ASC2ESCALATE: A US Phase 2, Open-Label, Single-Arm, Dose-Escalation Study of Asciminib (ASC) Monotherapy in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) As Second-Line (2L) and First-Line (1L) Treatment

Adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) have increased survival in CML, although resistance and intolerance remain challenges, which often necessitate switch to another TKI. Many pts discontinue 1L treatment due to resistance/intolerance and switch to 2L therapy, to which resistance is typically higher. A need exists for effective, safe treatment options for pts in 1L and 2L. ASC is thefirst approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), with activity against most BCR::ABL1 kinase domain mutations conferring resistance to ATP-competitive TKIs, potentially providing a new early-line treatment option. ASC was first approved in the United States for pts with CML-CP after ≥2 TKIs at 80 mg once daily (QD) or 40 mg twice daily (BID) and for pts with CML-CP with the T315I mutation at 200 mg BID. A large, phase 1, dose-escalation trial (NCT02081378) demonstrated efficacy and tolerability of ASC across a broad range of dosages. Also, with >2 years of follow-up, ASC demonstrated superior efficacy and better safety and tolerability compared with bosutinib in pts with CML-CP without the T315I mutation after ≥2 prior TKIs in the phase 3 ASCEMBL study (NCT03106779). We describe the phase 2 ASC2ESCALATE trial investigating efficacy and safety of ASC with dose escalation in pts with CML-CP receiving ASC as their 2L or 1L therapy. This is a phase 2, open-label, multicenter, single-arm, dose-escalation study with sites in the United States (NCT05384587) (Figure). Pts receiving ASC as their 2L TKI must be adults with non-T315I CML-CP who discontinued their first ATP-competitive TKI for warning response ( BCR::ABL1IS >1%-10% after 6 months or >0.1%-1% after 12 months of 1L treatment), resistance ( BCR::ABL1IS >10% after 6-12 months or >1% or loss of major molecular response [MMR] after >12 months of 1L treatment), or intolerance (with BCR::ABL1IS >0.1% at screening). In addition to pts receiving ASC as their 2L TKI, a separate cohort of newly diagnosed pts will be included, and these pts may receive up to 4 weeks of prior treatment with imatinib or an approved second-generation TKI (Table). All pts will start treatment with ASC 80 mg QD. Pts achieving BCR::ABL1IS ≤1% at 6 months will continue at the same dose; pts not achieving BCR::ABL1IS ≤1% at 6 months will have their dose escalated to 200 mg QD. In pts not achieving MMR at 12 months, dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 m