- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03578367
Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
A Phase 2, Multi-center, Open-label, Randomized Study of Oral Asciminib Added to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients With CML-CP Who Have Been Previously Treated With Imatinib and Have Not Achieved Deep Molecular Response
Study Overview
Status
Intervention / Treatment
Detailed Description
The study is a Phase 2, multi-center, open-label, randomized study of asciminib in two different doses (40 mg or 60 mg) in combination with imatinib 400 mg versus continued imatinib versus switch to nilotinib, versus asciminib 80mg single agent in subjects with chronic myeloid leukemia in chronic phase (CML-CP) who have been previously treated with imatinib first line therapy for at least one year and have not achieved deep molecular response (DMR). Eighty-four eligible subjects were randomized 1:1:1:1 to receive asciminib 60 mg once daily (QD) as add-on therapy to imatinib 400 mg QD, or 40 mg QD as add-on therapy to imatinib 400 mg QD, or to continue imatinib 400 mg QD, or to switch to nilotinib 300 mg twice a day (BID).
The asciminib single agent cohort will be conducted as an open label cohort. Approximately 20 eligible subjects will be enrolled to receive asciminib 80 mg QD. Amendment 3 aims to add the asciminib single agent cohort to assess whether asciminib single agent at the recommended dose of 80mg QD leads to similar efficacy and safety as observed in the add-on arms of asciminib and imatinib. This additional cohort will help to evaluate if the combination of asciminib with imatinib is needed to increase the likelihood of achieving DMR, or if this can be achieved by asciminib alone.
An interim analysis was performed to gain an early insight into the safety and efficacy of the asciminib add-on combination. The interim analysis was planned to be performed when at least 40 (50%) patients have been randomized and have been followed for their 24 weeks visit assessment or have discontinued treatment. The interim analysis cut-off was on 22-July-2020. No change in study conduct were performed based on the benefit/risk balance.
The primary analysis cut-off was on 10-Jan-2022. Eighty-four patients have been randomized in the study.
Subjects on the imatinib continuation arm who had not achieved MR4.5 at 48 weeks were allowed to cross-over (CO) to receive the add-on treatment within 4 weeks after week 48 visit. to receive the asciminib 60 mg combination add-on treatment, as this dose provided higher exposure. The cross-over is at the discretion of the investigator and the patient. Apart from a polymerase chain reaction (PCR) result of below MR4.5 at Week 48 visit, there are no other entry criteria for the cross-over part. Subjects on nilotinib are not allowed to cross- over to receive the add-on treatment.
Subjects on the study will continue on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks (in arms 1 to 4) / or 48 weeks (in asciminib single agent cohort) after the last randomized subject received the first dose of treatment. After the last dose received, every subject will be followed up for safety for 30 days.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Novartis Pharmaceuticals
- Phone Number: 1-888-669-6682
- Email: novartis.email@novartis.com
Study Contact Backup
- Name: Novartis Pharmaceuticals
- Phone Number: +41613241111
Study Locations
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Wien, Austria, 1140
- Novartis Investigative Site
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Quebec
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Montreal, Quebec, Canada, H1T 2M4
- Novartis Investigative Site
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Brno - Bohunice, Czechia, 625 00
- Novartis Investigative Site
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Copenhagen, Denmark, DK-2100
- Novartis Investigative Site
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Bordeaux, France, 33076
- Novartis Investigative Site
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Dresden, Germany, 01307
- Novartis Investigative Site
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MI
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Milano, MI, Italy, 20162
- Novartis Investigative Site
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RM
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Roma, RM, Italy, 00161
- Novartis Investigative Site
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Seocho Gu
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Seoul, Seocho Gu, Korea, Republic of, 06591
- Novartis Investigative Site
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Krakow, Poland, 31 531
- Novartis Investigative Site
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Warszawa, Poland, 02 776
- Novartis Investigative Site
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Wroclaw, Poland, 50 367
- Novartis Investigative Site
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Lisboa, Portugal, 1099 023
- Novartis Investigative Site
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Porto, Portugal, 4200-072
- Novartis Investigative Site
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Moscow, Russian Federation, 125167
- Novartis Investigative Site
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Moscow, Russian Federation, 125284
- Novartis Investigative Site
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Saint Petersburg, Russian Federation, 191024
- Novartis Investigative Site
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Saint Petersburg, Russian Federation, 197341
- Novartis Investigative Site
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Madrid, Spain, 28034
- Novartis Investigative Site
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Valencia, Spain, 46026
- Novartis Investigative Site
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Andalucia
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Sevilla, Andalucia, Spain, 41009
- Novartis Investigative Site
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Catalunya
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Badalona, Catalunya, Spain, 08916
- Novartis Investigative Site
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Changhua, Taiwan, 50006
- Novartis Investigative Site
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Taoyuan, Taiwan, 33305
- Novartis Investigative Site
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London, United Kingdom, W12 0HS
- Novartis Investigative Site
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Oxford, United Kingdom, OX3 7LJ
- Novartis Investigative Site
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Merseyside
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Wirral, Merseyside, United Kingdom, CH63 4JY
- Novartis Investigative Site
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Georgia
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Augusta, Georgia, United States, 30912
- Georgia Regents University
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Maryland
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Baltimore, Maryland, United States, 21205
- Sidney Kimmel Comprehensive Cancer Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Male or female patients ≥ 18 years of age with a confirmed diagnosis of Chronic Myeloid Leukemia in chronic phase (CML-CP).
Minimum of one year (12 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 300mg or 400 mg QD at randomization
For Korea only:
(i)a minimum of one year (12 calendar months) of prior treatment with imatinib for patients with BCR-ABL levels > 0.1%, ≤ 1% IS at the time of randomization.
(ii) a minimum of two years (24 calendar months) of prior treatment with imatinib for patients with BCR-ABL levels > 0.01%, ≤ 0.1% IS at the time of randomization.
- BCR-ABL1 levels > 0.01% IS (International Scale) and ≤ 1% IS at the time of randomization as confirmed with a central assessment at screening; patients must not have achieved deep molecular response (MR4 IS) confirmed by 2 consecutive tests at any time during prior imatinib treatment. An isolated, single test result with BCR-ABL1 levels < 0.01 % (MR4 IS) is allowed, however, it should not have been observed within the 9 months prior to randomization
Patient must meet the following laboratory values before randomization:
- Absolute Neutrophil Count ≥ 1.5 x 10E9/L
- Platelets ≥ 75 x 10E9/L
- Hemoglobin ≥ 9 g/dL
- Serum creatinine < 1.5 mg/dL
- Total bilirubin ≤ 1.5 x ULN (Upper Limit of Normal) except for patients with Gilbert's syndrome who may only be included with total bilirubin ≤ 3.0 x ULN
- Aspartate transaminase (AST) ≤ 3.0 x ULN
- Alanine transaminase (ALT) ≤ 3.0 x ULN
- Alkaline phosphatase ≤ 2.5 x ULN
- Serum lipase ≤ 1.5 x ULN
- Patients must have the following laboratory values ≥ Lower Limit of Normal or corrected to within normal limits with supplements prior to randomization: potassium increase of up to 6.0 mmol/L is acceptable if associated with creatinine clearance within normal limits ; calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with creatinine clearance* within normal limits) ; magnesium increase up to 3.0 mg/dL or 1.23 mmol/L if associated with creatinine clearance within normal limits.
Key Exclusion Criteria:
- Treatment failure according to European Leukemia Network (ELN) criteria 2013 during imatinib treatment.
- Known second chronic phase of CML after previous progression to Accelerated Phase (AP)/Blast Crisis (BC).
- Previous treatment with any tyrosine kinese inhibitors (TKIs) other than imatinib.
History or current diagnosis of ECG abnormalities indicating significant risk or safety for subjects participating in the study such as:
- History of myocardial infarction, angina pectoris, coronary artery bypass graft within 6 months prior to randomization
- Concomitant clinically significant arrhythmias
- Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to randomization
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
- Concomitant medications with a "known" risk of Torsades de Pointes
- 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, uncontrolled clinically significant hyperlipidemia and high serum amylase)
- History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis; on-going acute liver disease or history of chronic liver disease
- History of other active malignancy within 3 years prior to randomization with the exception of basal cell skin cancer, indolent prostate cancer and carcinoma in situ treated curatively.
Other protocol defined inclusion/exclusion may apply.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Asciminib 60mg QD + Imatinib 400mg QD
Asciminib 60 mg taken once daily in combination with Imatinib 400 mg taken once daily
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Asciminib 60 mg or 40 mg taken orally once daily.
Other Names:
Imatinib 400 mg taken orally once daily
Other Names:
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Experimental: Asciminib 40mg QD + Imatinib 400mg QD
Asciminib 40 mg taken once daily in combination with Imatinib 400 mg taken once daily
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Asciminib 60 mg or 40 mg taken orally once daily.
Other Names:
Imatinib 400 mg taken orally once daily
Other Names:
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Active Comparator: Imatinib 400mg QD
Imatinib 400 mg taken once daily
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Imatinib 400 mg taken orally once daily
Other Names:
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Active Comparator: Nilotinib 300mg BID
Nilotinib 300 mg taken twice daily
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Nilotinib 300 mg taken orally twice daily (total daily dose of 600 mg)
Other Names:
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Experimental: Asciminib 80mg QD
Asciminib 80 mg taken once daily
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Asciminib 80 mg taken orally once daily
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Molecular Response (MR)^4.5 rate between asciminib+imatinib and imatinib alone
Time Frame: at 48 weeks
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Percentage of subjects still treated with the randomized treatment at 48 weeks and are in MR4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks (± assessment window), among all subjects randomized to the respective treatment arm.
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at 48 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Rate of MR^4.5 by 48 and 96 weeks
Time Frame: by 48 weeks and 96 weeks
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Best observed rate of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) under randomized treatment up to the specific time point
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by 48 weeks and 96 weeks
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Sustained MR^4.5 from 48 weeks until 96 weeks
Time Frame: at 96 weeks
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Percentage of participants who are in MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 96 weeks and who have no loss of MR^4.5.
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at 96 weeks
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Time to MR^4.5
Time Frame: up to 96 weeks
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Time to MR^4.5 is the time from randomization to first MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) computed only for subjects who achieved MR^4.5
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up to 96 weeks
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Duration of MR^4.5
Time Frame: end of treatment
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Time from first MR^4.5 until loss of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%).
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end of treatment
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Incidence and severity of adverse events, changes in laboratory values, clinically notable ECG abnormalities and vital signs
Time Frame: end of study
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To characterize the safety and tolerability profile of asciminib 60 mg or 40 mg + imatinib vs continued imatinib or switch to nilotinib or asciminib 80mg QD
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end of study
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Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmax
Time Frame: up to 96 weeks
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The maximum (peak) observed drug concentration after dose administration
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up to 96 weeks
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Pharmacokinetic profile of asciminib and imatinib when administered in combination - Tmax
Time Frame: up to 96 weeks
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The time to reach maximum (peak) drug concentration after dose administration
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up to 96 weeks
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Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmin
Time Frame: up to 96 weeks
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Minimum drug concentration
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up to 96 weeks
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Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUClast
Time Frame: up to 96 weeks
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The AUC from time zero to the last measurable concentration sampling time (Tlast)
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up to 96 weeks
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Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUCtau
Time Frame: up to 96 weeks
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The AUC calculated to the end of a dosing interval (tau) at steady-state
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up to 96 weeks
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Time to MR^4.5
Time Frame: up to 48 weeks
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For subjects on asciminib 80mg QD: Time to MR^4.5 is the time from randomization to first MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) computed only for subjects who achieved MR^4.5
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up to 48 weeks
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Duration of MR^4.5
Time Frame: end of treatment
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Time from first MR^4.5 until loss of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) for subjects on asciminib 80mg QD
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end of treatment
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Pharmacokinetic profile of asciminib 80mg QD - Cmax
Time Frame: up to 48 weeks
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The maximum (peak) observed drug concentration after dose administration
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up to 48 weeks
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Pharmacokinetic profile of asciminib 80mg QD - Tmax
Time Frame: up to 48 weeks
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The time to reach maximum (peak) drug concentration after dose administration
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up to 48 weeks
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Pharmacokinetic profile of asciminib 80mg QD - Cmin
Time Frame: up to 48 weeks
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Minimum drug concentration
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up to 48 weeks
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Pharmacokinetic profile of asciminib 80mg QD - AUClast
Time Frame: up to 48 weeks
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The AUC from time zero to the last measurable concentration sampling time (Tlast)
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up to 48 weeks
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Pharmacokinetic profile of asciminib 80mg QD - AUCtau
Time Frame: up to 48 weeks
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The AUC calculated to the end of a dosing interval (tau) at steady-state
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up to 48 weeks
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MR^4.5 rate at 48 weeks
Time Frame: at 48 weeks
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Percentage of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib
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at 48 weeks
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Difference in rate of MR^4.5 at 48 weeks
Time Frame: at 48 weeks
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Difference in the percentage of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib
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at 48 weeks
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Rate of MR^4.5 at 96 weeks
Time Frame: at 96 weeks
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Percentage of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 96 weeks
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at 96 weeks
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MR^4.5 rate at 48 weeks
Time Frame: at 48 weeks
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The percentage of subjects on asciminib 80mg QD with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks
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at 48 weeks
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Collaborators and Investigators
Sponsor
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Disease Attributes
- Bone Marrow Diseases
- Myeloproliferative Disorders
- Chronic Disease
- Leukemia
- Leukemia, Myeloid
- Hematologic Diseases
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Micronutrients
- Protein Kinase Inhibitors
- Vitamins
- Vitamin B Complex
- Tyrosine Kinase Inhibitors
- Imatinib Mesylate
- Niacinamide
- Nilotinib
- Asciminib
Other Study ID Numbers
- CABL001E2201
- 2018-001594-24 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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