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Trial record 1 of 1 for:    CABL001E2201
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Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

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ClinicalTrials.gov Identifier: NCT03578367
Recruitment Status : Recruiting
First Posted : July 6, 2018
Last Update Posted : September 21, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib versus asciminib 80mg in pre-treated patients with Chronic Myeloid Leukemia in chronic phase (CML-CP)

Condition or disease Intervention/treatment Phase
CML Chronic Myelogenous Leukemia Leukemia, Myeloid Chronic Hematologic Diseases Drug: Asciminib add-on Drug: Imatinib Drug: Nilotinib Drug: Asciminib single agent 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, 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 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.

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. The results showed no excess of risk and/or reduced efficacy in the asciminib add-on arms. No change in study conduct were performed based on the benefit/risk balance.

This amendment aims to add an 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.

The primary analysis cut-off was on 10-Jan-2022. Eighty-four patients have been randomized in the study. The primary analysis results show activity of asciminib as an add-on therapy to imatinib, assessed by MR4.5 rate at Week 48. The MR4.5 rate at Week 48 was 19%, 28.6%, 0% and 4.8% in the asciminib 40 mg + imatinib, asciminib 60 mg + imatinib, continued imatinib and switch to nilotinib arm. Asciminib 40 mg QD or 60 mg QD added on to imatinib was well tolerated with no new or worsening events as compared to the known safety profile of single agent asciminib and imatinib.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Treatment arms 1 - 4 randomized; New Treatment arm 5 (asciminib single agent cohort) not randomized
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 : November 22, 2018
Actual Primary Completion Date : November 8, 2021
Estimated Study Completion Date : December 3, 2024


Arm Intervention/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 Name: 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 Name: 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 Name: 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 Name: AMN107, switch to nilotinib treatment

Experimental: Asciminib 80mg
Asciminib 80 mg taken once daily
Drug: Asciminib single agent
Asciminib 80 mg taken orally once daily
Other Name: ABL001 (asciminib)




Primary Outcome Measures :
  1. Molecular Response (MR)^4.5 rate between asciminib+imatinib and imatinib alone [ Time Frame: 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 [ Time Frame: 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. Difference in rate of MR^4.5 at 48 weeks [ Time Frame: 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

  3. Rate of MR^4.5 at 96 weeks [ Time Frame: at 96 weeks ]
    Proportion of subjects with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 96 weeks

  4. Rate of MR^4.5 by 48 and 96 weeks [ Time Frame: 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

  5. Sustained MR^4.5 from 48 weeks until 96 weeks [ Time Frame: at 96 weeks ]
    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.

  6. Time to MR^4.5 [ Time Frame: 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

  7. Duration of MR^4.5 [ Time Frame: end of treatment ]
    Time from first MR^4.5 until loss of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%).

  8. Incidence and severity of adverse events, changes in laboratory values, clinically notable ECG abnormalities and vital signs [ Time Frame: end of study ]
    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

  9. Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmax [ Time Frame: up to 96 weeks ]
    The maximum (peak) observed drug concentration after dose administration

  10. Pharmacokinetic profile of asciminib and imatinib when administered in combination - Tmax [ Time Frame: up to 96 weeks ]
    The time to reach maximum (peak) drug concentration after dose administration

  11. Pharmacokinetic profile of asciminib and imatinib when administered in combination - Cmin [ Time Frame: up to 96 weeks ]
    Minimum drug concentration

  12. Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUClast [ Time Frame: up to 96 weeks ]
    The AUC from time zero to the last measurable concentration sampling time (Tlast)

  13. Pharmacokinetic profile of asciminib and imatinib when administered in combination - AUCtau [ Time Frame: up to 96 weeks ]
    The AUC calculated to the end of a dosing interval (tau) at steady-state

  14. MR^4.5 rate at 48 weeks [ Time Frame: at 48 weeks ]
    The proportion of subjects on asciminib 80mg QD with MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) at 48 weeks

  15. Time to MR^4.5 [ Time Frame: up to 48 weeks ]
    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

  16. Duration of MR^4.5 [ Time Frame: end of treatment ]
    Time from first MR^4.5 until loss of MR^4.5 (BCR-ABL1 ratio of ≤ 0.0032%) for subjects on asciminib 80mg QD

  17. Pharmacokinetic profile of asciminib 80mg QD - Cmax [ Time Frame: up to 48 weeks ]
    The maximum (peak) observed drug concentration after dose administration

  18. Pharmacokinetic profile of asciminib 80mg QD - Tmax [ Time Frame: up to 48 weeks ]
    The time to reach maximum (peak) drug concentration after dose administration

  19. Pharmacokinetic profile of asciminib 80mg QD - Cmin [ Time Frame: up to 48 weeks ]
    Minimum drug concentration

  20. Pharmacokinetic profile of asciminib 80mg QD - AUClast [ Time Frame: up to 48 weeks ]
    The AUC from time zero to the last measurable concentration sampling time (Tlast)

  21. Pharmacokinetic profile of asciminib 80mg QD - AUCtau [ Time Frame: up to 48 weeks ]
    The AUC calculated to the end of a dosing interval (tau) at steady-state



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

  3. 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
  4. 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
  5. 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
  5. 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)
  6. 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
  7. 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03578367


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03578367    
Other Study ID Numbers: CABL001E2201
2018-001594-24 ( EudraCT Number )
First Posted: July 6, 2018    Key Record Dates
Last Update Posted: September 21, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

URL: https://www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
CML
Chronic Myelogenous Leukemia
leukemia, myeloid chronic
Hematologic Diseases
Asciminib
ABL001
Imatinib
Nilotinib
deep molecular response
DMR
Ph+ CML
chronic phase
cancer of the white blood cells
tyrosine kinase inhibitor
leukemia, myeloid
leukemia
CML without Ph+
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Hematologic Diseases
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Niacinamide
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Physiological Effects of Drugs