A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP

Inclusion Criteria for treatment period:

Participants eligible for inclusion in this study must meet all of the following criteria:

• Male or female patients ≥ 18 years of age.

• Participants with CML-CP within 3 months of diagnosis.

• Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of Philadelphia chromosome

Documented chronic phase CML will meet all the below criteria (Hochhaus et al 2020):

• < 15% blasts in peripheral blood and bone marrow,

• < 30% blasts plus promyelocytes in peripheral blood and bone marrow,

• < 20% basophils in the peripheral blood,

• Platelet count ≥ 100 x 10^9/L (≥ 100,000/mm^3),

• No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Adequate end organ function as defined by:

• Total bilirubin < 3 x ULN; patients with Gilbert's syndrome may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN

• Creatinine clearance (CrCl) ≥ 30 mL/min as calculated using Cockcroft-Gault formula,

• Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis

• Participants must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization:

• Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min)

• Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min)

• Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl* ≥ 90 mL/min)

• For patients with mild to moderate renal impairment (CrCl* ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be ≥ LLN or corrected to within normal limits with supplements prior to randomization.

• *CrCl as calculated using Cockcroft-Gault formula

• Ability to provide written informed consent prior to any study related screening procedures being performed.

• Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening which is amenable to standardized Real time quantitative polymerase chain reaction (RQ-PCR) quantification.

Exclusion Criteria for Treatment period:

• Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea and/or anagrelide. Treatment with either imatinib, or nilotinib, or dasatinib or bosutinib for ≤2 weeks is allowed, but no other treatment with other tyrosine kinase inhibitors prior to randomization is permitted.

• Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).

• Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following:

• History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)

• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)

• QTc ≥ 450 ms (male patients), ≥460 ms (female patients) on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.

• Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

• Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia

• Concomitant medication(s) with a "Known risk of Torsades de Pointes" per www.crediblemeds.org/ that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.•Inability to determine the QTcF interval

• Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection; uncontrolled arterial or pulmonary hypertension, uncontrolled clinically significant hyperlipidemia). Please refer to Section 6.3.1

• History of significant congenital or acquired bleeding disorder unrelated to cancer.

• Major surgery within 4 weeks prior to study entry or who have not recovered from prior surgery.

• History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively

• History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.

• History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.

• Known hypersensitivity to the study treatment

Other protocol-defined Inclusion/exclusion criteria will apply.

Inclusion Criteria for optional TFR period:

Participants meeting the following additional criteria are not eligible to enter the TRI Period:

• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures

• A minimum of 5 years of study treatment up to maximum of 6 years of study treatment (i.e. participants are eligible to enter TFR any time between year 5 and year 6 of their study treatment

• Sustained MR 4.0 (BCR::ABL1 IS ≤0.01%) or better, assessed by central laboratory for at least 2 years (equivalent to 104 weeks) which includes MR 4.5 (BCR::ABL1 IS ≤0.0032%) for at least 1 year (equivalent to 52 weeks) immediately prior to entry into the TFR Period, with the 5 last consecutive RQ-PCR (every 12 weeks) assessments at/or below MR 4.5. Entry into TFR Period should be no later than 12 weeks from the last MR 4.5 RQ-PCR assessment

• Separate signed informed consent must be obtained prior to participation in the TFR Period

Exclusion Criteria for optional TFR period:

• Participants meeting the following additional criterion are not eligible for the inclusion in the optional TFR Period:

• Participants in the treatment re-initiation (TRI) Period cannot re-enter TFR for a second TFR attempt

Exclusion Criteria for Treatment Re-initiation (TRI) Period

Participants meeting the following additional criterion are not eligible to enter the TRI Period:

• In case of a pregnancy during the TFR Period, the pregnant woman must be discontinued upon loss of MMR (>0.1% BCR::ABL1 IS at a single assessment) and cannot enter the TRI Period

• Impaired cardiac function or cardiac repolarization abnormality

• Severe and/or uncontrolled concurrent medical disease that in the opinion of the Investigator could cause unacceptable safety risks or compromise compliance with the protocol