Clinical Trials /

Bosutinib in Elderly Chronic Myeloid Leukemia

NCT02810990

Description:

The objective of the present study is to evaluate a new drug called bosutinib as it is believed that this agent may be able to predict an excellent prognosis in patients that did not obtain any benefit with other drugs before. Still, this needs to be proved and we hope this study is able to do so.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bosutinib in Elderly Chronic Myeloid Leukemia
  • Official Title: Bosutinib Efficacy, Safety, Tolerability (BEST) Study in Elderly Chronic Myeloid Leukemia Patients Failing Front-line Treatment With Other Tyrosine Kinase Inhibitors

Clinical Trial IDs

  • ORG STUDY ID: CML1516
  • SECONDARY ID: 2016-002216-40
  • NCT ID: NCT02810990

Conditions

  • Chronic Myeloid Leukemia

Interventions

DrugSynonymsArms
BosutinibBosutinib treatment

Purpose

The objective of the present study is to evaluate a new drug called bosutinib as it is believed that this agent may be able to predict an excellent prognosis in patients that did not obtain any benefit with other drugs before. Still, this needs to be proved and we hope this study is able to do so.

Detailed Description

      Bosutinib is a potent tyrosine kinase inhibitor (TKI) active at nM concentration on BCR-ABL1
      and most BCR-ABL1 mutations. Bosutinib has been approved by the FDA and the EMA for the
      treatment of patients with Ph+/BCR-ABL1+ chronic myeloid leukemia who fail treatment with
      other TKIs, first or second line. The goal of second-line treatment of CML is to achieve a
      response that would predict for a survival equal to, or very close to, the survival of non
      leukemic people, that is to say to achieve a complete cytogenetic response (CCyR) or a major
      molecular response (MMR). To achieve that goal, it is necessary to find and keep the right
      balance between activity, safety, and tolerability. There are no studies comparing TKIs in
      second-line. From phase 2, single-arm, studies, the reported efficacy of Bosutinib is similar
      to the reported efficacy of dasatinib and nilotinib. The median age of newly diagnosed CML
      patients is about 56 years, and at least 40% of all newly diagnosed patients are more than 60
      years old. Particularly for these patients, the choice of the TKI must take into account the
      safety and the tolerability profile of the TKIs. The use of dasatinib and nilotinib is
      burdened by pleural and pulmonary complications, by infections, and by cardiovascular,
      thrombotic and metabolic (diabetes mellitus, dyslipidemia) complications. These complications
      are more frequent and more clinically relevant in the elderly. The safety and tolerability of
      Bosutinib has been reported in first- as well as in second- and third-line. The standard dose
      (500 mg once daily) is tolerated and safe, but at that dose several adverse events (AEs)
      limit the tolerability, require dose reduction or interruption, and affect patient quality of
      life, including diarrhea, nausea, vomiting, skin rash. Also an increase of AST, ALT and
      lipase are of concern and a cause of treatment discontinuation. On the contrary, an increased
      frequency of infections and of pleuro-pulmonary, cardiovascular, thrombotic, and metabolic
      AEs has not been reported. The reported hematologic toxicity of Bosutinib is at least as low
      as, or even lower than, that reported for the other TKIs, in spite of the fact that Bosutinib
      is a dual, BCR-ABL1 and src inhibitor. Until today, all studies of TKIs in CML have tested a
      fixed initial dose, providing for dose adjustment in case of toxicity (dose decrease) or in
      case of unsatisfactory response (dose increase). No study so far was designed to test the
      adaptation of the dose to the response, taking advantage of the fact that the efficacy of TKI
      treatment can be assessed rapidly and precisely by measuring the BCR-ABL1 transcripts level
      with real-time PCR (RT-PCR) in peripheral blood cells. An RT-PCR monthly for the first few
      months provides the best assessment of the response to treatment. We predict that a more
      flexible strategy of treatment (adapting the dose to the response) will result into a more
      convenient balance between activity and toxicity, hence into a better outcome. Based on these
      premises, it is proposed to test the activity, the safety, and the tolerability of Bosutinib,
      second-line, beginning with a low dose and adjusting subsequent doses based on molecular
      response, and on AEs, in a population of elderly patients. In almost all prior studies of
      TKIs in second- or third-line, the primary efficacy was assessed using cytogenetic response,
      both major and complete, at different time points. To make the results of this study
      comparable to the results of prior studies, the cytogenetic response will be evaluated as
      specified in section 5, but since the response to therapy and the evaluation of the efficacy
      of therapy are more and more based on molecular response, dose adaptation and efficacy
      evaluation will be based primarily on molecular response.
    

Trial Arms

NameTypeDescriptionInterventions
Bosutinib treatmentExperimental
  • Bosutinib

Eligibility Criteria

        Inclusion Criteria:

          1. Molecular confirmed diagnosis of BCR-ABL1+ CML

          2. Chronic phase CML (ELN 2013 criteria)

          3. 60 years of age or older

          4. Prior first-line treatment with any other TKIs

          5. Intolerance to prior treatment, based on investigator and patient assessment or
             failure of prior treatment according to any one of the ELN 2013 criteria, as listed
             below

               -  Non complete hematologic response (CHR) at 3 months

               -  No cytogenetic response (Ph+ > 95%) at 6 months

               -  Less than Partial Cytogenetic Response (PCyR) (Ph+ >35%) at 6 months

               -  BCR-ABL1 > 10% at 6 months

               -  Non complete CyR (CCyR) (Ph+ > 0) at 12 months

               -  BCR-ABL1 > 1% at 12 months

               -  Loss of CHR at any time

               -  Loss of CCyR at any time

               -  Confirmed loss of major molecular response (MMR) (BCR-ABL1 > 0.1%) in two
                  consecutive tests, of which one > 1%, at any time

          6. An effective form of contraception from enrolment through 30 days after the end of
             treatment

          7. Signed written informed consent according to ICH/EU/GCP and national and local laws
             prior to any study procedures

          8. Willingness and ability to comply with scheduled visits and study procedures.

        Exclusion Criteria:

          1. Accelerated or blastic phase CML (according to ELN 2013 criteria)

          2. Patients with the T315I or the V299L mutation

          3. Patients previously treated with 2 TKIs or more

          4. Compelled to take medications that are known to be associated with Torsades de Pointes
             and/or with significant QTc prolongation

          5. Any condition or illness that, in the opinion of the Investigator, would compromise
             patient safety or interfere with the evaluation of the drug

          6. HBV markers positivity

          7. Lack of informed consent
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients who are in major molecular response (MMR)
Time Frame:One year treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of patients who obtain molecular response
Time Frame:At 6 and 12 months from treatment start
Safety Issue:
Description:
Measure:Number of patients discontinuing treatment for failure, adverse events or other reasons
Time Frame:At 12 and 36 months
Safety Issue:
Description:
Measure:Number of Adverse Events (AEs)
Time Frame:At 36 months
Safety Issue:
Description:
Measure:Number of patients alive
Time Frame:At 36 months
Safety Issue:
Description:
Measure:Number of patients on treatment at 200, 300 and 400 mg or more daily
Time Frame:At 6, 12 and 36 months
Safety Issue:
Description:
Measure:Number and type of BCR-ABL1 mutations
Time Frame:At 36 months
Safety Issue:
Description:
Measure:Patient reported quality of life
Time Frame:At 3, 6, and 12 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gruppo Italiano Malattie EMatologiche dell'Adulto

Trial Keywords

  • bosutinib
  • chronic myeloid leukemia

Last Updated

August 31, 2017