The purpose of this pivotal study is to compare the efficacy of 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 BCR-ABL1 ratio > 0.1% IS at screening and patients failing their most recent TKI therapy must meet the definition of treatment failure as per the 2013 ELN guidelines. Patients with documented treatment failure while on bosutinib treatment will have the option to switch to asciminib treatment within 96 weeks after the last patient has been randomized on study.
Name: ABL001
Description: 40 mg tablets will be taken orally twice a day (BID)Type: DrugABL001
Name: Bosutinib
Description: 500 mg tablets will be taken orally once daily (QD)Type: DrugBosutinib
Description: To compare the MMR rate of ABL001 versus bosutinib
Measure: Major Molecular Response (MMR) rate Time: at 24 weeksDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Major Molecular Response (MMR) rate Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib. Cytogenic response will include Complete, Partial, Major, Minor, Minimal and no response.
Measure: Complete Cytogenetic response rate Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Time to MMR Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Duration of MMR Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Time to CCyR Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Duration of CCyR Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Time to treatment failure Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Progression free survival Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Overall survival Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: Trough plasma concentrations Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: PK parameter: Cmax, Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: PK parameter: Tmax Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: PK parameter: AUC0-12h Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: PK parameter: CL/F Time: 96 weeks after the last patient received the first study doseAllocation: Randomized
Parallel Assignment
There are 2 SNPs
- 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. --- T315I ---
- 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. --- T315I --- --- V299L ---