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A Study in Patients With Chronic Leukemia, Where Previous Therapy Failed, and Who Will be Treated With Ponatinib as Second Line Therapy (PONS).

NCT03807479

Description:

This study will include patients suffering from chronic myeloid leukemia (CP-CML), who were treated with tyrosine kinase inhibitor (TKI, a substance that blocks the action of enzymes) in a previous therapy but which has not been effective. Patients will be treated with Ponatinib 30 mg in in this study. The aim of the study is to evaluate the safety and efficacy of Ponatinib as a second line treatment in patients failing or not tolerating first line therapy with any other approved TKIs. It is expected that Ponatinib, due to its efficacy, may be more effective as second line therapy than other approved TKIs and lead to improved overall survival. The effect will be determined by the molecular response rate (MMR) as the primary objective after 12 months of treatment. The safety of the drug will be evaluated on the basis if routine medical and laboratory examinations.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study in Patients With Chronic Leukemia, Where Previous Therapy Failed, and Who Will be Treated With Ponatinib as Second Line Therapy (PONS).
  • Official Title: Phase 2 Clinical Trial With Ponatinib as a Second Line Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to Prior First Line Tyrosine Kinase Inhibitor Treatment

Clinical Trial IDs

  • ORG STUDY ID: PONS_11272
  • NCT ID: NCT03807479

Conditions

  • Leukemia, Myeloid, Chronic-Phase

Interventions

DrugSynonymsArms
PonatinibIclusigPonatinib

Purpose

This study will include patients suffering from chronic myeloid leukemia (CP-CML), who were treated with tyrosine kinase inhibitor (TKI, a substance that blocks the action of enzymes) in a previous therapy but which has not been effective. Patients will be treated with Ponatinib 30 mg in in this study. The aim of the study is to evaluate the safety and efficacy of Ponatinib as a second line treatment in patients failing or not tolerating first line therapy with any other approved TKIs. It is expected that Ponatinib, due to its efficacy, may be more effective as second line therapy than other approved TKIs and lead to improved overall survival. The effect will be determined by the molecular response rate (MMR) as the primary objective after 12 months of treatment. The safety of the drug will be evaluated on the basis if routine medical and laboratory examinations.

Detailed Description

      Despite significant progress in the treatment of patients with chronic phase CML, there is
      still need to further optimize therapy to reach the goal of disease eradication for almost
      all patients. In case of imatinib failure, dasatinib and nilotinib are effective treatment
      options after an individualized treatment selection. Although MMR rates of around 30% after 2
      years of therapy are a significant achievement, options that may improve response rates in
      depth are still desirable. Ponatinib is a third generation TKI with very high anti-clonal
      activity in all CML phases. Moreover, it also eradicates most of the known and problematic
      mutations and only very few (compound) mutations may induce ponatinib-resistance.

      Based on its favourable target spectrum, it is expected that Ponatinib may be more effective
      than 2nd line dasatinib or nilotinib in achieving early (i.e., at 6 months) cytogenetic and
      molecular responses in patients after inappropriate response to imatinib, and more effective
      as 2nd line treatment after failure of initial treatment with dasatinib or nilotinib than a
      cross-over between the 2nd generation TKIs. The basic hypothesis underlying therapeutic
      programs in CML is to be able to achieve meaningful and long-lasting suppression of the
      Philadelphia chromosome and breakpoint cluster region-abelson fusion gen (BCR-ABL). Complete
      cytogenetic responses have been associated with improved survival in CML, while major
      molecular responses are associated with improved event-free survival.
    

Trial Arms

NameTypeDescriptionInterventions
PonatinibExperimentalPatients in this treatment arm receive Ponatinib: starting dose 30 mg once-daily. Doses may be increased in case of inappropriate response and reduced to manage drug-related adverse events (AEs) and may be re-escalated once events resolve.
  • Ponatinib

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female patients ≥18 years old

          2. Diagnosis of Ph-positive (by cytogenetics) or BCR-ABL-positive (by PCR) CP-CML

          3. Patients should have demonstrated to have

               -  a failure of a prior 1st line TKI treatment with either imatinib, dasatinib or
                  nilotinib. Failure is defined as per European LeukemiaNet (ELN) recommendations:

                    -  Less than Complete Hematologic Response (CHR) and/or Ph+ > 95% at or beyond
                       3 months

                    -  No cytogenetic response (Ph+>35%) and/or Abelson murine leukemia viral
                       oncogene homolog 1 (BCR-ABL1) >10% at or beyond 6 months

                    -  Less than CCyR at or beyond 12 months

                    -  Less than MMR at or beyond 18 months

                    -  Loss of response or development of mutations or other clonal chromosomal
                       abnormalities at any time during the first line TKI treatment

               -  or intolerance to prior TKI treatment defined as grade 3 or 4 toxicity, or
                  persistent grade 2 toxicity despite optimal management including dose adjustment,
                  or in a patient where dose reductions are considered to be not in the patient's
                  best interest to obtain an adequate response. Intolerant patients should not have
                  achieved or have lost major molecular response at the time of enrollment

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

        Exclusion Criteria:

          1. Any 1st line anti-CML treatment other than TKI (apart from therapy with hydroxyurea)

          2. Any 2nd line therapy with a tyrosine kinase inhibitor (>1 European Medicines Agency
             (EMA) approved TKI for CML, or any investigational non EMA-approved TKI)

          3. Concurrent participation in any other clinical trial involving another investigational
             drug within 4 weeks prior to enrollment and throughout participation in PONS-Study

          4. New York Heart Association (NYHA) cardiac class 3-4 heart disease

          5. Cardiac Symptoms within the past 12 months prior recruitment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Major Molecular Response (MMR) of treatment
Time Frame:by 12 moths
Safety Issue:
Description:To estimate the proportion of CP-CML patients with tyrosine kinase inhibitor (TKI)-resistance or intolerance to first line therapy with TKI, attaining MMR by 12 months of treatment with second line Ponatinib therapy.

Secondary Outcome Measures

Measure:Time to toxicity
Time Frame:up to 24 months
Safety Issue:
Description:To evaluate the toxicity profile of ponatinib in patients with CML in chronic phase after one TKI failure toxicities will be followed up at each visit during the treatment phase and will be assessed using CTCAE v.5.0. Type of toxicity (hematologic or non-hematologic) along with the grading will be followed up on.
Measure:Time to response
Time Frame:at 3, 6, 9, 12, 18 and 24 months
Safety Issue:
Description:To estimate the time to CCyR, MMR, MCyR and MR4 for patients treated with Ponatinib as second line therapy for CP-CML (chronic phase-chronic myelogenous leukemia).
Measure:Durations of response
Time Frame:at 3, 6, 9, 12, 18 and 24 month
Safety Issue:
Description:To evaluate the duration of hematologic, cytogenetic and molecular response to Ponatinib after one TKI failure.
Measure:Occurrence of BCR-ABL-mutations
Time Frame:at 3, 6, 9, 12, 18 and 24 months
Safety Issue:
Description:To evaluate the occurrence of BCR-ABL-mutations in patients with failure of Ponatinib 2nd line therapy.
Measure:Time to progression
Time Frame:at 3, 6, 9, 12, 18 and 24 months
Safety Issue:
Description:To define the time to progression for patients with CML in chronic phase treated with Ponatinib after one TKI failure.
Measure:Time to overall survival
Time Frame:at 3, 6, 9, 12, 18 and 24 month
Safety Issue:
Description:To define the time to overall survival for patients with CML in chronic phase treated with Ponatinib after one TKI failure.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GWT-TUD GmbH

Trial Keywords

  • CP-CML
  • CML in chronic phase
  • Chronic Myelogenous Leukemia
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive

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