CMLXI: Frontline Asciminib Combination in Chronic Phase CML

Sponsor
University of Jena (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03906292
Collaborator
Ludwig-Maximilians - University of Munich (Other), Novartis Pharmaceuticals (Industry)
125
21
5
99.4
6
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Study Details

Study Description

Brief Summary

Adult male and female patients with newly diagnosed Philadelphia chromosome positive (Ph+) and/or BCR-ABL1 positive CML can be included in the study until 3 months after diagnosis. A <4 week pretreatment with hydroxyurea is permitted. Patients treated for <6 weeks with nilotinib 300 mg BID, imatinib 400 mg QD, dasatinib 100 mg QD or without any therapy are eligible for recruitment and will be allocated to the respective cohort. All patients must provide written informed consent to be enrolled in the trial. Cohorts were designed to allow assessment of QD and BID asciminib based combinations to optimize quality of life and compliance. Patients will not be randomized. In general, cohorts will be filled consecutively. Asciminib therapy will be commenced 12 weeks after start of nilotinib, imatinib or dasatinib and after recovery of hematopoiesis or in case of no therapy so far 6 weeks after diagnosis as first line treatment. Referred patients already treated with imatinib, nilotinib or dasatinib will remain on the initial drug and will be allocated to the respective cohort.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Despite the dramatic progress made over the past decade with TKIs in the treatment of CML, allogeneic stem cell transplant remains the only proven curative therapy. To achieve cure or benefit from treatment-free remissions with pharmacologically-based therapies, it is estimated that patients will likely need to achieve a sustained reduction in tumor burden corresponding to a deep molecular response of at least 4 logs (MR4). Currently, only 30.8% of patients achieve a deep molecular response after 12 months of treatment with single agent nilotinib.

The development of the novel and potent BCR-ABL1 allosteric inhibitor, asciminib, presents an opportunity to assess the effect of a different mechanism of inhibition of BCR-ABL1 in the first-line treatment of CML to enhance speed of response and to increase the patient population benefitting from deep molecular response. Dosing a combination of asciminib with an ATP-site inhibitor also has the potential to prevent the emergence of resistance due to point mutations being acquired in one of the binding sites.

The safety, tolerability and pharmacokinetic profile of asciminib as a single agent and in combination with either nilotinib or imatinib or dasatinib was assessed in a phase-I study. At the doses chosen here, all three combination treatments were well tolerated.

Since in all patient cohorts the standard of care therapy will remain the backbone of initial therapy, there is no reason to expect an efficacy problem with the combination therapies.

Study Design

Study Type:
Interventional
Actual Enrollment :
125 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
5 parallel cohorts5 parallel cohorts
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Frontline Asciminib Combination in Chronic Phase CML
Actual Study Start Date :
Aug 19, 2019
Anticipated Primary Completion Date :
Dec 1, 2027
Anticipated Study Completion Date :
Dec 1, 2027

Arms and Interventions

Arm Intervention/Treatment
Experimental: Asciminib 60mg QD

Standard therapy of Imatinib 400 mg QD and asciminib 60 mg QD

Drug: Imatinib
Imatinib 400 mg QD and asciminib 60 mg QD
Other Names:
  • Imatinib 400 mg QD and asciminib 60 mg QD
  • Drug: Asciminib
    Asciminib 80 mg QD Monotherapy

    Experimental: Asciminb 20 mg BID

    Standard therapy of Nilotinib 300 mg BID and asciminib 20 mg BID

    Drug: Nilotinib 300 mg
    Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD
    Other Names:
  • Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD
  • Drug: Asciminib
    Asciminib 80 mg QD Monotherapy

    Experimental: Asciminib 40 mg QD

    Standard therapy of Nilotinib 300 mg BID and asciminib 40 mg QD

    Drug: Nilotinib 300 mg
    Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD
    Other Names:
  • Nilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QD
  • Drug: Asciminib
    Asciminib 80 mg QD Monotherapy

    Experimental: Asciminib 80 mg QD

    Standard therapy of Dasatinib 100 mg QD and asciminib 80 mg QD

    Drug: Dasatinib
    Dasatinib 100 mg QD and asciminib 80 mg QD
    Other Names:
  • Dasatinib 100 mg QD and asciminib 80 mg QD
  • Drug: Asciminib
    Asciminib 80 mg QD Monotherapy

    Experimental: Asciminib 80 mg QD monotherapy

    Asciminib 80 mg QD as a single agent

    Drug: Asciminib
    Asciminib 80 mg QD Monotherapy

    Outcome Measures

    Primary Outcome Measures

    1. deep molecular response (Rate of MR4) [at month 12 after Start of Standard-Therapy]

      Achievement of deep molecular response (MR4) throught standardized testing of BCR-ABL-transcript Levels

    2. deep molecular Response (Rate of MR4.5) [at month 36 after Start of Standard-Therapy]

      Achievement of deep molecular response (MR4.5) throught standardized testing of BCR-ABL-transcript Levels

    Secondary Outcome Measures

    1. molecular response (MMR and MR4.5) [at and by 6, 12, 18, 24, 36 and 60 months after Start of Therapy]

      Achievement of deep molecular response throught standardized testing of BCR-ABL-transcript levels

    2. Adverse Events [at and by baseline, 3, 6, 12, 15, 18, 21, 24, 36 and 60 months after Start of Therapy]

      Incidence of adverse events grade 1-5 and 3-5

    3. Progression free survival [at month 60 after Start of Therapy]

      Progression free survival at the end of the study

    4. Overall survival [at month 60 after Start of Therapy]

      Overall survival at the end of the study

    5. Maintenance of MR4.5 during Asciminib-monotherapy [at month 36 and 60 after Start of Therapy]

      Achievement of deep molecular response (MR4.5) throught standardized testing of BCR-ABL-transcript Levels

    6. Achievement and durability of treatment-free remission [months 37 and 60 after Start of Therapy]

      Achievement of deep molecular response (MR4) throught standardized testing of BCR-ABL-transcript Levels

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of the Ph+ chromosome [t(9;22)(q34;q11)].

    • Ph-negative cases or patients with variant translocations who are BCR-ABL1 positive in multiplex PCR 35 will be also considered eligible.

    • ECOG performance status of ≤2.

    • Age ≥ 18 years old (no upper age limit is given)

    • Serum levels of potassium, magnesium, total calcium within the normal limits (≥LLN [lower limit of normal] and ≤ULN [upper limit of normal]). Correction of electrolytes levels with supplements to fulfil enrolment criteria is allowed.

    • AST and ALT ≤2.5 x ULN or 5.0 x ULN if considered due to leukemia

    • Alkaline phosphatase ≤2.5 x ULN unless considered due to leukemia

    • Total bilirubin ≤1.5 x ULN, except known Gilbert disease

    • Serum creatinine ≤2 x ULN

    • Written informed consent prior to any study procedures being performed.

    Exclusion Criteria:
    • Allogeneic stem cell transplantation

    • Known impaired cardiac function, including any of the following:

    • Congenital long QT syndrome

    • History of or presence of clinically significant ventricular or atrial tachyarrhythmia

    • QTc >450 msec on screening ECG

    • Myocardial infarction within 12 months prior to starting therapy

    • Other clinical significant heart disease (e.g. unstable angina, congestive heart failure)

    • Acute or chronic viral hepatitis with moderate or severe hepatic impairment (Child-Pugh scores >6), even if controlled

    • Other concurrent uncontrolled medical conditions (e.g., active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol

    • Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)

    • Concomitant medications known to be strong inducers or inhibitors of the CYP450 isoenzyme CYP3A4

    • Patients who have undergone major surgery ≤2 weeks prior to starting study drug or who have not recovered from side effects of such therapy

    • Patients who are pregnant or breastfeeding or women of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study start. Post-menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential. Male and female patients must agree to employ an effective method of birth control throughout the study and for up to 2 weeks following discontinuation of study drug

    • Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)

    • Known serious hypersensitivity reactions to asciminib, imatinib, nilotinib or dasatinib

    • Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention

    • Patients unwilling or unable to comply with the protocol.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Universitätsklinikum Aachen Medizinische Klinik IV Aachen Germany 52074
    2 Charite Universitätsmeditin Berlin, Campus Virchow Klinikum Berlin Germany 13353
    3 Universitätsklinikum Bonn Bonn Germany 53105
    4 Klinikum Bremen Mitte Bremen Germany 28177
    5 Klinikum Chemnitz gGmbH Chemnitz Germany 09113
    6 GOKOS GmbH Dresden Germany 01307
    7 Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden Dresden Germany 01307
    8 Universitätsklinikum Erlangen Erlangen Germany 91054
    9 Universitätsklinikum Essen Essen Germany 45122
    10 Universitätsklinikum Frankfurt Frankfurt Germany 60590
    11 Universitätsklinikum Freiburg Freiburg Germany 79106
    12 Universitätsklinikum Jena Jena Germany 07747
    13 Universitätsklinikum Leipzig Leipzig Germany 04103
    14 Gemeinschaftspraxis Dres. Müller/ Kröning/ Jentsch-Ullrich/ Tietze/ Krogel Magdeburg Germany 39104
    15 Universitätsmedizin der Johannes- Gutenberg Universität Mainz Mainz Germany 55131
    16 Universitätsmedizin Mannheim Mannheim Germany 68169
    17 Universitätsklinikum Gießen und Marburg Marburg Germany 35043
    18 Klinikum rechts der Isar München Germany 81675
    19 Brüderkrankenhaus St. Josef Paderborn Paderborn Germany 33098
    20 Krankenhaus Barmherzige Brüder Regensburg Regensburg Germany 93049
    21 Universitätsklinikum Ulm Ulm Germany 89081

    Sponsors and Collaborators

    • University of Jena
    • Ludwig-Maximilians - University of Munich
    • Novartis Pharmaceuticals

    Investigators

    • Principal Investigator: Thomas Ernst, Prof. Dr., University Hospital Jena

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Thomas Ernst, PD Dr. med., Principal Investigator, University of Jena
    ClinicalTrials.gov Identifier:
    NCT03906292
    Other Study ID Numbers:
    • Fascination
    • 2018-002256-33
    First Posted:
    Apr 8, 2019
    Last Update Posted:
    Jun 2, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jun 2, 2022