A phase III, multi-center, open-label, randomized study of oral asciminib versus Investigator selected TKI in patients with newly diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase

Despite the significant advances in the treatment of chronic myelogenous
leukemia (CML) thanks to the introduction of tyrosine-kinase inhibitors (TKIs),
many patients treated with two or more TKIs experience intolerance. In addition
resistance rates in later treatment lines remain high (see protocol page 21,
item 1.1.2).
Asciminib (ABL001) is a novel investigational treatment specifically targeting
the ABL myristoyl pocket (STAMP). As a STAMP inhibitor, asciminib might help
address TKI resistance and intolerance. Asciminib is being evaluated for the
treatment of patients with CML (see protocol page 22, item 1.2.1).
Results at 24 weeks from a phase III study in patients with Philadelphia
chromosome positive CML in chronic phase previously treated with two or more
TKIs demonstrate that, asciminib nearly doubled the major molecular response
rate compared to bosutinib (25.5% vs. 13.2%). Complete cytogenetic response at
24 weeks was 40.5% for asciminib and 24.2% for bosutinib. Safety and
tolerability data (grade >=3 AEs, treatment discontinuation due to AEs, dose
reduction or interruption due to AEs) were more favorable in the asciminib arm
(see protocol page 24, item 1.2.2.2).
In 2020 EMA has granted asciminib the orphan status. In 2021 FDA has granted
asciminib breakthrough therapy designation for adults with Philadelphia
chromosome positive CML in the chronic phase.

The purpose of this pivotal study is to compare the efficacy of asciminib with
that of BCR-ABL1 TKIs, such as imatinib, nilotinib, dasatinib and bosutinib in
adult patients with newly diagnosed Philadelphia chromosome positive CML in the
chronic phase.

Primary:
To compare the efficacy of asciminib versus Investigator selected TKI with
respect to the proportion of patients that are in Major Molecular Response at
Week 48.
To compare the efficacy of asciminib versus Investigator selected TKI, within
the stratum of patients with imatinib as the pre-randomization selected TKI,
with respect to the proportion of patients that are in Major Molecular Response
at Week 48

Secondary:
To compare the efficacy of asciminib versus Investigator selected TKI, with
respect to the proportion of patients that are in Major Molecular Response at
Week 96.
To compare the efficacy of asciminib versus Investigator selected TKI, within
the stratum of patients with imatinib as the pre-randomization selected TKI,
with respect to the proportion of patients that are in Major Molecular Response
at Week 96.

Phase III multicenter open-label randomized (1:1) study, designed to compare
the efficacy of the asciminib tablets 80 mg QD versus Investigator selected TKI
for the treatment of newly diagnosed, previously untreated patients with
Philadelphia Chromosome positive CML in the chronic phase. The Investigator
selected TKI will be one of the following treatment options for first-line
treatment of CML in the chronic phase:
• Imatinib tablets 400 mg QD
• Nilotinib capsules 300 mg BID
• Dasatinib tablets 100 mg QD
• Bosutinib tablets 400 mg QD.
Dose escalation for asciminib or nilotinib is not permitted. Dose escalation
for the other investigator selected TKIs is allowed (see protocol page 52).
Study treatment until end of study (5 years after last patient first visit) or
treatment failure, disease progression, intolerance or investigator or patient
decision.
In case of premature discontinuation: follow up for survival until end of
study.

Treatment with asciminib versus imatinib, or nilotinib, or dasatinib, or
bosutinib.

Risk: Adverse events of the study medication.
Burden:
• Visits: screening, week 1, 2, 4, 6, 8, 10, 12 and every 12 weeks thereafter,
end of study.
• Physical examination: every visit.
• Blood draws: every visit, fasting, 15-60 mL blood per occasion.
• Pregnancy tests: monthly blood (urine if blood test not feasible).
• ECG: screening, week 1, 2, 4, 10, 12, 48, 96, end of study.
• Bone marrow biopsy: <=once.
• Questionnaires: PRO-CTCAE and FACIT GP5 (at home) weekly first 6 months,
monthly thereafter. QLQ-C30, QLQ-CML24 and EQ-5D-5L 8 visits in total.
Optional:
• Blood sample for pharmacogenetics (6 mL).