy are lacking. Additionally, patients with CML harboring the T315I mutation have limited treatment options because this mutation confers resistance to most ATP-binding TKIs. Asciminib is a recently approved, BCR::ABL1 inhibitor that targets the ABL1 myristoyl pocket. 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 the T315I mutation have been demonstrated in a large phase I trial (MMR at 6 months, 25%). We present the enrolling phase IIIb Asciminib in Monotherapy 4CML (AIM4CML) trial, further assessing asciminib efficacy and safety and exploring a once-daily (QD) dose. Objective: To evaluate the efficacy and safety of asciminib 80mg QD and 40mg twice daily (BID) in patients with CML-CP without the T315I mutation treated with ≥2 prior TKIs and 200mg BID in patients with the T315I mutation 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 the T315I mutation treated with ≥2 or ≥1 TKIs, respectively, with failure/intolerance to their most recent therapy are eligible. Baseline mutation testing to confirm historical T315I mutation status and ensure patients have not acquired new kinase domain mutations is required for all eligible patients. Interventions: Patients without a detected T315I mutation will be randomized to receive asciminib 80mg QD or 40mg BID; patients with the T315I mutation will receive asciminib 200mg BID. End of study treatment is 72 weeks after the last patient receives the first dose, or upon premature discontinuation. Main Outcome Measures: Adverse events (AEs), serious AEs, and laboratory test results for 24 weeks are primary endpoints, with additional safety and efficacy secondary endpoints.