A Phase II clinical trial protocol for the ASC2ESCALATE study evaluating asciminib in chronic myeloid leukemia (CML) was recently published in Future Oncology. This ongoing, multicenter, single-arm, dose-escalation study is investigating asciminib as second-line and first-line therapy for patients with chronic phase CML (CML-CP). The trial is being conducted in the United States and is sponsored by Novartis Pharmaceuticals Corporation.
The primary purpose of the ASC2ESCALATE study is to determine the efficacy of asciminib in patients with CML-CP in the second-line setting. Secondary objectives include evaluating molecular response rates, progression-free survival, overall survival, and safety/tolerability. The study will also assess patient-reported outcomes, healthcare resource utilization, and characterize BCR::ABL1 gene mutations as exploratory endpoints.
The trial aims to enroll approximately 92 patients in the second-line cohort and 60-90 patients in the first-line cohort. For the second-line cohort, eligible patients must have CML-CP and meet criteria for warning, failure or intolerance to first-line tyrosine kinase inhibitor (TKI) therapy. Patients are excluded if they have received ≥2 prior ATP-binding site TKIs. For the first-line cohort, newly diagnosed CML-CP patients are eligible, including those treated with a prior TKI for ≤4 weeks. Key exclusion criteria for both cohorts include prior asciminib treatment, known second chronic phase CML after progression to accelerated/blast phase, history of hematopoietic stem cell transplant, and presence of the T315I mutation.
All patients will initiate treatment with asciminib 80 mg once daily. The protocol allows for dose escalation to 200 mg once daily at 6 months if BCR::ABL1IS >1% and to 200 mg twice daily at 12 months if major molecular response (MMR) is not achieved. The primary endpoint is the proportion of second-line patients achieving MMR at 12 months. The study is designed to demonstrate success if the lower limit of the 95% confidence interval for MMR rate exceeds 30%.
While efficacy results are not yet available for this ongoing trial, the study design is based on promising data from earlier asciminib studies. The Phase I dose-finding trial demonstrated asciminib could be effective and safe at doses up to 200 mg twice daily in heavily pretreated patients. In the Phase III ASCEMBL trial, asciminib showed superior efficacy compared to bosutinib in patients after ≥2 prior TKIs, with MMR rates of 25.5% vs 13.2% at 24 weeks. ASC2ESCALATE will be the first study to evaluate asciminib specifically in the second-line setting.
The dose-escalation strategy employed in this trial is supported by prior experience with other TKIs in CML. Studies of imatinib dose escalation have shown patients experiencing resistance can achieve durable responses with higher doses. The ENESTxtnd study found most patients who escalated nilotinib dosing due to suboptimal response were able to achieve MMR.
Some limitations of the ASC2ESCALATE study design include its single-arm nature and relatively small sample size, which may limit the ability to draw definitive conclusions or comparisons to other therapies. Additionally, the 24-month study duration may not be sufficient to fully assess long-term efficacy and safety outcomes.
The investigators conclude there is a strong rationale for evaluating asciminib earlier in the treatment course for CML-CP, given its unique mechanism of action and promising efficacy/safety profile demonstrated to date. They hypothesize that a dose-escalation approach may allow more patients to achieve optimal responses without switching therapies.
If successful, this trial could potentially expand the role of asciminib in CML treatment algorithms. Demonstrating efficacy in the second-line setting would provide an important new option for patients experiencing treatment failure or intolerance to first-line TKI therapy. The dose-escalation strategy, if proven effective and tolerable, could help optimize outcomes for individual patients. Additionally, positive results in newly diagnosed patients could support future investigation of asciminib as a first-line therapy.
However, it will be important to await the final efficacy and safety results before drawing conclusions about the potential clinical impact. Longer-term follow-up and comparisons to standard-of-care options in randomized trials may ultimately be needed to determine asciminib's optimal place in therapy. Nonetheless, the ASC2ESCALATE study represents an important step in further characterizing this novel targeted therapy for CML.
References
Atallah EL, Mauro MJ, Sasaki K, et al. Dose-escalation of second-line and first-line asciminib in chronic myeloid leukemia in chronic phase: the ASC2ESCALATE Phase II trial. Future Oncol. 2024;20(38):3065-3075. doi:10.1080/14796694.2024.2402680
