Asciminib as Initial Therapy With Addition of Lower Dose Tyrosine Kinase Inhibitors for Patients With Chronic Myeloid Leukemia Who do Not Achieve Optimal Response or a Deep Molecular Remission (ALERT CML)

Summary

This study is a multicenter Phase 2, non-randomized, open-label single-group frontline study administering asciminib in patients with newly diagnosed Chronic Myeloid Leukemia-Chronic Phase (CML-CP). The aim of this study is to evaluate the efficacy and safety of asciminib in newly diagnosed CML-CP. Patients will receive asciminib 80 mg orally once daily during the single asciminib phase. Response is determined by PCR (polymerase chain reaction) blood test during the study. Patients who have not achieved a response after 24 months (but no later than 36 months) of single agent asciminib will be offered the addition of a low dose tyrosine kinase inhibitor (low-TKI) namely dasatinib, imatinib, or nilotinib at the investigator's discretion. The following doses of the TKIs will be used: 1. Dasatinib 50 mg daily 2. Imatinib 300 mg daily 3. Nilotinib 300 mg daily Patients will discontinue study treatment if they experience disease progression, or unacceptable toxicity.

Detailed description

Asciminib is a potent allosteric inhibitor of BCR-ABL1 oncogene that confers resistance to tyrosine kinase inhibitors (TKIs). Asciminib has potential to combine with TKIs to prevent the emergence of BCR-ABL1 mutations, increasing the depth of molecular response in CML-CP patients. Anticipated enrollment is 50 subjects across sites. Primary Objective: To estimate the proportion of patients with previously untreated CML-CP who attain BCR::ABL1 \<0.01% (MR4.0) IS by RQ-PCR with single agent asciminib therapy. Secondary Objectives: 1. To estimate the proportion of patients achieving molecular response at specific time points 2. To estimate the time to molecular response 3. To evaluate the duration of hematologic and molecular response to asciminib 4. To define the time to progression and overall survival for patients with CML in early CP treated with asciminib 5. To evaluate the safety profile of asciminib in patients with CML-CP 6. To evaluate the development of ABL mutations for patients with CML in early CP treated with asciminib 7. To analyze differences in response rates and in prognosis within different risk groups and patient characteristics 8. To evaluate patient-reported outcomes in patients with CML receiving asciminib 9. To investigate treatment-free remission after at least 2 years of sustained deep molecular remission for patients receiving single agent asciminib or combination (asciminib + low TKI) Exploratory objectives: 1. To evaluate the safety and efficacy of concomitant use of low TKI with asciminib in patients who have not achieved MR4.5. 2. To evaluate the rate of successful treatment discontinuation for patients using the combination of asciminib and low TKI 3. To evaluate the safety and efficacy of concomitant use of lowTKI with asciminib in patients who experience treatment failure at any time with single agent asciminib 4. To evaluate the safety and efficacy of concomitant use of lowTKI with asciminib in patients who have not achieved an optimal response after 12 months of single agent asciminib 5. Evaluate the role of Digital droplet PCR (ddPCR) in predicting TFR 6. Evaluating the correlation between the gene expression signature of patients and the chances of achieving MMR and DMR 7. Evaluate whether B, NK and T cells DNA mutation and RNA expression are relevant and whether they can predict response in patients with CML using single cell analysis. Subjects must meet all inclusion criteria and none of the exclusion criteria of the study. No enrollment waivers will be granted. After successful screening, subjects will be enrolled and treatment will start within 7 days of enrollment. Eligible subjects will begin asciminib on cycle 1 day 1 of the trial. After 2 years (but no later than 3 years), subjects will be offered the addition of taking nilotinib, dasatinib, or imatinib with asciminib if a molecular response is not met (PCR blood test). Duration of each participant is expected to take approximately 5 years on treatment and up to a total of 8 years if attempting treatment free remission. Regimen Description Asciminib 80 mg Oral Once a day 4 weeks (28 days) Nilotinib 300 mg\* Oral Once a day 4 weeks (28 days) Dasatinib 50 mg\* Oral Once a day 4 weeks (28 days) Imatinib 300 mg\* Oral Once a day 4 weeks (28 days) \*Nilotinib, dasatinib, or imatinib will be taken if indicated. Dose levels and dose modifications of the study drugs will be made per protocol.

Arms & interventions

• DrugSingle Agent Asciminib

  taken orally once a day starting cycle 1 day 1 for up to 24 months during the single agent asciminib phase. Asciminib is a potent allosteric inhibitor of BCR::ABL1.

• Combination ProductLow TKI

  Low dose tyrosine kinase inhibitor (lowTKI) (dasatinib 50 mg daily or imatinib 300 mg daily or nilotinib 300 mg daily) at investigators discretion, may be added to asciminib in the following situations: * Patients who have treatment failure at any time based on ELN criteria (Appendix 7) * Patients who have a warning response after 12 months of single agent asciminib based on ELN criteria (Appendix 7) * Patients who have not achieved MR4.5 after 24 months, but no later than 36 months, of single agent asciminib.

• OtherElective Free Treatment

  Once central eligibility has been obtained the patient should discontinue asciminib and if applicable lowTKI within 14 days.

Outcome measures

Eligibility criteria