Clinical Trials /

Frontline Asciminib Combination in Chronic Phase CML

NCT03906292

Description:

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, or dasatinib 100 mg QD 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. Referred patients already treated with imatinib, nilotinib or dasatinib will remain on the initial drug and will be allocated to the respective cohort.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Frontline Asciminib Combination in Chronic Phase CML
  • Official Title: Frontline Asciminib Combination in Chronic Phase CML

Clinical Trial IDs

  • ORG STUDY ID: Fascination
  • SECONDARY ID: 2018‐002256‐33
  • NCT ID: NCT03906292

Conditions

  • Chronic Myeloid Leukemia

Interventions

DrugSynonymsArms
ImatinibImatinib 400 mg QD and asciminib 60 mg QDAsciminib 60mg QD
Nilotinib 300 mgNilotinib 300 mg BID and asciminib 20 mg BID or 40 mg QDAsciminb 20 mg BID
DasatinibDasatinib 100 mg QD and asciminib 80 mg QDAsciminib 80 mg QD
AsciminibAsciminib 60mg QD

Purpose

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, or dasatinib 100 mg QD 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. Referred patients already treated with imatinib, nilotinib or dasatinib will remain on the initial drug and will be allocated to the respective cohort.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Asciminib 60mg QDExperimentalStandard therapy of Imatinib 400 mg QD and asciminib 60 mg QD
  • Imatinib
  • Asciminib
Asciminb 20 mg BIDExperimentalStandard therapy of Nilotinib 300 mg BID and asciminib 20 mg BID
  • Nilotinib 300 mg
  • Asciminib
Asciminib 40 mg QDExperimentalStandard therapy of Nilotinib 300 mg BID and asciminib 40 mg QD
  • Nilotinib 300 mg
  • Asciminib
Asciminib 80 mg QDExperimentalStandard therapy of Dasatinib 100 mg QD and asciminib 80 mg QD
  • Dasatinib
  • Asciminib

Eligibility Criteria

        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 3 months 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:deep molecular response (Rate of MR4)
Time Frame:at month 12 after Start of Therapy
Safety Issue:
Description:Achievement of deep molecular response (MR4) throught standardized testing of BCR-ABL-transcript Levels

Secondary Outcome Measures

Measure:molecular response (MMR and MR4.5)
Time Frame:at and by 6, 12, 18 and 24 months after Start of Therapy
Safety Issue:
Description:Achievement of deep molecular response throught standardized testing of BCR-ABL-transcript levels
Measure:Adverse Events
Time Frame:at and by baseline, 3, 6, 12, 15, 18, 21 and 24 months after Start of Therapy
Safety Issue:
Description:Incidence of adverse events grade 1-5 and 3-5
Measure:Progression free survival
Time Frame:at month 24 after Start of Therapy
Safety Issue:
Description:Progression free survival at the end of the study
Measure:Overall survival
Time Frame:at month 24 after Start of Therapy
Safety Issue:
Description:Overall survival at the end of the study

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Prof. Dr. med. Andreas Hochhaus

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