Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs
Condition: Chronic Myelogenous Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Intervention: Asciminib; Bosutinib
Intervention description: 40 mg tablets was taken orally twice a day (BID); 500 mg tablets was taken orally once daily (QD)
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 233.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Phase 3; Chronic Myelogenous Leukemia; CML; bosutinib; ABL001; tyrosine kinase inhibitor; Chronic myelogenous leukemia (CML); chronic myeloid leukemia (CML); chronic myelocytic leukemia (CML); chronic granulocytic leukemia (CGL); cancer of the white blood cells; clonal bone marrow stem cell disorder; proliferation of mature granulocytes

Summary:

      The purpose of this pivotal study was to compare the efficacy of asciminib (ABL001) with that
      of bosutinib in the treatment of patients with CML-CP having previously been treated with a
      minimum of two prior ATP-binding site TKIs.

      Patients intolerant to the most recent TKI therapy must have had BCR-ABL1 ratio > 0.1% IS at
      screening and patients failing their most recent TKI therapy must have met the definition of
      treatment failure as per the 2013 European LeukemiaNet (ELN) recommendations.

      Patients with documented treatment failure as per 2013 ELN recommendations while on bosutinib
      treatment had the option to switch to asciminib treatment within 96 weeks after the last
      patient has been randomized on study.
    

Eligibility criteria:

        Inclusion Criteria:

        Male or female patients with a diagnosis of CML-CP ≥ 18 years of age

        Patients must meet all of the following laboratory values at the screening visit:

          -  < 15% blasts in peripheral blood and bone marrow

          -  < 30% blasts plus promyelocytes in peripheral blood and bone marrow

          -  < 20% basophils in the peripheral blood

          -  ≥ 50 x 109/L (≥ 50,000/mm3) platelets

          -  Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior to
             screening) is acceptable

          -  No evidence of extramedullary leukemic involvement, with the exception of
             hepatosplenomegaly

        BCR-ABL1 ratio > 0.1% IS according to central laboratory at the screening examination for
        patients intolerant to the most recent TKI therapy

        Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib,
        dasatinib, radotinib or ponatinib)

        Failure (adapted from the 2013 ELN Guidelines Bacarrani 2013) or intolerance to the most
        recent TKI therapy at the time of screening

          -  Failure is defined for CML-CP patients (CP at the time of initiation of last therapy)
             as follows. Patients must meet at least 1 of the following criteria.

          -  Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases

          -  Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+
             metaphases

          -  Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+
             metaphases

          -  At any time after the initiation of therapy, loss of CHR, CCyR or PCyR

          -  At any time after the initiation of therapy, the development of new BCR-ABL1 mutations
             which potentially cause resistance to study treatment

          -  At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive
             tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS

          -  At any time after the initiation of therapy, new clonal chromosome abnormalities in
             Ph+ cells: CCA/Ph+

          -  Intolerance is defined as:

          -  Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or
             with persistent grade 2 toxicity, unresponsive to optimal management, including dose
             adjustments (unless dose reduction is not considered in the best interest of the
             patient if response is already suboptimal)

          -  Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil
             count [ANC] or platelets) while on therapy that is recurrent after dose reduction to
             the lowest doses recommended by manufacturer

        Exclusion Criteria:

        Known presence of the T315I or V299L mutation at any time prior to study entry Known second
        chronic phase of CML after previous progression to AP/BC Previous treatment with a
        hematopoietic stem-cell transplantation Patient planning to undergo allogeneic
        hematopoietic stem cell transplantation

        Cardiac or cardiac repolarization abnormality, including any of the following:

          -  History within 6 months prior to starting study treatment of myocardial infarction
             (MI), angina pectoris, coronary artery bypass graft (CABG)

          -  Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete
             left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type
             II and third degree AV block)

          -  QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients)

          -  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 (TdP) including uncorrected hypokalemia or
             hypomagnesemia, history of cardiac failure, or history of clinically
             significant/symptomatic bradycardia

          -  Concomitant medication(s) with a known risk of Torsades de Pointes per
             www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting
             study drug by safe alternative medication.

          -  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, pulmonary
             hypertension)

          -  History of acute pancreatitis within 1 year of study entry or past medical history of
             chronic pancreatitis

          -  History of acute or chronic liver disease

          -  Treatment with medications that meet one of the following criteria and that cannot be
             discontinued at least one week prior to the start of treatment with study treatment

          -  Moderate or strong inducers of CYP3A

          -  Moderate or strong inhibitors of CYP3A

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             during dosing and for 3 days after last dose of ABL001 and one month after last dose
             of bosutinib. Highly effective contraception methods include:

          -  Total abstinence (when this is in line with the preferred and usual lifestyle of the
             subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
             methods) and withdrawal are not acceptable methods of contraception

          -  Female sterilization (have had surgical bilateral oophorectomy (with or without
             hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before
             taking study treatment). In case of oophorectomy alone, only when the reproductive
             status of the woman has been confirmed by follow up hormone level assessment

          -  Male sterilization (at least 6 months prior to screening). The vasectomized male
             partner should be the sole partner for that subject.

          -  Use of oral, injected or implanted hormonal methods of contraception or placement of
             an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal
             contraception that have comparable efficacy (failure rate <1%), for example hormone
             vaginal ring or transdermal hormone contraception.

          -  In case of use of oral contraception women should have been stable on the same pill
             for a minimum of 3 months before taking study treatment.

          -  Women are considered post-menopausal and not of child bearing potential if they have
             had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
             (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
             oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal
             ligation at least six weeks before taking study medication. In the case of
             oophorectomy alone, women are considered post-menopausal and not of child bearing
             potential only when the reproductive status of the woman has been confirmed by follow
             up hormone level assessment.