Clinical Trials /

Asciminib in Monotherapy for Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With and Without T315I Mutation

NCT04666259

Description:

This study will be a multicenter Phase IIIb open-label, three-cohort study of asciminib in patients with CML-CP without T315I mutation who have had at least 2 prior TKIs and CML-CP harboring the T315I mutation with at least 1 prior TKI

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Asciminib in Monotherapy for Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With and Without T315I Mutation
  • Official Title: An Open Label, Multi-center Phase IIIb Study of Asciminib (ABL001) Monotherapy in Previously Treated Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With and Without T315I Mutation

Clinical Trial IDs

  • ORG STUDY ID: CABL001AUS04
  • NCT ID: NCT04666259

Conditions

  • Chronic Myelogenous Leukemia - Chronic Phase

Interventions

DrugSynonymsArms
ABL001Cohort A

Purpose

This study will be a multicenter Phase IIIb open-label, three-cohort study of asciminib in patients with CML-CP without T315I mutation who have had at least 2 prior TKIs and CML-CP harboring the T315I mutation with at least 1 prior TKI

Detailed Description

      This trial consists of three periods: screening and baseline for up to 21 days, active
      treatment for up to 72 weeks and a safety follow up period for 30 days.

      One hundred and fifteen (115) patients with chronic myeloid leukemia in chronic phase
      (CML-CP) without T315I mutation who have had at least 2 prior Tyrosine Kinase Inhibitors
      (TKIs) and CML-CP with the T315I mutation with at least 1 prior TKI will be considered for
      the current study

      Informed consent will be obtained before any procedures are performed for the study including
      eligibility assessments. The results of the real time quantitative polymerase chain reaction
      (RQ-PCR) must be available prior to randomization and first dose of study treatment.

      Patients with CML-CP without T315I mutation will be randomly assigned to either cohort A or
      B. Patients with the T315I mutation will be enrolled in cohort C. During treatment period
      asciminib will be taken orally: Cohort A will be administered 40 mg twice a day, Cohort B
      will be administered 80 mg once a day and Cohort C will be administered 200 mg twice a day.
      The patients will be treated up to end of study treatment period defined as up to 72 weeks
      after the last patient receives the first dose. Patients may be discontinued from treatment
      with the study drug at any time due to unacceptable toxicity, disease progression and/or at
      the discretion of the investigator or the patient.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimental40 mg asciminib orally twice daily (BID)
  • ABL001
Cohort BExperimental80 mg asciminib orally once daily (QD)
  • ABL001
Cohort CExperimental200 mg asciminib orally twice daily (BID)
  • ABL001

Eligibility Criteria

        Inclusion Criteria

        Participants eligible for inclusion in this study must meet all of the following criteria:

          1. Written informed consent must be obtained and signed prior to participation in the
             study

          2. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age

          3. Patients must meet all of the following laboratory values at the screening visit:

               -  < 15% blasts in peripheral blood and/or bone marrow

               -  < 30% blasts plus promyelocytes in peripheral blood and/or 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

          4. Mutation Analysis testing performed 6 months before study entry

          5. Prior treatment with a minimum of:

               -  2 prior ATP-site TKIs (i.e. imatinib, nilotinib, bosutinib, dasatinib or
                  ponatinib) in case of absence of T315I mutation

               -  1 prior ATP site TKI (i.e. imatinib, nilotinib, bosutinib, dasatinib or
                  ponatinib) in case of presence of T315I mutation

          6. Failure (adapted from the 2020 ELN Recommendations) or intolerance to the most recent
             TKI therapy at the time of screening

               -  Failure for CML-CP patients (CP at the time of initiation of last therapy) is
                  defined as meeting at least one of the following criteria.

               -  Three months after the initiation of therapy: >10% BCR-ABL1 on International
                  Scale (IS) if confirmed within 1-3 months

               -  Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS

               -  Twelve months after initiation of therapy: BCR-ABL1 ratio > 1% IS

               -  At any time after the initiation of therapy, loss of CHR, MR2

               -  At any time after the initiation of therapy, the development of new BCR-ABL1
                  mutations which potentially cause resistance to current treatment

               -  At any time 12 months after the initiation of therapy, BCR-ABL1 ratio ≥ 1% IS or
                  loss of MMR

               -  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

          7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2

          8. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening
             which are amenable to standardized RQ-PCR quantification.

          9. Adequate end organ function, within 12 days before the first dose of asciminib
             treatment. Patients with mild to moderate renal and hepatic impairment are eligible
             if:

               -  Total bilirubin ≤ 3.0 x ULN without AST/ALT increase

               -  Aspartate transaminase (AST) ≤ 5.0 x ULN

               -  Alanine transaminase (ALT) ≤ 5.0 x ULN

               -  Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value should be
                  considered not clinically significant and not associated with risk factors for
                  acute pancreatitis

               -  Alkaline phosphatase ≤ 2.5 x ULN

               -  Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft-Gault formula

         10. Patients must avoid consumption of grapefruit, Seville oranges or products containing
             the juice of each during the entire study and preferably 7 days before the first dose
             of study medications, due to potential CYP3A4 interaction with the study medications.
             Orange juice is allowed.

         11. Treatment with medications that meet one of the following criteria is allowed if used
             with caution 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

         12. Patients must have the following electrolyte values (as per central laboratory tests)
             within normal limits or corrected to be within normal limits with supplements prior to
             first dose of study medication:

               -  Potassium (potassium increase of up to 6.0 mmol/L is acceptable at study entry if
                  associated with creatinine clearance within normal limits)

               -  Total calcium (corrected for serum albumin); (calcium increase of up to 12.5
                  mg/dl or 3.1 mmol/L is acceptable at study entry if associated with creatinine
                  clearance within normal limits)

               -  Magnesium, with the exception of magnesium increase > ULN - 3.0 mg/dL; > ULN -
                  1.23 mmol/L associated with creatinine clearance (calculated using
                  Cockcroft-Gault formula) within normal limits.

        Exclusion Criteria:

        Patients eligible for this study must not meet any of the following criteria:

          1. Known second chronic phase of CML after previous progression to AP/BC

          2. Previous treatment with a hematopoietic stem-cell transplantation

          3. 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
                  wwwcrediblemeds.org/ that cannot be discontinued or replaced 7 days prior to
                  starting study drug by safe alternative medication.

               -  Inability to determine the QTcF interval

          4. 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)

          5. History of acute pancreatitis within 1 year of study entry or past medical history of
             chronic pancreatitis

          6. Known presence of significant congenital or acquired bleeding disorder unrelated to
             cancer

          7. History of other active malignancy within 3 years prior to study entry with the
             exception of previous or concomitant basal cell skin cancer and previous carcinoma in
             situ treated curatively

          8. Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea,
             vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass
             surgery)

          9. Previous treatment with or known/ suspected hypersensitivity to asciminib or any of
             its excipients.

         10. Participation in a prior investigational study within 30 days prior to randomization
             or within 5 half-lives of the investigational product, whichever is longer

         11. Pregnant or nursing (lactating) women

         12. Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception.

             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.

         13. Sexually active males unwilling to use a condom during intercourse while taking study
             treatment and for 3 days after stopping study (only for patients treated with
             asciminib). A condom is required for all sexually active male participants on
             asciminib treatment to prevent them from fathering a child AND to prevent delivery of
             study treatment via seminal fluid to their partner. In addition, these male
             participants must not donate sperm for the time period specified above.

         14. If a patient is presenting with symptoms suggestive of possible COVID-19 infection, we
             advise ruling it out by appropriate testing recommended by health authorities.

               -  Nucleic acid amplification tests for viral RNA (polymerase chain reaction), in
                  order to measure current infection with SARS-CoV-2

               -  Antigen tests for rapid detection of SARS-CoV-2

               -  Antibody (serology) tests to detect the presence of antibodies to SARS-CoV-2
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Adverse Events and Serious Adverse Events for cohorts A and B up to 24 weeks
Time Frame:Baseline to up to 24 Weeks
Safety Issue:
Description:Adverse events (AEs) and serious adverse events (SAEs) will be summarized by cohort. Clinically significant findings for vitals, laboratory values and electrocardiogram (ECG) will be reported as adverse events and or serious adverse events as determined by the investigator.

Secondary Outcome Measures

Measure:Number of Adverse Events and Serious Adverse Events for cohorts A, B and C up to 24 weeks
Time Frame:Baseline up to 48 and 72 weeks
Safety Issue:
Description:Adverse events (AEs) and serious adverse events (SAEs) will be summarized by cohort. Clinically significant findings for vitals, laboratory values and electrocardiogram (ECG) will be reported as adverse events and or serious adverse events as determined by the investigator.
Measure:Percentage of patients achieving complete hematologic response (CHR) for Cohorts A, B and C
Time Frame:Baseline to 12, 24, 48, 72 weeks
Safety Issue:
Description:A complete hematologic response (CHR) is defined as all of the following present for ≥ 4 weeks: white blood count (WBC) <10 x 109/L, platelet count <450 x 109/L, basophils <5%, no blasts and promyelocytes in peripheral blood, myelocytes + metamyelocytes < 5% in peripheral blood, no evidence of extramedullary disease, including spleen and liver
Measure:Percentage of patients achieving molecular response (MR2), major molecular response (MMR) and molecular response of MR4 and MR4.5 for cohorts A, B and C
Time Frame:Baseline up to 12, 24, 48, 72 weeks
Safety Issue:
Description:The rate of molecular response (MR2) by 12, 24, 48 and 72 weeks after the start of first study medication is defined as ≥ 2 log reduction of BCR-ABL (transcript from standardized baseline or ≤ 1% BCR-ABL/ABL % by international scale, measured by real-time quantitative polymerase chain reaction (RQ-PCR). BCR-ABL fusion gene is also called the Philadelphia chromosome. Rate for MMR is defined as ≥ 3 log reduction, MR4 is defined as ≥ 4 log reduction and MR4.5 is defined as ≥ 4.5 log reduction.
Measure:Time to achieve CHR, MR2, MMR, MR4, MR4.5 for cohorts A, B and C
Time Frame:Baseline up to 72 weeks
Safety Issue:
Description:Time to achieving a response level is defined as the time from the date of the first dose of study medication to the first documented achievement of a each defined response level. Time to achieve a specific response level will be analyzed using the Kaplan-Meier Product-Limit method. Patients who are known to be without achieving that response level will be censored at the last adequate assessment.
Measure:Duration of CHR, MR2, MMR, MR4 and MR4.5 for cohorts A, B and C
Time Frame:Baseline up 72 weeks
Safety Issue:
Description:Duration of Response (DOR) is the time from the date of the first documented a molecular response level to the date of first documented loss of the response level or death due to any cause, whichever occurs first. DOR for each response level will be analyzed using the Kaplan-Meier Product-Limit method. Participants continuing without that event will be censored at the date of their last adequate response assessment.
Measure:Progression Free Survival (PFS) for cohorts A, B and C
Time Frame:Baseline up to 72 weeks
Safety Issue:
Description:Progression Free Survival (PFS) is defined as time from the first dose of study medication to disease progression to accelerated phase/blast crisis (AP/BC) or death due to any cause, whichever occurs first. PFS will be analyzed using the Kaplan-Meier Product-Limit method
Measure:Overall Survival Overall Survival (OS) for cohorts A, B and C
Time Frame:Baseline up to 72 weeks
Safety Issue:
Description:Overall Survival (OS) is defined as the time from the first dose of study medication to death due to any cause during study. If a patient is not known to have died, then OS will be censored at the latest date the patient was known to be alive. OS will be analyzed using the Kaplan-Meier Product-Limit method

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • CML
  • T315I mutation
  • CP
  • Asciminib,
  • BCR-ABL,
  • ABL001,
  • CML-AP,
  • ELN
  • MMR
  • Molecular Response
  • MR4.5
  • MR4
  • RQ-PCR
  • AIM4CML,
  • tyrosine Kinase Inhibitor
  • TKI
  • adult

Last Updated

March 18, 2021