<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03807479</url>
  </required_header>
  <id_info>
    <org_study_id>PONS_11272</org_study_id>
    <nct_id>NCT03807479</nct_id>
  </id_info>
  <brief_title>Study in Patients With Chronic Leukemia</brief_title>
  <acronym>PONS</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>GWT-TUD GmbH</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Incyte Biosciences International Sàrl</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>GWT-TUD GmbH</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will include patients suffering from chronic myeloid leukemia (CP-CML), who were&#xD;
      treated with tyrosine kinase inhibitor (TKI, a substance that blocks the action of enzymes)&#xD;
      in a previous therapy but which has not been effective. Patients will be treated with&#xD;
      Ponatinib 30 mg in in this study. The aim of the study is to evaluate the safety and efficacy&#xD;
      of Ponatinib as a second line treatment in patients failing or not tolerating first line&#xD;
      therapy with any other approved TKIs. It is expected that Ponatinib, due to its efficacy, may&#xD;
      be more effective as second line therapy than other approved TKIs and lead to improved&#xD;
      overall survival. The effect will be determined by the molecular response rate (MMR) as the&#xD;
      primary objective after 12 months of treatment. The safety of the drug will be evaluated on&#xD;
      the basis if routine medical and laboratory examinations.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Despite significant progress in the treatment of patients with chronic phase CML, there is&#xD;
      still need to further optimize therapy to reach the goal of disease eradication for almost&#xD;
      all patients. In case of imatinib failure, dasatinib and nilotinib are effective treatment&#xD;
      options after an individualized treatment selection. Although MMR rates of around 30% after 2&#xD;
      years of therapy are a significant achievement, options that may improve response rates in&#xD;
      depth are still desirable. Ponatinib is a third generation TKI with very high anti-clonal&#xD;
      activity in all CML phases. Moreover, it also eradicates most of the known and problematic&#xD;
      mutations and only very few (compound) mutations may induce ponatinib-resistance.&#xD;
&#xD;
      Based on its favourable target spectrum, it is expected that Ponatinib may be more effective&#xD;
      than 2nd line dasatinib or nilotinib in achieving early (i.e., at 6 months) cytogenetic and&#xD;
      molecular responses in patients after inappropriate response to imatinib, and more effective&#xD;
      as 2nd line treatment after failure of initial treatment with dasatinib or nilotinib than a&#xD;
      cross-over between the 2nd generation TKIs. The basic hypothesis underlying therapeutic&#xD;
      programs in CML is to be able to achieve meaningful and long-lasting suppression of the&#xD;
      Philadelphia chromosome and breakpoint cluster region-abelson fusion gen (BCR-ABL). Complete&#xD;
      cytogenetic responses have been associated with improved survival in CML, while major&#xD;
      molecular responses are associated with improved event-free survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    less recruting&#xD;
  </why_stopped>
  <start_date type="Actual">December 11, 2018</start_date>
  <completion_date type="Actual">August 31, 2023</completion_date>
  <primary_completion_date type="Actual">February 28, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Major Molecular Response (MMR) of treatment</measure>
    <time_frame>by 12 moths</time_frame>
    <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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to toxicity</measure>
    <time_frame>up to 24 months</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to response</measure>
    <time_frame>at 3, 6, 9, 12, 18 and 24 months</time_frame>
    <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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Durations of response</measure>
    <time_frame>at 3, 6, 9, 12, 18 and 24 month</time_frame>
    <description>To evaluate the duration of hematologic, cytogenetic and molecular response to Ponatinib after one TKI failure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of BCR-ABL-mutations</measure>
    <time_frame>at 3, 6, 9, 12, 18 and 24 months</time_frame>
    <description>To evaluate the occurrence of BCR-ABL-mutations in patients with failure of Ponatinib 2nd line therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to progression</measure>
    <time_frame>at 3, 6, 9, 12, 18 and 24 months</time_frame>
    <description>To define the time to progression for patients with CML in chronic phase treated with Ponatinib after one TKI failure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to overall survival</measure>
    <time_frame>at 3, 6, 9, 12, 18 and 24 month</time_frame>
    <description>To define the time to overall survival for patients with CML in chronic phase treated with Ponatinib after one TKI failure.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Leukemia, Myeloid, Chronic-Phase</condition>
  <arm_group>
    <arm_group_label>Ponatinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients 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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ponatinib</intervention_name>
    <description>2 film-coated tablets à 15mg for oral administration on a daily basis</description>
    <arm_group_label>Ponatinib</arm_group_label>
    <other_name>Iclusig</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female patients ≥18 years old&#xD;
&#xD;
          2. Diagnosis of Ph-positive (by cytogenetics) or BCR-ABL-positive (by PCR) CP-CML&#xD;
&#xD;
          3. Patients should have demonstrated to have&#xD;
&#xD;
               -  a failure of a prior 1st line TKI treatment with either imatinib, dasatinib or&#xD;
                  nilotinib. Failure is defined as per European LeukemiaNet (ELN) recommendations:&#xD;
&#xD;
                    -  Less than Complete Hematologic Response (CHR) and/or Ph+ &gt; 95% at or beyond&#xD;
                       3 months&#xD;
&#xD;
                    -  No cytogenetic response (Ph+&gt;35%) and/or Abelson murine leukemia viral&#xD;
                       oncogene homolog 1 (BCR-ABL1) &gt;10% at or beyond 6 months&#xD;
&#xD;
                    -  BCR-ABL (on international scale) &gt;1% and/or PH+ &gt;0%&#xD;
&#xD;
                    -  Less than MMR at or beyond 18 months&#xD;
&#xD;
                    -  Loss of response or development of mutations or other clonal chromosomal&#xD;
                       abnormalities at any time during the first line TKI treatment&#xD;
&#xD;
               -  or intolerance to prior TKI treatment defined as grade 3 or 4 toxicity, or&#xD;
                  persistent grade 2 toxicity despite optimal management including dose adjustment,&#xD;
                  or in a patient where dose reductions are considered to be not in the patient's&#xD;
                  best interest to obtain an adequate response. Intolerant patients should not have&#xD;
                  achieved or have lost major molecular response at the time of enrollment&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any 1st line anti-CML treatment other than TKI (apart from therapy with hydroxyurea)&#xD;
&#xD;
          2. Any 2nd line therapy with a tyrosine kinase inhibitor (&gt;1 European Medicines Agency&#xD;
             (EMA) approved TKI for CML, or any investigational non EMA-approved TKI)&#xD;
&#xD;
          3. Concurrent participation in any other clinical trial involving another investigational&#xD;
             drug within 4 weeks prior to enrollment and throughout participation in PONS-Study&#xD;
&#xD;
          4. New York Heart Association (NYHA) cardiac class 3-4 heart disease&#xD;
&#xD;
          5. Cardiac Symptoms within the past 12 months prior recruitment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philipp le Coutre, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Charité Berlin - Department of Hematology, Oncology and Tumor Immunology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital</name>
      <address>
        <city>Halle (Saale)</city>
        <state>Saxony-Anhalt</state>
        <zip>06097</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital RWTH Aachen,Clinic for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Department IV</name>
      <address>
        <city>Aachen</city>
        <zip>52074</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charité University Medicine Berlin - Medical Clinic, Department of Hematology, Oncology and Tumor Immunology</name>
      <address>
        <city>Berlin</city>
        <zip>13353</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Essen gGmbH, Westdeutsches Tumorzentrum; Internal Medicine (Tumor Research)</name>
      <address>
        <city>Essen</city>
        <zip>45122</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medicine Greifswald, Clinic and Policlinic - Internal Medicine C - Hematology and Oncology</name>
      <address>
        <city>Greifswald</city>
        <zip>17475</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asklepios Clinic St. Georg - Department of Oncology, Section Hematology</name>
      <address>
        <city>Hamburg</city>
        <zip>20099</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Mannheim GmbH, III. Medical Clinic for Hematology and Oncology</name>
      <address>
        <city>Mannheim</city>
        <zip>68167</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinic for Hematologie</name>
      <address>
        <city>Marburg</city>
        <zip>35043</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UKRUB University Hospital of Ruhr-University Bochum, Clinic for Hematology and Oncology</name>
      <address>
        <city>Minden</city>
        <zip>32429</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Ulm - Department for internal medicine III</name>
      <address>
        <city>Ulm</city>
        <zip>89081</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>November 7, 2018</study_first_submitted>
  <study_first_submitted_qc>January 14, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 17, 2019</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CP-CML</keyword>
  <keyword>CML in chronic phase</keyword>
  <keyword>Chronic Myelogenous Leukemia</keyword>
  <keyword>Leukemia, Myelogenous, Chronic, BCR-ABL Positive</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myelogenous, Chronic, BCR-ABL Positive</mesh_term>
    <mesh_term>Leukemia, Myeloid, Chronic-Phase</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ponatinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03807479
org study id: PONS_11272
nct id: NCT03807479
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Major Molecular Response (MMR) of treatment
time frame: by 12 moths
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.
measure: Time to toxicity
time frame: up to 24 months
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
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
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
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
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
description: To define the time to overall survival for patients with CML in chronic phase treated with Ponatinib after one TKI failure.
arm group label: Ponatinib
arm group type: Experimental
description: Patients 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.
intervention type: Drug
intervention name: Ponatinib
description: 2 film-coated tablets à 15mg for oral administration on a daily basis
arm group label: Ponatinib
other name: Iclusig
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Philipp le Coutre, Prof.
role: Principal Investigator
affiliation: Charité Berlin - Department of Hematology, Oncology and Tumor Immunology
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
mesh term: Leukemia, Myeloid, Chronic-Phase
mesh term: Ponatinib
sharing ipd: No