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

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 to join the treatment period.

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.

Apart from the treatment period described above, the present study comprises an optional Treatment-Free Remission (TFR) Period enrolling consenting participants of the treatment period (receiving asciminib or IS-TKI) who will discontinue their randomized treatment if they meet per protocol eligibility criteria. The optional TFR Period will last at least 2 years to assess the feasibility of TFR and TFR outcomes following discontinuation of their randomized treatment (asciminib or IS-TKI).

In addition, during the TFR Period, participants who will lose major molecular response (MMR) must re-initiate treatment and will enter into a Treatment Reinitiation (TRI) Period.

During the treatment period, no crossover of study treatment across arms and no change of study treatment within the Investigator selected TKI will be allowed. For specifically participants who must transition into the TRI Period, at the time of treatment re-initiation: a) participants who were previously treated with asciminib will resume asciminib at the same dose prior to entry into TFR. b) participants who were on IS-TKI may either continue with the same study treatment they were randomized to and at the same dose prior to entry into TFR or may switch to asciminib with a starting dose of 80 mg QD.

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

Duration of study: The End of Study will occur 8 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.

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