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)
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.
• Age ≥18 years old
• Willing and able to give informed consent
• Newly diagnosed with CML in chronic phase within 6 months from confirmed diagnosis via bone marrow biopsy/aspirate and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR::ABL1 protein. Subtype classification whether b3a2 (e14a2) or b2a2 (e13a2) is not required for study eligibility.
• Minimal prior CML therapy with a TKI for less than or equal to 30 days. Treatment with hydroxyurea, busulfan, anagrelide or other non-specific chemotherapy agents is allowed with no time restrictions within the eligible time from diagnosis.
• ECOG performance status 0-2 (appendix 1)
• Adequate organ function:
‣ AST and ALT \< 3 times the institutional upper limit of normal (ULN)
⁃ eGFR ≥ 30 mL/min as calculated using the 2021 chronic kidney disease epidemiology (CKD-EPI) creatinine equation (https://www.kidney.org/professionals/kdoqi/gfr\_calculator)
⁃ Total bilirubin \< 1.5 times the institutional ULN or \< 3.0 x the institutional ULN with Gilbert Syndrome (unless direct bilirubin is within normal limits)
• Adequately controlled blood pressure, defined as systolic blood pressure of \<140 mmHq and diastolic of \<90 mmHg, at the time of enrollment.
• Lipase ≤ 1.5 x ULN. For lipase \> ULN - ≤ 1.5 x ULN, value should be considered not clinically significant and not associated with risk factors for acute pancreatitis.
• Creatine phosphokinase \< 2.5 x ULN
⁃ Female patients must meet one of the following:
• Postmenopausal for at least one year before the screening visit,
∙ Surgically sterile
∙ If they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug,
∙ Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
∙ Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable contraception methods.)
⁃ Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:
• Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose
∙ Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
∙ Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.)