Asciminib As Initial Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)-H. Jean Khoury Cure CML Consortium Study

Abstract

Background: Although tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients with CML, there remains need for improvement as less than 50% achieve sustained MR4.5 by 10 years (sine qua non for treatment discontinuation) and approximately 40% need change of therapy within 5 years because of lack of efficacy or unacceptable toxicity. Asciminib is a potent allosteric inhibitor of BCR::ABL1, effective in vitro against BCR::ABL1 mutations that confer resistance to ABL-competitive tyrosine kinase inhibitors (TKIs). Asciminib has potential to combine with TKIs to prevent the emergence of resistant clones, potentially increasing the depth of molecular response in a greater number of patients compared with single-agent treatment. In a phase I study of asciminib, 48% of patients with CP-CML resistant to or intolerant of multiple prior TKIs achieved a major molecular response. The significant efficacy of asciminib in this setting suggests it might be more effective than other available options in achieving deep early responses in patients with newly diagnosed CML. Our goal in this study is to evaluate the role of asciminib in the treatment of patients with newly diagnosed CML-CP. Study Design and methods: This study is a multicenter phase 2, non-randomized open-label single-group study of asciminib in patients with newly diagnosed CP-CML (NCT05143840). The primary outcome is to evaluate the proportion of patients attaining MR4.5 within 12 months of therapy. In addition, patient reported outcomes will be collected at multiple timepoints. Patients will receive asciminib 40 mg orally twice daily. Peripheral blood BCR::ABL1 by RQ-PCR will be monitored in a central lab. Patients who do not achieved MR4.5 after 24 months of single agent asciminib will be offered the addition of nilotinib with the goal to attain MR4.5. In those instances, nilotinib will be started at 300 mg BID added to asciminib. Patients will discontinue study treatment if they experience disease progression, treatment failure according to ELN criteria or unacceptable toxicity. Patients who, after three years of asciminib +/- nilotinib, achieve sustained MR4.5 for at least 2 years may discontinue study treatment for an attempt at treatment-free remission. Sustained MR4.5 is defined as BCR::ABL1<0.0032% for approximately 2 years or more on at least 4 tests performed approximately 3 months apart. The primary objective of this study is to determine the rate of deep molecular response (DMR), defined as BCR::ABL1 <0.0032% IS by RQ-PCR at 12 months with asciminib compared to historical second generation TKI. With a total of 50 subjects, the study will have a 90% power to detect a 13.5% difference with an improvement of DMR at 12 months from 5% (based on historical experience with second generation TKIs used in frontline setting) to 18.5%. The exploratory endpoint of evaluating the rate of DMR after adding nilotinib at 24 months for patients not in DMR will be assessed at 36 months (after 12 months on combination therapy) and compared to the historical rate of 25% DMR with single agent nilotinib at 36 months. The study will have a 82% power to detect a 10% difference, 95% power to detect 15% difference and 99% power to detect a 20% difference.