CML-433 ASC2ESCALATE Trial in Progress: A Phase 2 Single-Arm Dose Escalation Study of Asciminib Monotherapy in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated With 1 Prior Tyrosine Kinase Inhibitor (TKI)

Abstract

TKI resistance/intolerance in patients with CML-CP represents a clinical challenge, with treatment failure rates of 50%-60% in second line (2L). Approved TKIs targeting the adenosine triphosphate (ATP)-binding site have a broad kinase target spectrum. Asciminib is the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), conferring high selectivity for ABL1/BCR::ABL1. The phase 1 dose-finding X2101 trial investigated asciminib doses of 80-200mg once daily (QD) and 10-200mg twice daily (BID); the maximum tolerated dose of asciminib was not reached and no differing safety signals were noted between patients receiving 200mg BID vs the total treatment population. Asciminib was recently approved in the US for patients with CML-CP after ≥2 TKIs at 80mg QD and 40mg BID and CML-CP with the T315I mutation at 200mg BID. Here, we present key features of the phase 2 ASC2ESCALATE trial. To evaluate the efficacy and safety of 2L asciminib in patients with CML-CP. starting at 80mg QD and escalating to 200mg QD or 200mg BID in patients who have not achieved response milestones. This is a phase 2, multicenter, open-label, single-arm dose-escalation study in the US (NCT05384587; not yet enrolling). Adult patients with CML-CP without the T315I mutation treated with 1 prior ATP-competitive TKI for ≥6 months who experienced treatment resistance or intolerance are eligible. All patients start with asciminib monotherapy 80mg QD. Doses will increase to 200mg QD in patients who have not achieved BCR::ABL1IS <1% at 6 months. Doses will increase from 80mg QD to 200mg QD or from 200mg QD to 200mg BID in patients who have not achieved major molecular response (MMR) at 12 months; dependent on investigator's clinical judgement, switch to treatment of choice with removal from study is allowed. Dose escalation considered only for those who experience no grade ≥3 toxicity or persistent grade 2 toxicity unresponsive to optimal management. Patients meeting response milestones at each timepoint will continue at their current dose. The primary endpoint is rate of MMR at 12 months. Secondary endpoints include additional efficacy outcomes at 3, 6, 18, and 24 months and safety measures.