A Study to Investigate Tolerability and Efficacy of Asciminib (Oral) Versus Nilotinib (Oral) in Adult Participants (≥18 Years of Age) With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP)

Prior treatment

• 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.
• Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for a period of time after stopping study medication.
• 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).
• Major surgery within 4 weeks prior to study entry or patients 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.

Other illness

• Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is positive, HBV-DNA evaluation will be carried out at screening. A patient having positive HBV-DNA will not be enrolled in the study. Also, a patient with positive HBsAg will not be enrolled in the study. HCV Ab testing will also be performed at screening. For details on the criteria see Appendix 4.
• History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
• Known hypersensitivity to the study treatment.
• History of significant congenital or acquired bleeding disorder unrelated to cancer.
• History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.

Lab values

• Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following: • History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment. • 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). • QTcF ≥ 450 ms on the average of three serial baseline ECG (using the QTcF formula). If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF. • 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 crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study treatment by safe alternative medication. • Inability to determine the QTcF interval.

Other

• Pregnant or nursing (lactating) women
• Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).

• Signed informed consent must be obtained prior to participation in the study.
• Male or female patients ≥ 18 years of age
• Patients with CML-CP within 3 months of diagnosis
• Diagnosis of CML-CP (European Leukemia Network [ELN] 2020 criteria) with cytogenetic confirmation of the Philadelphia (Ph) chromosome. A cryptic Ph chromosome should be confirmed by metaphase Fluorescence in situ Hybridization (FISH) •Documented chronic phase CML will meet all the below criteria (Baccarani et al 2013): •< 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 (PLT) count ≥ 100 x 109/L (≥ 100,000/mm3) •No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.
• Evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2] which is amenable to standardized RQ-PCR quantification by the central laboratory assessment. However, if a local qualitative assay, validated according to local regulation, from an accredited local laboratory has confirmed evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2], these results can be used for eligibility if the central Real Time Quantitative Polymerase Chain Reaction (RQ-PCR) results arrived are not available at the time of randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate end organ function as defined by: •Total bilirubin (TBL) < 3 x Upper Limit of Normal (ULN); patients with Gilbert’s syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN, •Creatinine Clearance (CrCl) ≥ 30 milliliters per minute (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.
• Patients 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 within normal limits or corrected to within normal limits with supplements prior to randomization. *CrCl as calculated using Cockcroft-Gault formula. ** pseudohyperkaliemia in case of thrombocytosis is not an exclusion criterion