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

The study is designed to compare the efficacy of asciminib 80 mg QD versus Investigator selected Tyrosine Kinase Inhibitor (TKI) for the treatment of newly diagnosed, previously untreated patients with Ph+ CML-CP. The Investigator selected TKI will be one of the following treatment options for first-line treatment of CML-CP - imatinib 400 mg QD or nilotinib 300 mg BID or dasatinib 100 mg QD or bosutinib 400 mg QD.

This study is a phase III, multi-center, open-label, randomized study of oral asciminib 80 mg QD versus Investigator selected TKI (imatinib, nilotinib, dasatinib, or bosutinib) in adult patients with newly diagnosed Ph+ CML-CP. All comparator TKIs will be made available, unless not permitted by local regulations or local Health Authority, or not approved for the treatment of CML in the country.

Approximately 402 patients will be randomized in a 1:1 ratio to asciminib and Investigator selected TKI.

Randomization will be stratified based on the following two stratification factors:

* ELTS score (low versus intermediate versus high)
* Pre-randomization selected TKI (imatinib versus 2G TKI (nilotinib or dasatinib or bosutinib)).

Prior to randomization, the Investigator, in consultation with the patient, considering the current treatment paradigm and patient characteristics and comorbidities, will make a selection of preference for imatinib or 2G TKI (nilotinib or dasatinib or bosutinib) if the patient is randomized to the comparator arm. The stratified randomization based on these two stratification factors will help to achieve a balance across the treatment arms for the possible comorbidities and baseline characteristics of patients enrolled in the study.

To further ensure that the distribution of patients, between imatinib and 2G TKIs (nilotinib or dasatinib or bosutinib), in the Investigator selected TKI arm is reflective of the use of these agents in clinical practice, the enrollment into the strata of imatinib versus 2G TKI (nilotinib or dasatinib or bosutinib) based on the pre-randomization selection of TKI will be managed by Interactive Response Technology to be approximately 50% versus 50%.

Treatment arms: The study will have 2 treatment arms:

* Arm 1: asciminib 80 mg QD under fasting conditions
* Arm 2: Investigator selected TKI that will include one of the below treatments:
* Imatinib 400 mg QD administered with food
* Nilotinib 300 mg BID administered under fasting conditions
* Dasatinib 100 mg QD administered with or without meal
* Bosutinib 400 mg QD administered with food.

No crossover of study treatment across arms and no change of study treatment within the Investigator selected TKI will be allowed.

Duration of Study treatment: Patients on the study will continue to receive the assigned treatment until the End of Study, or until premature discontinuation due to treatment failure, disease progression or intolerance or due to Investigator or participant decision.

Duration of study: The End of Study will occur 5 years from the last patient first treatment in the study. Patients who discontinue study treatment prematurely due to any reason, will be followed up for survival and progression (to AP/BC) until the End of Study.

Eligibility Criteria:
Inclusion Criteria:

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:

* 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.