Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03578367
Collaborator
(none)
84
Enrollment
30
Locations
4
Arms
47.6
Anticipated Duration (Months)
2.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib in pre-treated patients with Chronic Myeloid Leukemia in chronic phase (CML-CP)

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

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 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). The eligible subjects will be randomized 1:1:1:1 to receive asciminib 60 mg 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).

Subjects on the study will continue on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks after the last randomized subject received the first dose of treatment (the end of treatment (EOT) will be the same day for all the ongoing subjects). After the last dose received, every subject will be followed up for safety for 30 days.

An interim analysis will 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. At the time of the interim analysis, if excessive toxicity without added benefit is observed in one of the investigational arms, discontinuation of that treatment arm will be considered. The decision to discontinue an investigational arm in the study will be taken based on the risk benefit balance of the two investigational arms, and in context of the other two treatment options available for the patients in the study, namely: continue on imatinib with no potential improvement of efficacy; or switch to nilotonib with a potential to improve efficacy however, with a relatively adverse safety profile as compared to imatinib. If a decision is taken to discontinue asciminib 60 mg + imatinib treatment arm at interim analysis, subjects ongoing on that treatment arm will be provided an opportunity to continue on the study at a lower dose (asciminib 40 mg + imatinib) if the investigator considers that is in the best interest of the patient.

Subjects on the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross-over (CO) to receive the add-on treatment within 4 weeks after week 48 visit. It is planned that these subjects cross-over to receive the asciminib 60 mg combination add-on treatment, as this dose provides higher exposure. Based on the results of the interim analysis or emerging data, cross-over may be changed to the asciminib 40 mg add-on treatment. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
84 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Nov 22, 2018
Actual Primary Completion Date :
Nov 8, 2021
Anticipated Study Completion Date :
Nov 11, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: Asciminib 60mg QD + Imatinib 400mg QD

Asciminib 60 mg taken once daily in combination with Imatinib 400 mg taken once daily

Drug: Asciminib add-on
Asciminib 60 mg or 40 mg taken orally once daily in addition to Imatinib 400 mg taken orally once daily
Other Names:
  • ABL001 (asciminib), STI571 (imatinib)
  • Experimental: Asciminib 40mg QD + Imatinib 400mg QD

    Asciminib 40 mg taken once daily in combination with Imatinib 400 mg taken once daily

    Drug: Asciminib add-on
    Asciminib 60 mg or 40 mg taken orally once daily in addition to Imatinib 400 mg taken orally once daily
    Other Names:
  • ABL001 (asciminib), STI571 (imatinib)
  • Active Comparator: Imatinib 400mg QD

    Imatinib 400 mg taken once daily

    Drug: Imatinib
    Imatinib 400 mg taken orally once daily
    Other Names:
  • STI571, continuation treatment
  • Active Comparator: Nilotinib 300mg BID

    Nilotinib 300 mg taken twice daily

    Drug: Nilotinib
    Nilotinib 300 mg taken orally twice daily (total daily dose of 600 mg)
    Other Names:
  • AMN107, switch to nilotinib treatment
  • Outcome Measures

    Primary Outcome Measures

    1. Molecular Response (MR)^4.5 rate between asciminib+imatinib and imatinib alone [at 48 weeks]

      Proportion 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.

    Secondary Outcome Measures

    1. MR^4.5 rate at 48 weeks [at 48 weeks]

      Difference in the proportion of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib

    2. Rate of MR^4.5 at 96 weeks [at 96 weeks]

      Proportion of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 96 weeks

    3. Rate of MR^4.5 by 48 and 96 weeks [by 48 weeks and 96 weeks]

      Best observed rate of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) under randomized treatment up to the specific time point

    4. Sustained MR^4.5 from 48 weeks until 96 weeks [from 48 weeks until 96 weeks]

      Percentage of participants who are in MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at both 48 and 96 weeks and who have no loss of MR^4.5 in between those two time points. This endpoint will be analyzed at 96 weeks.

    5. Time to MR^4.5 [up to 96 weeks]

      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

    6. Difference in rate of MR^4.5 at 48 weeks [at 48 weeks]

      Difference in the proportion of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks between asciminib+imatinib and nilotinib

    7. Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmax [up to Week 4 Day 28]

      The maximum (peak) observed drug concentration after dose administration

    8. Pharmacokinetic profile of asciminib and imatinib when administered in combination - Tmax [up to Week 4 Day 28]

      The time to reach maximum (peak) drug concentration after dose administration

    9. Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmin [up to 96 weeks]

      Minimum drug concentration

    10. Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUClast [up to Week 4 Day 28]

      The AUC from time zero to the last measurable concentration sampling time (Tlast)

    11. Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUCtau [up to Week 4 Day 28]

      The AUC calculated to the end of a dosing interval (tau) at steady-state

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Male or female patients ≥ 18 years of age with a confirmed diagnosis of Chronic Myeloid Leukemia in chronic phase (CML-CP).

    2. Minimum of one year (12 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 400 mg QD at randomization and had no dose change in the past three months).

    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.

    1. 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

    2. 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

    1. 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:
    1. Treatment failure according to European Leukemia Network (ELN) criteria 2013 during imatinib treatment.

    2. Known second chronic phase of CML after previous progression to Accelerated Phase (AP)/Blast Crisis (BC).

    3. Previous treatment with any tyrosine kinese inhibitors (TKIs) other than imatinib.

    4. 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

    1. 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)

    2. 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

    3. 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.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Georgia Regents UniversityAugustaGeorgiaUnited States30912
    2University of ChicagoChicagoIllinoisUnited States60637
    3Sidney Kimmel Comprehensive Cancer CenterBaltimoreMarylandUnited States21205
    4Novartis Investigative SiteWienAustria1140
    5Novartis Investigative SiteMontrealQuebecCanadaH1T 2M4
    6Novartis Investigative SiteBrno - BohuniceCzechia639 01
    7Novartis Investigative SiteHerlevDenmarkDK 2730
    8Novartis Investigative SiteBordeauxFrance33076
    9Novartis Investigative SiteDresdenGermany01307
    10Novartis Investigative SiteMilanoMIItaly20162
    11Novartis Investigative SiteRomaRMItaly00161
    12Novartis Investigative SiteUijeongbu siGyeonggi DoKorea, Republic of11759
    13Novartis Investigative SiteSeoulSeocho GuKorea, Republic of06591
    14Novartis Investigative SiteKrakowPoland31 531
    15Novartis Investigative SiteWarszawaPoland02 776
    16Novartis Investigative SiteWroclawPoland50 367
    17Novartis Investigative SiteLisboaPortugal1099 023
    18Novartis Investigative SitePortoPortugal4200-072
    19Novartis Investigative SiteMoscowRussian Federation125167
    20Novartis Investigative SiteMoscowRussian Federation125284
    21Novartis Investigative SiteSaint PetersburgRussian Federation191024
    22Novartis Investigative SiteSaint PetersburgRussian Federation197341
    23Novartis Investigative SiteSevillaAndaluciaSpain41009
    24Novartis Investigative SiteMadridSpain28034
    25Novartis Investigative SiteValenciaSpain46026
    26Novartis Investigative SiteChanghuaTaiwan50006
    27Novartis Investigative SiteTaoyuanTaiwan33305
    28Novartis Investigative SiteWirralMerseysideUnited KingdomCH63 4JY
    29Novartis Investigative SiteLondonUnited KingdomW12 0HS
    30Novartis Investigative SiteOxfordUnited KingdomOX3 7LJ

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT03578367
    Other Study ID Numbers:
    • CABL001E2201
    • 2018-001594-24
    First Posted:
    Jul 6, 2018
    Last Update Posted:
    Feb 7, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Feb 7, 2022