Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs

A Phase 3, Multi-center, Open-label, Randomized Study of Oral ABL001 Versus Bosutinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), Previously Treated With 2 or More Tyrosine Kinase Inhibitors

The purpose of this pivotal study was to compare the efficacy of asciminib (ABL001) with that of bosutinib in the treatment of patients with CML-CP having previously been treated with a minimum of two prior ATP-binding site TKIs.

Patients intolerant to the most recent TKI therapy must have had BCR-ABL1 ratio > 0.1% IS at screening and patients failing their most recent TKI therapy must have met the definition of treatment failure as per the 2013 European LeukemiaNet (ELN) recommendations.

Patients with documented treatment failure as per 2013 ELN recommendations while on bosutinib treatment had the option to switch to asciminib treatment within 96 weeks after the last patient has been randomized on study.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Myelogenous Leukemia
• Intervention / Treatment: Drug: Asciminib; Drug: Bosutinib

Detailed Description

Patients were randomized in a 2:1 ratio to asciminib 40 mg BID or bosutinib 500 mg QD. Randomization was stratified by major cytogenetic response (MCyR) at screening. Patients with documented treatment failure (specifically meeting lack of efficacy criteria adapted from the 2013 ELN recommendations) while on bosutinib treatment were offered the option to switch to asciminib treatment within 96 weeks after the last patient was randomized to the study.

• Study Type: Interventional
• Enrollment (Actual): 233
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Capital Federal, Argentina, C1114AAN
    • Novartis Investigative Site
  • Cordoba, Argentina, X5016KEH
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1221ADH
      • Novartis Investigative Site
• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Novartis Investigative Site
• Brazil
  • Porto Alegre, Brazil, 90035-003
    • Novartis Investigative Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 20.211-030
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 05403 000
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 08270-070
      • Novartis Investigative Site
• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • Novartis Investigative Site
  • Varna, Bulgaria, 9000
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• Czechia
  • Brno Bohunice, Czechia, 625 00
    • Novartis Investigative Site
  • Poruba
    • Ostrava, Poruba, Czechia, 708 52
      • Novartis Investigative Site
• France
  • Bordeaux, France, 33076
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Paris 10, France, 75475
    • Novartis Investigative Site
  • Vandoeuvre les Nancy, France, 54511
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Duesseldorf, Germany, 40225
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Jena, Germany, 07740
    • Novartis Investigative Site
  • Kiel, Germany, 24116
    • Novartis Investigative Site
  • Baden Wuerttemberg
    • Mannheim, Baden Wuerttemberg, Germany, 68305
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1097
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Israel
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Zrifin, Israel, 70300
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80132
    • Novartis Investigative Site
  • BA
    • Bari, BA, Italy, 70124
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
• Japan
  • Akita, Japan, 010-8543
    • Novartis Investigative Site
  • Aomori, Japan, 030 8553
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 453-8511
      • Novartis Investigative Site
    • Toyoake city, Aichi, Japan, 470 1192
      • Novartis Investigative Site
  • Chiba
    • Kashiwa, Chiba, Japan, 277 8577
      • Novartis Investigative Site
  • Hyogo
    • Kobe-shi, Hyogo, Japan, 650-0017
      • Novartis Investigative Site
  • Osaka
    • Osaka Sayama, Osaka, Japan, 589 8511
      • Novartis Investigative Site
    • Suita, Osaka, Japan, 565 0871
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo ku, Tokyo, Japan, 113-8677
      • Novartis Investigative Site
  • Yamanashi
    • Chuo-city, Yamanashi, Japan, 409-3898
      • Novartis Investigative Site
• Korea, Republic of
  • Busan, Korea, Republic of, 49201
    • Novartis Investigative Site
  • Jeollanam, Korea, Republic of, 519763
    • Novartis Investigative Site
  • Gyeonggi Do
    • Uijeongbu si, Gyeonggi Do, Korea, Republic of, 11759
      • Novartis Investigative Site
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Novartis Investigative Site
• Lebanon
  • Ashrafieh, Lebanon, 166830
    • Novartis Investigative Site
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
• Mexico
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
  • Dordrecht, Netherlands, 3318AT
    • Novartis Investigative Site
• Romania
  • Cluj-Napoca, Romania, 400124
    • Novartis Investigative Site
  • Timisoara, Romania, 300079
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 125167
    • Novartis Investigative Site
  • Moscow, Russian Federation, 125284
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 191024
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197341
    • Novartis Investigative Site
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • Novartis Investigative Site
• Serbia
  • Belgrade, Serbia, 11000
    • Novartis Investigative Site
  • Novi Sad, Serbia, 400107
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Castilla La Mancha
    • Toledo, Castilla La Mancha, Spain, 45071
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
  • Pais Vasco
    • Bilbao, Pais Vasco, Spain, 48013
      • Novartis Investigative Site
• Switzerland
  • Zürich, Switzerland, 8091
    • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01330
    • Novartis Investigative Site
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
  • Samsun, Turkey, 55139
    • Novartis Investigative Site
  • TUR
    • Istanbul, TUR, Turkey, 34098
      • Novartis Investigative Site
• United Kingdom
  • Cardiff, United Kingdom, CF4 4XN
    • Novartis Investigative Site
  • Glasgow, United Kingdom, G12 0YN
    • Novartis Investigative Site
  • London, United Kingdom, W12 0HS
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novartis Investigative Site
  • Merseyside
    • Wirral, Merseyside, United Kingdom, CH63 4JY
      • Novartis Investigative Site
• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospital
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Indiana Blood and Marrow Institute Regulatory - 2
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Sidney Kimmel Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Clinical Trials Office Main Site
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute .
    • New York, New York, United States, 10021
      • Weill Cornell Medicine NY-Presb
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Ctr .
  • Texas
    • Houston, Texas, United States, 77030
      • Uni of TX MD Anderson Cancer Cntr
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Utah Huntsman Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Male or female patients with a diagnosis of CML-CP ≥ 18 years of age

Patients must meet all of the following laboratory values at the screening visit:

• < 15% blasts in peripheral blood and bone marrow
• < 30% blasts plus promyelocytes in peripheral blood and bone marrow
• < 20% basophils in the peripheral blood
• ≥ 50 x 109/L (≥ 50,000/mm3) platelets
• Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior to screening) is acceptable
• No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly

BCR-ABL1 ratio > 0.1% IS according to central laboratory at the screening examination for patients intolerant to the most recent TKI therapy

Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib, dasatinib, radotinib or ponatinib)

Failure (adapted from the 2013 ELN Guidelines Bacarrani 2013) or intolerance to the most recent TKI therapy at the time of screening

• Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as follows. Patients must meet at least 1 of the following criteria.
• Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases
• Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases
• Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases
• At any time after the initiation of therapy, loss of CHR, CCyR or PCyR
• At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to study treatment
• At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS
• At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+
• Intolerance is defined as:
• 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)
• 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

Exclusion Criteria:

Known presence of the T315I or V299L mutation at any time prior to study entry Known second chronic phase of CML after previous progression to AP/BC Previous treatment with a hematopoietic stem-cell transplantation Patient planning to undergo allogeneic hematopoietic stem cell transplantation

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), ≥460 msec (female patients)
• 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, pulmonary hypertension)
• History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
• History of acute or chronic liver disease
• Treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with study treatment
• Moderate or strong inducers of CYP3A
• Moderate or strong inhibitors of CYP3A
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 days after last dose of ABL001 and one month after last dose of bosutinib. 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, post-ovulation 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.

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 were randomized to asciminib 40mg BID	Drug: Asciminib; 40 mg tablets was taken orally twice a day (BID); Other Names: ABL001
Active Comparator: Bosutinib; Patients were randomized to bosutinib 500mg QD	Drug: Bosutinib; 500 mg tablets was taken orally once daily (QD)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Major Molecular Response (MMR) Rate at 24 Weeks	MMR was defined as a ≥ 3.0 log reduction in BCR-ABL1 transcripts compared to the standardized baseline equivalent to ≤ 0.1% BCR-ABL1/ABL% by IS as measured by RQ-PCR.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Major Molecular Response (MMR) Rate	To compare additional parameters of the efficacy asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Complete Cytogenetic Response Rate	To compare additional parameters of the efficacy of asciminib versus bosutinib. Cytogenic response will include Complete, Partial, Major, Minor, Minimal and no response.	96 weeks after the last patient received the first study dose
Time to MMR	To compare additional parameters of the efficacy of asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Duration of MMR	To compare additional parameters of the efficacy of asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Time to CCyR	To compare additional parameters of the efficacy of asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Duration of CCyR	To compare additional parameters of the efficacy of asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Time to Treatment Failure	To compare additional parameters of the efficacy of asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Progression Free Survival	To compare additional parameters of the efficacy of asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Overall Survival	To compare additional parameters of the efficacy of asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Trough Plasma Concentrations	To characterize the PK of asciminib in the CML-CP population	96 weeks after the last patient received the first study dose
PK Parameter: Cmax,	To characterize the PK of asciminib in the CML-CP population	96 weeks after the last patient received the first study dose
PK Parameter: Tmax	To characterize the PK of asciminib in the CML-CP population	96 weeks after the last patient received the first study dose
PK Parameter: AUC0-12h	To characterize the PK of asciminib in the CML-CP population	96 weeks after the last patient received the first study dose
PK Parameter: CL/F	To characterize the PK of asciminib in the CML-CP population	96 weeks after the last patient received the first study dose

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Li YF, Combes FP, Hoch M, Lorenzo S, Sy SKB, Ho YY. Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases. Clin Pharmacokinet. 2022 Oct;61(10):1393-1403. doi: 10.1007/s40262-022-01148-9. Epub 2022 Jun 28. Erratum In: Clin Pharmacokinet. 2022 Aug 17;:
• Rea D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, Turkina A, Kim DW, Apperley JF, Abdo A, Fogliatto LM, Kim DDH, le Coutre P, Saussele S, Annunziata M, Hughes TP, Chaudhri N, Sasaki K, Chee L, Garcia-Gutierrez V, Cortes JE, Aimone P, Allepuz A, Quenet S, Bedoucha V, Hochhaus A. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021 Nov 25;138(21):2031-2041. doi: 10.1182/blood.2020009984.
• Yuda J, Doki N, Matsuoka H, Yokota T, Tomita A, Takahashi N, Matsumura I, Kubo K, Goto T, Kirito K, Maki A, Aoki M, Allepuz A, Minami Y. Asciminib vs bosutinib in CML patients pretreated with >/=2 tyrosine kinase inhibitors: Results from the Japanese subgroup analysis of ASCEMBL study. Cancer Med. 2023 Feb;12(3):2990-2998. doi: 10.1002/cam4.5212. Epub 2022 Sep 27.

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2017
• Primary Completion (Actual): May 25, 2020
• Study Completion (Estimated): December 18, 2024

Study Registration Dates

• First Submitted: March 9, 2017
• First Submitted That Met QC Criteria: April 4, 2017
• First Posted (Actual): April 10, 2017

Study Record Updates

• Last Update Posted (Actual): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: tyrosine kinase inhibitor; CML; Phase 3; Chronic Myelogenous Leukemia; ABL001; bosutinib; Chronic myelogenous leukemia (CML); chronic myeloid leukemia (CML); chronic myelocytic leukemia (CML); chronic granulocytic leukemia (CGL); cancer of the white blood cells; clonal bone marrow stem cell disorder; proliferation of mature granulocytes
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chronic Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: CABL001A2301

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 expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the 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
• product manufactured in and exported from the U.S.: No