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

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

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 has three periods: 1. Treatment period for all randomized participants, 2. Optional Treatment-Free Remission (TFR) period only for participants meeting TFR eligibility criteria and 3. Treatment Re-Initiation (TRI) period only for participants who relapsed after TFR attempt.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive
• Intervention / Treatment: Drug: Asciminib; Drug: Imatinib; Drug: Bosutinib; Drug: Nilotinib; Drug: Dasatinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 405
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • Southport, Australia, 4215
    • Novartis Investigative Site
  • New South Wales
    • Kingswood, New South Wales, Australia, 2747
      • Novartis Investigative Site
    • Port Macquarie, New South Wales, Australia, 2444
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
• Austria
  • Upper Austria
    • Linz, Upper Austria, Austria, 4010
      • Novartis Investigative Site
• Belgium
  • Brussels, Belgium, 1000
    • Novartis Investigative Site
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3000
      • Novartis Investigative Site
• Bulgaria
  • Varna, Bulgaria, 9010
    • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 5G2
      • Novartis Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8V 1C3
      • Novartis Investigative Site
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• China
  • Beijing, China, 100044
    • Novartis Investigative Site
  • Beijing, China, 100730
    • Novartis Investigative Site
  • Lanzhou, China, 730000
    • Novartis Investigative Site
  • Tianjin, China, 300020
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Novartis Investigative Site
    • Shenzhen, Guangdong, China, 518037
      • Novartis Investigative Site
  • Henan
    • Zhengzhou, Henan, China, 450008
      • Novartis Investigative Site
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Novartis Investigative Site
    • Suzhou, Jiangsu, China, 215004
      • Novartis Investigative Site
  • Shanxi
    • Xian, Shanxi, China, 710068
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Novartis Investigative Site
    • Wenzhou, Zhejiang, China, 325000
      • Novartis Investigative Site
• Czechia
  • Brno, Czechia, 625 00
    • Novartis Investigative Site
  • Hradec Králové, Czechia, 500 05
    • Novartis Investigative Site
  • Poruba
    • Ostrava, Poruba, Czechia, 708 52
      • Novartis Investigative Site
• Denmark
  • Aarhus N, Denmark, 8200
    • Novartis Investigative Site
  • Copenhagen, Denmark, 2100
    • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00290
    • Novartis Investigative Site
• France
  • Bordeaux, France, 33076
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Nantes, France, 44093
    • Novartis Investigative Site
  • Paris, France, 75475
    • Novartis Investigative Site
• Germany
  • Aachen, Germany, 52074
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Lübeck, Germany, 23538
    • Novartis Investigative Site
  • Baden-Wurttemberg
    • Mannheim, Baden-Wurttemberg, Germany, 68305
      • Novartis Investigative Site
  • Hesse
    • Frankfurt am Main, Hesse, Germany, 60590
      • Novartis Investigative Site
  • Thuringia
    • Jena, Thuringia, Germany, 07740
      • Novartis Investigative Site
• Hungary
  • Kaposvár, Hungary, 7400
    • Novartis Investigative Site
  • Kecskemét, Hungary, 6001
    • Novartis Investigative Site
  • Hajdu Bihar Megye
    • Debrecen, Hajdu Bihar Megye, Hungary, 4032
      • Novartis Investigative Site
• India
  • Delhi, India, 110085
    • Novartis Investigative Site
• Israel
  • Petah Tikva, Israel, 4941492
    • Novartis Investigative Site
  • Ramat Gan, Israel, 5265601
    • Novartis Investigative Site
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20122
      • Novartis Investigative Site
  • RE
    • Reggio Emilia, RE, Italy, 42123
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00161
      • Novartis Investigative Site
  • VR
    • Verona, VR, Italy, 37134
      • Novartis Investigative Site
• Japan
  • Akita, Japan, 0108543
    • Novartis Investigative Site
  • Fukuoka, Japan, 8128582
    • Novartis Investigative Site
  • Fukushima, Japan, 9601295
    • Novartis Investigative Site
  • Osaka, Japan, 5458586
    • Novartis Investigative Site
  • Yamagata, Japan, 9909585
    • Novartis Investigative Site
  • Aichi-ken
    • Nagoya, Aichi-ken, Japan, 4538511
      • Novartis Investigative Site
    • Toyoake, Aichi-ken, Japan, 4701192
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 0608648
      • Novartis Investigative Site
  • Hyōgo
    • Kobe, Hyōgo, Japan, 6500047
      • Novartis Investigative Site
  • Okayama-ken
    • Kurashiki, Okayama-ken, Japan, 7108602
      • Novartis Investigative Site
  • Osaka
    • Sakai, Osaka, Japan, 5900197
      • Novartis Investigative Site
    • Suita, Osaka, Japan, 5650871
      • Novartis Investigative Site
  • Tochigi
    • Shimotsuke, Tochigi, Japan, 3290498
      • Novartis Investigative Site
  • Yamanashi
    • Chūō, Yamanashi, Japan, 4093898
      • Novartis Investigative Site
• Malaysia
  • Kuala Selangor, Malaysia, 68000
    • Novartis Investigative Site
  • Pahang
    • Kuantan, Pahang, Malaysia, 25100
      • Novartis Investigative Site
  • Pulau Pinang
    • George Town, Pulau Pinang, Malaysia, 10450
      • Novartis Investigative Site
  • Selangor
    • Subang Jaya, Selangor, Malaysia, 47500
      • Novartis Investigative Site
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1081 HV
      • Novartis Investigative Site
• Norway
  • Bergen, Norway, NO-5021
    • Novartis Investigative Site
  • Oslo, Norway, 0372
    • Novartis Investigative Site
• Portugal
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
  • Vila Nova de Gaia, Portugal, 4434-502
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119074
    • Novartis Investigative Site
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• Slovakia
  • Košice, Slovakia, 041 90
    • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 03080
    • Novartis Investigative Site
  • Seoul, South Korea, 06351
    • Novartis Investigative Site
  • Seoul, South Korea, 06591
    • Novartis Investigative Site
  • Gyeonggi-do
    • Uijeongbu-si, Gyeonggi-do, South Korea, 11759
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08036
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Andalusia
    • Granada, Andalusia, Spain, 18014
      • Novartis Investigative Site
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Novartis Investigative Site
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Novartis Investigative Site
• Sweden
  • Gothenburg, Sweden, 413 45
    • Novartis Investigative Site
  • Lund, Sweden, 221 85
    • Novartis Investigative Site
  • Stockholm, Sweden, 141 86
    • Novartis Investigative Site
• Switzerland
  • Bellinzona, Switzerland, 6850
    • Novartis Investigative Site
• Taiwan
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, W12 0HS
    • Novartis Investigative Site
  • Nottingham, United Kingdom, NG5 1PB
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LE
    • Novartis Investigative Site
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Centers
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
    • Tallahassee, Florida, United States, 32308
      • Florida Cancer Specialists Pan
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Uni of Massachusetts Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Williamette Cancer Center
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Onc And Hem Assoc PC
  • Texas
    • Amarillo, Texas, United States, 79124
      • Texas Oncology
    • Dallas, Texas, United States, 75246
      • Texas Oncology-Baylor USO
    • Dallas, Texas, United States, 75251
      • Texas Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Asciminib; Patients will take asciminib 80 mg QD under fasting conditions on ongoing basis; Patients will be randomized 1:1 asciminib versus Investigator selected TKIs	Drug: Asciminib; Comes in 40 mg tablets and taken orally; Other Names: ABL001
Active Comparator: Investigator selected TKIs; Patients will take on ongoing basis the Investigator selected TKIs 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 a meal Bosotunib 400 mg QD administered with food	Drug: Imatinib; Comes in 100 mg and 400 mg tablets and taken orally; Other Names: STI571; Drug: Bosutinib; Comes in 100 mg and 400 mg tablets and taken orally; Drug: Nilotinib; Comes in 150 mg and 200 mg capsules and taken orally; Other Names: AMN107; Drug: Dasatinib; Comes in 20 mg, 50 mg, 70 mg and 100 mg tablets and taken orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Ascimimib vs. Investigator Selected TKI	Molecular response is assessed using BCR-ABL1 transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).	At 48 weeks
Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Asciminib (Imatinib Stratum) vs Investigator Selected TKI (Imatinib Stratum)	Molecular response is assessed using BCR-ABL1 transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL1/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).	At 48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of MMR	Duration of MMR is defined as the time between the date of the first documented achievement of MMR and the earliest date of loss of MMR, treatment failure, progression to Accelerated Phase/Blast Crisis, or CML-related death	Planned total follow-up duration of 5 years
Duration of MR4.0	Duration of MR4.0 is defined as the time between the date of the first documented achievement of MR4.0 and the earliest date of loss of MR4.0, treatment failure, progression to Accelerated Phase/Blast Crisis, or CML-related death	Planned total follow-up duration of 5 years
Duration of MR4.5	Duration of MR4.5 is defined as the time between the date of the first documented achievement of MR4.5 and the earliest date of loss of MR4.5, treatment failure, progression to Accelerated Phase/Blast Crisis, or CML-related death	Planned total follow-up duration of 5 years
Failure Free Survival (FFS)	FFS is defined as the time from the date of randomization to the earliest occurrence of the following events: treatment failure per ELN, confirmed loss of MMR, progression to AP/BC, death from any cause. For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the date of last study treatment assessment or last post-treatment follow-up.	Planned total follow-up duration of 5 years
Event Free Survival (EFS)	EFS is defined as the time from the date of randomization to the earliest occurrence of the following events: treatment failure as per ELN, confirmed loss of MMR ,discontinuation of study treatment due to AE, progression to AP/BC, death from any cause. For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the date of last study treatment assessment or last post-treatment follow-up.	Planned total follow-up duration of 5 years
Progression Free Survival (PFS)	PFS is defined as the time from the date of randomization to the earliest occurrence of progression to AP/BC or death from any cause. For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the date of last study treatment assessment or last post-treatment follow-up.	Planned total follow-up duration of 5 years
Overall Survival (OS)	OS is defined as the time from the date of randomization to the date of death from any cause. For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the date of last contact before the cut-off date.	Planned total follow-up duration of 5 years
Major Molecular Response at Week 96	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).	at 96 weeks (96 weeks after last patient first dose)
Time to Discontinuation of Study Treatment Due to Adverse Events (TTDAE)	TTDAE is defined as the time from the date of first dose of study treatment to the date of discontinuation of study treatment due to Adverse Event (AE). For patients ongoing without study treatment discontinuation, on or prior to the analysis cut-off date, the time will be censored at the at the analysis cut-off date.	96 weeks after last patient first dose
Major Molecular Response at Scheduled Data Collection Time Points	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).	Planned total follow-up duration of 5 years
Major Molecular Response by Scheduled Data Collection Time Points	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).	Planned total follow-up duration of 5 years
MR4.0 at Scheduled Data Collection Time Points	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MR4.0 is defined as a ratio BCR-ABL/ABL ≤0.01% on the international scale (ie, at least 4 log reduction from a standardized baseline value).	Planned total follow-up duration of 5 years
MR4.5 at All Scheduled Data Collection Time Points	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MR4.5 is defined as a ratio BCR-ABL/ABL ≤0.0032% on the international scale (ie, at least 4.5 log reduction from a standardized baseline value).	Planned total follow-up duration of 5 years
MR4.0 by Scheduled Data Collection Time Points	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MR4.0 is defined as a ratio BCR-ABL/ABL ≤0.01% on the international scale (ie, at least 4 log reduction from a standardized baseline value).	Planned total follow-up duration of 5 years
MR4.5 by All Scheduled Data Collection Time Points	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MR4.5 is defined as a ratio BCR-ABL/ABL ≤0.0032% on the international scale (ie, at least 4.5 log reduction from a standardized baseline value).	Planned total follow-up duration of 5 years
Complete Hematological Response (CHR) at All Scheduled Data Collection Time Points	Hematologic response will be assessed by CBC and physical examination at each visit. Complete Hematological Response (CHR) will be defined as all of the following present for ≥ 4 weeks: white blood cell(s) (WBC) count < 10 x 10^9/L PLT count < 450 x 10^9/L Basophils < 5% No blasts and promyelocytes in peripheral blood Myelocytes + metamyelocytes < 5% in peripheral blood No evidence of extramedullary disease, including spleen and liver	Planned total follow-up duration of 5 years
Complete Hematological Response (CHR) by All Scheduled Data Collection Time Points	Hematologic response will be assessed by CBC and physical examination at each visit. Complete Hematological Response (CHR) will be defined as all of the following present for ≥ 4 weeks: white blood cell(s) (WBC) count < 10 x 10^9/L PLT count < 450 x 10^9/L Basophils < 5% No blasts and promyelocytes in peripheral blood Myelocytes + metamyelocytes < 5% in peripheral blood No evidence of extramedullary disease, including spleen and liver	Planned total follow-up duration of 5 years
Percentage of Participants With Complete Cytogenic Response (CCyR) by Week 48 & Week 96	The CCyR response status was to be based on bone marrow assessment. Bone marrow examination for cytogenetic assessment was to be performed locally by the Investigator at baseline for all participants. Thereafter, during the course of the study, cytogenetic assessment was not mandatory and only performed if clinically indicated.	By week 48 and by week 96 (48 weeks and 96 weeks after last patient first dose); data collection/analysis is ongoing for the 96 week time point, and the data will be reported later
Time to First MMR	Time to first MMR is defined as the time from the date of randomization to the date of the first documented occurrence of MMR. Time will be censored at the last molecular assessment date while on treatment, or the End Of Treatment (whichever comes first) for patients who have not experienced MMR.	Planned total follow-up duration of 5 years
Time to First MR4.0	Time to first MR4.0 is defined as the time from the date of randomization to the date of the first documented occurrence of MR4.0. Time will be censored at the last molecular assessment date while on treatment, or the End Of Treatment (whichever comes first) for patients who have not experienced MR4.0.	Planned total follow-up duration of 5 years
Time to First MR4.5	Time to first MR4.5 is defined as the time from the date of randomization to the date of the first documented occurrence of MR4.5. Time will be censored at the last molecular assessment date while on treatment, or the End Of Treatment (whichever comes first) for patients who have not experienced MR4.5.	Planned total follow-up duration of 5 years
BCR-ABL1≤1% at Scheduled Data Collection Time Points	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.	Planned total follow-up duration of 5 years
BCR-ABL1≤1% by Scheduled Data Collection Time Points	Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction.	Planned total follow-up duration of 5 years
Time to Treatment Failure (TTF)	TTF is defined as the time from date of randomization to the first/earliest documented date of any of the following events: treatment failure as per ELN, Confirmed loss of MMR while on study treatment, discontinuation from study treatment due to any reason For patients that have not experienced an event prior to or at the analysis cut-off date, the time will be censored at the last study assessment date while on treatment, or the EOT (whichever comes first) .	Planned total follow-up duration of 5 years
Trough Plasma Concentrations.	Trough plasma concentration will measure the concentration of asciminib in the blood immediately before the next dose is administered.	Week 48
Pharmacokinetics (PK) of Asciminib: Cmax	Cmax is the maximum serum concentration of asciminib during a dosing interval (mass x volume-1).	Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose)
PK of Asciminib: Tmax	Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration (time)	Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose)
PK of Asciminib: AUCtau and AUClast	AUCtau is the area under the plasma concentration-time curve over the dosing interval. AUClast is the area under the plasma concentration-time curve from time zero (time of dose administration) to time of last measurable concentration (mass x time x volume-1)	Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose)
PK of Asciminib: CL/F	CL/F is the apparent total body clearance of asciminib from plasma after oral administration (volume x time-1).	Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose)
Change From Baseline in Overall Scores (Global Health Status) and Individual Scales of the EORTC QLQ-C30 at Week 48 and Week 96	The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assesses the quality of life of cancer patients. It consists of functioning scales, symptom scales, and the global health status quality of life (QoL) scale. A high score for functional and QoL items/scales from the QLQ-30 represents better function and QOL. A high score in symptoms items from QLQ-30 represents worse symptoms.	Baseline, week 48 and week 96
Change From Baseline in EORTC QLQ-CML24 Scales at Week 48 and Week 96	The QLQ-CML24 consists of multi-scale items: symptom burden, impact on worry/mood, impact on daily life, body image problems, satisfaction with care and information and satisfaction with social life. A higher score on most of the item scales in QLQ-CML24 reflects a larger impairment in the corresponding domain, with the exception of the satisfaction with care and information, and problems and satisfaction with social life, where a higher score reflects a higher level of satisfaction.	Baseline, week 48 and week 96.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Hochhaus A, Wang J, Kim DW, Kim DDH, Mayer J, Goh YT, le Coutre P, Takahashi N, Kim I, Etienne G, Andorsky D, Issa GC, Larson RA, Bombaci F, Kapoor S, McCulloch T, Malek K, Yau L, Ifrah S, Hoch M, Cortes JE, Hughes TP; ASC4FIRST Investigators. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med. 2024 Sep 12;391(10):885-898. doi: 10.1056/NEJMoa2400858. Epub 2024 May 31.
• Cortes JE, Hochhaus A, Takahashi N, Larson RA, Issa GC, Bombaci F, Ramscar N, Ifrah S, Hughes TP. Asciminib monotherapy for newly diagnosed chronic myeloid leukemia in chronic phase: the ASC4FIRST phase III trial. Future Oncol. 2022 Dec;18(38):4161-4170. doi: 10.2217/fon-2022-0923. Epub 2022 Dec 16.
• Cortes JE, Hughes TP, Wang J, Kim DW, Kim DDH, Mayer J, Goh YT, le Coutre P, Etienne G, Kim I, Andorsky DJ, Bombaci F, Issa GC, Takahashi N, Kapoor S, Jinwal R, Malek K, McCulloch T, Yau L, Larson RA, Hochhaus A. Asciminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4FIRST trial. Blood. 2026 Mar 26;147(13):1433-1446. doi: 10.1182/blood.2025029210.
• Takahashi N, Kim DW, Kim I, Du X, Lee SE, Hu Y, Kikushige Y, Jiang Q, Wang Y, Chen S, Zhu H, Goto T, Tomita A, Ichii M, Nakamae H, Liu L, Liu B, Malek K, Zhu T, Wu S, Wang J. Asciminib Provides Better Efficacy and Favorable Safety and Tolerability Against Investigator-Selected Tyrosine Kinase Inhibitors in East Asian Patients With Newly Diagnosed Chronic Myeloid Leukemia: Results From a Subgroup Analysis of the Pivotal ASC4FIRST Study. Cancer Med. 2026 Jun;15(6):e72019. doi: 10.1002/cam4.72019.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2021
• Primary Completion (Actual): November 28, 2023
• Study Completion (Estimated): January 18, 2031

Study Registration Dates

• First Submitted: June 8, 2021
• First Submitted That Met QC Criteria: July 12, 2021
• First Posted (Actual): July 21, 2021

Study Record Updates

• Last Update Posted (Actual): August 28, 2026
• Last Update Submitted That Met QC Criteria: August 26, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Nilotinib; Chronic Myeloid Leukemia; CML; Imatinib; Bosutinib; Asciminib; Dasatinib; Philadelphia Chromosome; TKIs; Treatment-free remission
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Myeloproliferative Disorders; Translocation, Genetic; Chromosome Aberrations; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Amides; Pyrimidines; Benzene Derivatives; Acids, Carbocyclic; Benzoates; Benzamides; Piperazines; Imatinib Mesylate; Dasatinib; nilotinib; asciminib; bosutinib
• Other Study ID Numbers: CABL001J12301; 2023 (U.S. NIH Grant/Contract: GRAMMY Museum Foundation); 2023-508838-33-00 (Registry Identifier: EU CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No