1. Signed informed consent must be obtained prior to participation in the study

2. CML-CP, no previous AP or BC
3. ≥ 18 years of age
4. ECOG performance status of 0, 1, or 2
5. Adequate end organ function within 14 days before the first dose of asciminib treatment.
Patients with mild to moderate renal and hepatic impairment are eligible if:
 Total bilirubin ≤ 3.0 x ULN without AST/ALT increase
 Aspartate transaminase (AST) ≤ 5.0 x ULN
 Alanine transaminase (ALT) ≤ 5.0 x ULN
 Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN and ≤ 1.5 x ULN, value
should be considered not clinically significant and not associated with risk
factors for acute pancreatitis
 Alkaline phosphatase ≤ 2.5 x ULN
 Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft-Gault formula
Criteria #6 and 7 are specific to the 2L patient cohort
6. Warning or failure (according to 2020 ELN Recommendations; Hochhaus et al) to 1L TKI
therapy at the time of screening
a. Warning is defined as:
i. Six months after the initiation of treatment: BCR-ABL1IS >1-10%
ii. Twelve months after the initiation of treatment: BCR-ABL1IS >0.1-1%
b. Treatment failure/resistance to 1L TKI is defined as:
i. BCR-ABL1IS >10% if 1L treatment duration between 6 and 12 months
ii. BCR-ABL1IS >1% if 1L treatment longer than 12 months
iii. Beyond 12 months after the initiation of treatment: loss of MMR
7. Treatment intolerance to 1L TKI,
a. BCR-ABL1IS > 0.1% at screening
b. Intolerance is defined as:
i. Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while
on therapy, or with persistent grade 2 toxicity, unresponsive to optimal
management, including dose adjustments (unless dose reduction is not
considered in the best interest of the patient if response is already
suboptimal)
ii. Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute
neutrophil count [ANC] or platelets) while on therapy that is recurrent
after dose reduction to the lowest doses recommended by manufacturer
Criteria #8 is specific to the 1L patient cohort
8. Patients with newly diagnosed CML-CP (treatment with a prior TKI (imatinib, or
nilotinib, or dasatinib or bosutinib) for ≤ 4 weeks is allowed)

1. Previous treatment
a. With 2 or more ATP-binding site TKIs (for 2L patient cohort)
b. More than 4 weeks with 1 ATP-binding site TKIs (for 1L patient cohort)
2. Previous treatment with asciminib
3. Known presence of the T315I mutation at any time prior to study entry
4. Known second chronic phase of CML after previous progression to AP/BC
5. Previous treatment with a hematopoietic stem-cell transplantation
6. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
7. Cardiac or cardiac repolarization abnormality, including any 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)
 QTcF at screening ≥450 msec (male patients), ≥450 msec (female patients)
 Long QT syndrome, family history of idiopathic sudden death or congenital long
QT syndrome, or any of the following:
o Risk factors for Torsades de Pointes (TdP) including uncorrected
hypokalemia or hypomagnesemia, history of cardiac failure, or history of
clinically significant/symptomatic bradycardia
o 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.
o Inability to determine the QTcF interval
8. History of acute pancreatitis within 1 year of study entry or past medical history of
chronic pancreatitis
9. Participation in a prior investigational study within 30 days prior to randomization or
within 5 half-lives of the investigational product, whichever is longer
10. Treatment with medications that meet one of the following criteria is not allowed and
should be switched to an alternative at least one week prior to the start of treatment
with study treatment:
 Strong inducers of CYP3A for patients on the dose of 80 mg QD and 200mg QD
 Strong inducers and inhibitors of CYP3A for patients on the dose of 200 mg BID
11. Pregnant or nursing (lactating) women
12. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception.
 Highly effective contraception methods include:
 Total 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

 Female sterilization (have had surgical bilateral oophorectomy (with or without
hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks
before taking study treatment). In case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone
level assessment
 Male sterilization (at least 6 months prior to screening). The vasectomized
male partner should be the sole partner for that subject
 Use of oral, injected or implanted hormonal methods of contraception or
placement of an intrauterine device (IUD) or intrauterine system (IUS) or other
forms of hormonal contraception that have comparable efficacy (failure rate
<1%), for example hormone vaginal ring or transdermal hormone
contraception
 In case of use of oral contraception women should have been stable on the
same pill for a minimum of 3 months before taking study treatment
 Women are considered post-menopausal and not of child bearing potential if
they have had 12 months of natural (spontaneous) amenorrhea with an
appropriate clinical profile (e.g. age appropriate, history of vasomotor
symptoms) or have had surgical bilateral oophorectomy (with or without
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks
before taking study medication. In the case of oophorectomy alone, women are
considered post-menopausal and not of child-bearing potential only when the
reproductive status of the woman has been confirmed by follow up hormone
level assessment.
 Highly effective contraception for women should be maintained throughout the
study and for at least 7 days after the last dose.
13. Sexually active males unwilling to use a condom during intercourse while taking study
treatment and for 7 days after stopping study (only for patients treated with asciminib).
A condom is required for all sexually active male participants on asciminib treatment
to prevent them from fathering a child AND to prevent delivery of study treatment via
seminal fluid to their partner. In addition, these male participants must not donate
sperm for the time period specified above.
14. 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).
15. 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.
16. Known hypersensitivity to the study treatment.