Background: ATP–competitive TKIs extend life expectancy in CML; yet up to 40% of newly diagnosed pts with CML-CP stop first-line (1L) therapy by 5 years due to resistance or intolerance and switch to second-line (2L) therapy. There is also an unmet need to overcome high rates of resistance in 2L. Studies show some pts with resistance achieve responses with higher doses of TKIs, while use of another second-generation (2G) TKI may not clinically benefit pts with resistance to a 2G TKI. Asciminib is the 1^st BCR:ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), giving it activity against most BCR:ABL1 mutations imparting resistance to ATP-competitive TKIs. Asciminib was 1^st approved in the US for patients with CML-CP after ≥2 TKIs at 80 mg once daily (QD) and 40 mg twice daily (BID) and CML-CP with the T315I mutation at 200 mg BID. In the phase 3 ASCEMBL study, asciminib 40 mg BID showed superior efficacy vs bosutinib 500 mg QD in pts with CML-CP after ≥2 prior TKIs at weeks 24 (major molecular response [MMR], 25.5% vs 13.2%) and 96 (MMR, 37.6% vs 15.8%) and favorable tolerability with > 2 years’ follow-up. The phase 1 dose-finding X2101 trial investigated asciminib doses of 80-200 mg QD and 10-200 mg BID; the maximum tolerated dose of asciminib was not reached and no differing safety signals were noted in patients receiving 200 mg BID vs the total treatment population. Here, we describe the phase 2 ASC2ESCALATE trial investigating efficacy and safety of 2L asciminib with dose escalation in pts with CML-CP (NCT05384587). Methods: This is a phase 2, open-label, multicenter, single-arm, dose-escalation study in the US. Adults with CML-CP without the T315I mutation with treatment resistance/failure (BCR:ABL1^IS> 10% with 6-12 months of 1L treatment or > 1% with > 12 months of 1L treatment ) or intolerance (BCR:ABL1^IS> 0.1%) with ≥6 months of treatment with 1 prior ATP-competitive TKI are eligible. All pts start treatment with asciminib 80 mg QD. For pts not achieving BCR:ABL1^IS≤1% at 6 months, dose will be escalated to 200 mg QD if pts do not have grade ≥3 or persistent grade 2 toxicity refractory to optimal management. For those without MMR at 12 months, either dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 mg BID will occur or pts can be switched to an investigator’s agent of choice and taken off study treatment. Pts achieving MMR at 12 months will continue asciminib at their current dose. Pts continuing to derive clinical benefit from asciminib per investigator assessment may receive post-trial access. Recruitment for this study began August 2022 with an estimated enrollment of 92 pts with CML-CP across ≈40 sites. The primary endpoint is MMR at 12 months. Secondary endpoints include additional efficacy outcomes at 3, 6, 18, and 24 months and safety measures. Clinical trial information: NCT05384587.