Chronic Myelogenous Leukemia
Conditions
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
Brief summary
The purpose of this pivotal study was to compare the efficacy of asciminib (ABL001) with that of bosutinib in the treatment of participants with chronic myeloid leukemia - chronic phase (CML-CP) having previously been treated with a minimum of two prior ATP-binding site tyrosine kinase inhibitors (TKIs).
Detailed description
Participants with a diagnosis of CML-CP who had received prior treatment with 2 or more ATP binding site TKIs and were treatment failure (as per guidelines adapted from the 2013 ELN recommendations) or intolerant to the most recent TKI. Participants 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. Participants with documented treatment failure (as per 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.
Interventions
DRUGAsciminib
40 mg tablets was taken orally twice a day (BID)
DRUGBosutinib
500 mg tablets was taken orally once daily (QD)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Molecular Response (MMR) Rate at 24 Weeks | 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 international scale (IS) as measured by RQ-PCR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Molecular Response (MMR) Rate at 96 Weeks (Key Secondary Endpoint) | 96 Weeks | MMR at 96 weeks was defined as the percentage of participants with MMR at 96 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 international scale (IS) as measured by RQ-PCR. |
| Complete Cytogenetic Response (CCyR) Rate at Scheduled Time Points | at 24, 48, 72, 96, 120 and 144 weeks | Cytogenic response included Complete, Partial, Major, Minor, Minimal and no response. Cytogenetic response was assessed as the percentage of Ph+ metaphases in the bone marrow and is defined as the following: Complete (CCyR) - 0% Ph+ metaphases; Partial (PCyR) - \>0 to 35% Ph+ metaphases; Major (MCyR) - 0 to 35% Ph+ metaphases; Minor (mCyR) - \>35 to 65% Ph+ metaphases; Minimal - \>65 to 95% Ph+ metaphases; None - \>95 to 100% Ph+ metaphases. |
| Complete Cytogenetic Response Rate by Scheduled Time Points | by 24, 48, 72, 96, 120 and 144 weeks | Cytogenic response included Complete, Partial, Major, Minor, Minimal and no response. Cytogenetic response was assessed as the percentage of Ph+ metaphases in the bone marrow and is defined as the following: Complete (CCyR) - 0% Ph+ metaphases; Partial (PCyR) - \>0 to 35% Ph+ metaphases; Major (MCyR) - 0 to 35% Ph+ metaphases; Minor (mCyR) - \>35 to 65% Ph+ metaphases; Minimal - \>65 to 95% Ph+ metaphases; None - \>95 to 100% Ph+ metaphases. |
| Major Molecular Response (MMR) Rate at All Scheduled Data Collection Time Points Except Weeks 24 & 96 | at Weeks 36, 48, 60, 72, 84, 108, 120, 132, 144 & 156 | 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 international scale (IS) as measured by RQ-PCR. |
| Major Molecular Response (MMR) Rate by All Scheduled Data Collection Time Points | by Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 & 156, Overall | 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 international scale (IS) as measured by RQ-PCR. Overall time point has the count indicating participants achieving MMR at any time during the study. |
| Time to Major Molecular Response (MMR) | 216 Weeks | Time to MMR was defined as the time from the date of randomization to the date of the first documented MMR. |
| Duration of Major Molecular Response (MMR) | 216 Weeks | Duration of MMR was defined as the time from the date of first documented MMR to the earliest date of loss of MMR, progression to Accelerated phase (AP) or Blast crisis (BC), or Chronic myeloid leukemia (CML)-related death. |
| Time to Complete Cytogenetic Response Rate (CCyR) Among Participants Who Achieved CCyR | 216 Weeks | Time to CCyR was defined as the time from the date of randomization to the date of the first documented CCyR. |
| Duration of Complete Cytogenetic Response (CCyR) | 144 weeks | Duration of CCyR was defined as the time between date of first documented CCyR and the earliest date of loss of CCyR, progression to AP/BC, or CML-related death for participants in the Cytogenetic Responder Set. The time was censored at the last cytogenetic assessment date on treatment for participants for whom none of the events was reported or last PCR evaluation on treatment indicating MMR. |
| Time to Treatment Failure (TTF) | From the first dose of treatment up to 5 years, through treatment completion, an average of 2.3 years, approximately | TTF was defined as the time from date of randomization to an event of treatment failure. Treatment failure was defined as meeting a lack of efficacy criterion or discontinuing treatment due to any reason. |
| Progression Free Survival Per Percentage Event-free Kaplan-Meier Estimates | From the first dose of treatment up to study completion, up to 5 years | Progression-free survival was defined as the time from the date of randomization to the earliest occurrence of documented disease progression to AP/BC or the date of death from any cause (including progressions and deaths observed during the survival follow-up period), per Kaplan-Meier. |
| Overall Survival (OS) Per Event Free Percentage Per Kaplan-Meier Estimates | From the first dose of treatment to study completion, up to 5 years | Overall survival is defined as the time from the date of randomization to the date of death (including the survival follow-up period) per Kaplan-Meier (KM). |
| Trough Plasma Concentrations for Asciminib | Week 2 Day 1 at: 0hr (pre-dose), 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr & 12hr post-dose | Measured concentration at the end of a dosing interval at steady state (taken directly before next administration) |
| PK Parameter: Cmax for Asciminib | Week 2 Day 1 at pre-dose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr & 12hr post-dose | Maximum (peak) observed plasma concentration after dose administration (mass x volume-1). |
| PK Parameter: Tmax for Asciminib | Week 2 Day 1 at: 0hr (pre-dose), 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr & 12hr post-dose | Time to reach maximum (peak) plasma concentration after dose administration (time). Actual sampling times were taken into consideration for the pharmacokinetic analysis. |
| PK Parameter: AUC0-12h for Asciminib | Week 2 Day 1 at: 0hr (pre-dose), 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr & 12hr post-dose | Area under the plasma concentration-time curve from time zero to 12 hours (mass x time x volume-1) |
| PK Parameter: CL/F for Asciminib | Week 2 day 1 at: 0hr (pre-dose), 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr & 12hr post-dose | Total apparent body clearance of drug from the plasma after oral administration (volume x time-1). |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Japan, Lebanon, Mexico, Netherlands, Romania, Russia, Saudi Arabia, Serbia, South Korea, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
Participants were treated at a total of 84 sites.
Pre-assignment details
Randomization was stratified by major cytogenetic response (MCyR) at screening.
Participants by arm
| Arm | Count |
|---|---|
| Asciminib Patients randomized to asciminib 40mg BID | 157 |
| Bosutinib Patients randomized to bosutinib 500mg QD | 76 |
| Total | 233 |
Baseline characteristics
| Characteristic | Asciminib | Bosutinib | Total |
|---|---|---|---|
| Age, Continuous | 51.0 years STANDARD_DEVIATION 13.49 | 51.0 years STANDARD_DEVIATION 13.95 | 51.0 years STANDARD_DEVIATION 13.61 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 22 participants | 11 participants | 33 participants |
| Race/Ethnicity, Customized Black or African American | 8 participants | 2 participants | 10 participants |
| Race/Ethnicity, Customized Other | 5 participants | 7 participants | 12 participants |
| Race/Ethnicity, Customized Unknown | 3 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized White | 118 participants | 56 participants | 174 participants |
| Sex: Female, Male Female | 75 Participants | 45 Participants | 120 Participants |
| Sex: Female, Male Male | 82 Participants | 31 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 156 | 1 / 76 | 0 / 25 | 11 / 135 | 8 / 61 | 3 / 24 |
| other Total, other adverse events | 130 / 156 | 72 / 76 | 20 / 25 | 7 / 135 | 3 / 61 | 0 / 24 |
| serious Total, serious adverse events | 34 / 156 | 20 / 76 | 2 / 25 | 1 / 135 | 0 / 61 | 0 / 24 |
Outcome results
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.
Time frame: 24 weeks
Population: Full Analysis Set (FAS): The FAS comprised of all randomized patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asciminib | Number of Participants With Major Molecular Response (MMR) Rate at 24 Weeks | 40 Participants |
| Bosutinib | Number of Participants With Major Molecular Response (MMR) Rate at 24 Weeks | 10 Participants |
p-value: 0.02995% CI: [2.19, 22.3]Cochran-Mantel-Haenszel
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.
Time frame: 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
Time frame: 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
Time frame: 96 weeks after the last patient received the first study dose
Secondary
Number of Participants With Major Molecular Response (MMR) Rate
To compare additional parameters of the efficacy asciminib versus bosutinib
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 96 weeks after the last patient received the first study dose