Clinical trial NCT03106779: Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Myelogenous Leukemia
Keywords: Phase 3
Chronic Myelogenous Leukemia
CML
bosutinib
ABL001
tyrosine kinase inhibitor
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-04-10
Enrollment: 233
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Major Molecular Response (MMR) Rate at 24 Weeks
timeFrame: 24 weeks
Secondary outcomes:
measure: Number of Participants With Major Molecular Response (MMR) Rate
timeFrame: 96 weeks after the last patient received the first study dose
measure: Complete Cytogenetic Response Rate
timeFrame: 96 weeks after the last patient received the first study dose
measure: Time to MMR
timeFrame: 96 weeks after the last patient received the first study dose
measure: Duration of MMR
timeFrame: 96 weeks after the last patient received the first study dose
measure: Time to CCyR
timeFrame: 96 weeks after the last patient received the first study dose
measure: Duration of CCyR
timeFrame: 96 weeks after the last patient received the first study dose
measure: Time to Treatment Failure
timeFrame: 96 weeks after the last patient received the first study dose
measure: Progression Free Survival
timeFrame: 96 weeks after the last patient received the first study dose
measure: Overall Survival
timeFrame: 96 weeks after the last patient received the first study dose
measure: Trough Plasma Concentrations
timeFrame: 96 weeks after the last patient received the first study dose
measure: PK Parameter: Cmax,
timeFrame: 96 weeks after the last patient received the first study dose
measure: PK Parameter: Tmax
timeFrame: 96 weeks after the last patient received the first study dose
measure: PK Parameter: AUC0-12h
timeFrame: 96 weeks after the last patient received the first study dose
measure: PK Parameter: CL/F
timeFrame: 96 weeks after the last patient received the first study dose
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago Hospital
state: Illinois
city: Beech Grove
country: United States
facility: Indiana Blood and Marrow Institute
state: Indiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Clinical Trials Office
state: Michigan
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine NY-Presb
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Ctr
state: New York
city: Houston
country: United States
facility: Uni Of TX MD Anderson Cancer Cntr
state: Texas
city: Salt Lake City
country: United States
facility: Utah Huntsman Cancer Center
state: Utah
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Capital Federal
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Murdoch
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
city: Plovdiv
country: Bulgaria
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Ostrava
country: Czechia
facility: Novartis Investigative Site
state: Poruba
city: Brno Bohunice
country: Czechia
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Vandoeuvre Les Nancy
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Zerifin
country: Israel
facility: Novartis Investigative Site
city: Bari
country: Italy
facility: Novartis Investigative Site
state: BA
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Toyoake city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Osaka Sayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Suita
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo
country: Japan
facility: Novartis Investigative Site
state: Yamanashi
city: Akita
country: Japan
facility: Novartis Investigative Site
city: Aomori
country: Japan
facility: Novartis Investigative Site
city: Kobe shi
country: Japan
facility: Novartis Investigative Site
city: Uijeongbu si
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Busan
country: Korea, Republic of
facility: Novartis Investigative Site
city: Jeollanam
country: Korea, Republic of
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo Leon
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Dordrecht
country: Netherlands
facility: Novartis Investigative Site
city: Cluj-Napoca
country: Romania
facility: Novartis Investigative Site
city: Timisoara
country: Romania
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Riyadh
country: Saudi Arabia
facility: Novartis Investigative Site
city: Belgrade
country: Serbia
facility: Novartis Investigative Site
city: Novi Sad
country: Serbia
facility: Novartis Investigative Site
city: Toledo
country: Spain
facility: Novartis Investigative Site
state: Castilla La Mancha
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Bilbao
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Samsun
country: Turkey
facility: Novartis Investigative Site
city: Cardiff
country: United Kingdom
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.