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

Chronic Myelogenous Leukemia Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03106779
• Other study ID #: CABL001A2301
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 29, 2016
• Est. completion date: December 18, 2024

Study information

• Verified date: April 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 233
• Est. completion date: December 18, 2024
• Est. primary completion date: May 25, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Myelogenous Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• Asciminib
40 mg tablets was taken orally twice a day (BID)
• Bosutinib
500 mg tablets was taken orally once daily (QD)

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal
Argentina	Novartis Investigative Site	Cordoba
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Melbourne	Victoria
Australia	Novartis Investigative Site	Murdoch	Western Australia
Brazil	Novartis Investigative Site	Porto Alegre
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Varna
Canada	Novartis Investigative Site	Toronto	Ontario
Czechia	Novartis Investigative Site	Brno Bohunice
Czechia	Novartis Investigative Site	Ostrava	Poruba
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Vandoeuvre les Nancy
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Jena
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Mannheim	Baden Wuerttemberg
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Zrifin
Italy	Novartis Investigative Site	Bari	BA
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Japan	Novartis Investigative Site	Akita
Japan	Novartis Investigative Site	Aomori
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Chuo-city	Yamanashi
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Kobe-shi	Hyogo
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Osaka Sayama	Osaka
Japan	Novartis Investigative Site	Suita	Osaka
Japan	Novartis Investigative Site	Toyoake city	Aichi
Korea, Republic of	Novartis Investigative Site	Busan
Korea, Republic of	Novartis Investigative Site	Jeollanam
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Uijeongbu si	Gyeonggi Do
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Beirut
Mexico	Novartis Investigative Site	Monterrey	Nuevo Leon
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Dordrecht
Romania	Novartis Investigative Site	Cluj-Napoca
Romania	Novartis Investigative Site	Timisoara
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Saint Petersburg
Saudi Arabia	Novartis Investigative Site	Riyadh
Serbia	Novartis Investigative Site	Belgrade
Serbia	Novartis Investigative Site	Novi Sad
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Bilbao	Pais Vasco
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Toledo	Castilla La Mancha
Switzerland	Novartis Investigative Site	Zürich
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul	TUR
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Samsun
United Kingdom	Novartis Investigative Site	Cardiff
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Oxford
United Kingdom	Novartis Investigative Site	Wirral	Merseyside
United States	University Of MI Clnl Trials Office Main Site	Ann Arbor	Michigan
United States	Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	Indiana Blood and Marrow Institute Regulatory - 2	Beech Grove	Indiana
United States	Dana Farber Cancer Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute .	Buffalo	New York
United States	University of Chicago Hospital	Chicago	Illinois
United States	Uni of TX MD Anderson Cancer Cntr	Houston	Texas
United States	Memorial Sloan Kettering Cancer Ctr .	New York	New York
United States	Weill Cornell Medicine NY-Presb	New York	New York
United States	Utah Huntsman Cancer Center	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Lebanon,  Mexico,  Netherlands,  Romania,  Russian Federation,  Saudi Arabia,  Serbia,  Spain,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall Survival	To compare additional parameters of the efficacy of asciminib versus bosutinib	96 weeks after the last patient received the first study dose
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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