<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/NCT01725204</url>
  </required_header>
  <id_info>
    <org_study_id>NordCML007</org_study_id>
    <secondary_id>2011-005989-38</secondary_id>
    <nct_id>NCT01725204</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Pegylated IFN-alpha 2B Added to Dasatinib in Newly Diagnosed Chronic Phase Myeloid Leukemia</brief_title>
  <acronym>NordCML007</acronym>
  <official_title>A Safety and Efficacy Study of Adding Low Dose Pegylated IFN-alpha 2B to Standard Dose Dasatinib in Patients With Newly Diagnosed Chronic Phase Myeloid Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Norwegian University of Science and Technology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Norwegian University of Science and Technology</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Patients with newly diagnosed CML have excellent outcomes with tyrosine kinase inhibitors&#xD;
      (TKI). However, a few patients will be cured with TKIs alone, and thus need continued&#xD;
      life-long treatment. Some patients achieve complete molecular remission (CMR), and this rate&#xD;
      is higher with second generation TKIs compared with imatinib. Some experience with drug&#xD;
      discontinuation in CMR has been derived from a few small studies, most notably the French&#xD;
      STIM study. Approximately 40 % of patients with a minimum of two years in MR4.5 (4.5 log&#xD;
      reduction in molecular response) can stop imatinib without relapse, indicating possible cure.&#xD;
      To increase the non-relapse rate is of major importance. To achieve a permanent &quot;cure&quot;&#xD;
      without stem cell transplantation is presently the most relevant goal of clinical studies in&#xD;
      CML.&#xD;
&#xD;
      The investigators hypothesize that to significantly increase cure rates in CML, therapy&#xD;
      should eradicate leukemic stem cells and/or induce or restore anti-CML immunity. Second&#xD;
      generation TKIs may have a more profound effect on the stem cell pool as compared to&#xD;
      imatinib. This is assessed in our current randomized study with a reduction in leukemic stem&#xD;
      cell burden as the primary endpoint (NordCML006). Interferon-alpha (IFN) has a prominent&#xD;
      immunomodulatory and antiproliferative mode of action, and has also activity in stem cells.&#xD;
      Pegylated IFN in combination with imatinib results in improved therapy responses as compared&#xD;
      to imatinib monotherapy. This advantage may translate into higher cure rates.&#xD;
&#xD;
      Dasatinib has a unique dual mechanism of action: it is the most potent of available TKIs and&#xD;
      induces immunological effects that are different from those of IFN. Both of these drugs may&#xD;
      have immunological adverse-effects when used as a monotherapy. However, immunological&#xD;
      adverse-effects may also be markers of anti-leukemia efficacy. A combination of dasatinib and&#xD;
      pegylated IFN (PegIFN) may have additive or synergistic effects and should be tested in a&#xD;
      clinical study.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2012</start_date>
  <completion_date type="Actual">May 2016</completion_date>
  <primary_completion_date type="Actual">May 2016</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 rates</measure>
    <time_frame>1 year</time_frame>
    <description>defined as ≤0.1% BCR-ABL1 on the MMR International Scale</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>overall survival</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>quality of life</measure>
    <time_frame>up to 18 months (after 3, 6, 12, 18 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of CCgR</measure>
    <time_frame>up to 18 months (after 3, 6, 12 and 18 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of MR4.0 and MR4.5</measure>
    <time_frame>up to 24 months (after 3, 6, 12, 15, 18, and 24 months)</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Leukemia, Myeloid, Chronic-Phase</condition>
  <arm_group>
    <arm_group_label>Dasatinib + PegIFN</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dasatinib 100mg OD for three months single drug, with subsequent addition of PegIFN 15 μg/ week for 3 months. If well tolerated (less than grade 2 non-hematological or grade 3 hematological AE) the dose should be increased to 25μg weekly for the remaining 9 months on combination treatment. Thereafter dasatinib will be given as monotherapy. Patients will be followed for 24 months totally.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dasatinib + PegIFN</intervention_name>
    <arm_group_label>Dasatinib + PegIFN</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of chronic myeloid leukemia in chronic phase (CML-CP) associated with&#xD;
             BCR-ABL1 quantifiable by RQ-PCR (IS)&#xD;
&#xD;
          -  No other current or planned anti-leukemia therapies excluding hydroxyurea treatment&#xD;
             for up to two months.&#xD;
&#xD;
          -  ECOG Performance status 0,1, or 2&#xD;
&#xD;
          -  Adequate organ function as defined by: Total bilirubin &lt; 1.5 x ULN (ULN = upper limit&#xD;
             of normal in a local institution lab) in absence of Gilbert genotype; ASAT and ALAT &lt;&#xD;
             2.5 x ULN. Creatinine &lt; 2x ULN. Potassium, magnesium and phosphate not below LLN (LLN=&#xD;
             lower level of normal)&#xD;
&#xD;
          -  Life expectancy of more than 12 months in the absence of any intervention&#xD;
&#xD;
          -  Patient has given written informed consent to participate in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior accelerated phase or blast crisis&#xD;
&#xD;
          -  Uncontrolled or significant cardiovascular disease, including any of the following:&#xD;
&#xD;
               -  A myocardial infarction within 6 months&#xD;
&#xD;
               -  Uncontrolled angina within 3 months&#xD;
&#xD;
               -  Congestive heart failure within 3 months&#xD;
&#xD;
               -  Diagnosed or suspected congenital long QT syndrome&#xD;
&#xD;
               -  Any history of clinically significant ventricular arrhythmias (such as&#xD;
                  ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe)&#xD;
&#xD;
               -  Prolonged QTcF interval &gt; 450 msec on pre-entry ECG&#xD;
&#xD;
          -  Atypical BCR-ABL1 transcript not quantifiable by RQ-PCR.&#xD;
&#xD;
          -  Another primary malignant disease, which requires systemic treatment (chemotherapy or&#xD;
             radiation) Severe and/or life-threatening medical disease including acute liver&#xD;
             disease&#xD;
&#xD;
          -  History of significant congenital or acquired bleeding disorder unrelated to cancer&#xD;
&#xD;
          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly&#xD;
             alter the absorption of dasatinib&#xD;
&#xD;
          -  Patients actively receiving therapy with strong CYP3A4 inhibitors and the treatment&#xD;
             cannot be either discontinued or switched to a different medication prior to starting&#xD;
             study drug&#xD;
&#xD;
          -  Patients who are currently receiving treatment with any medications that have the&#xD;
             potential to prolong the QT interval and the treatment cannot be either discontinued&#xD;
             or switched to a different medication prior to starting study drug&#xD;
&#xD;
          -  Female patients who are: pregnant, breast feeding or potentially fertile without a&#xD;
             negative pregnancy test prior to baseline or unwilling to use contraception on trial&#xD;
&#xD;
          -  Previous history of pericarditis or pleuritis&#xD;
&#xD;
          -  History of non-compliance, abuse of alcohol, illicit drugs, severe psychiatric&#xD;
             disorders or other inability to grant informed consent.&#xD;
&#xD;
          -  Current treatment for depression.&#xD;
&#xD;
          -  Hypersensitivity to any interferon preparation;&#xD;
&#xD;
          -  Autoimmune hepatitis or a history of autoimmune disease;&#xD;
&#xD;
          -  Pre-existing thyroid disease unless it can be controlled with conventional treatment;&#xD;
&#xD;
          -  Epilepsy and/or compromised central nervous system (CNS) function;&#xD;
&#xD;
          -  HCV/HIV patients&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Henrik Hjorth-Hansen, MD PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Norwegian University of Science and Technology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Helsinki University Central Hospital</name>
      <address>
        <city>Helsinki</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bergen University Central Hospital</name>
      <address>
        <city>Bergen</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rikshospitalet</name>
      <address>
        <city>Oslo</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stavanger University Hospital</name>
      <address>
        <city>Stavanger</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Northern Norway</name>
      <address>
        <city>Tromsø</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Olavs Hospital - Trondheim University Hospital</name>
      <address>
        <city>Trondheim</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Linköping University Hospital</name>
      <address>
        <city>Linköping</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sunderby Sjukhus</name>
      <address>
        <city>Luleå</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lund University Hospital</name>
      <address>
        <city>Lund</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sundsvall County Hospital</name>
      <address>
        <city>Sundsvall</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Umeå University Hospital</name>
      <address>
        <city>Umeå</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uppsala University Hospital</name>
      <address>
        <city>Uppsala</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Örebro University Hospital</name>
      <address>
        <city>Örebro</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Finland</country>
    <country>Norway</country>
    <country>Sweden</country>
  </location_countries>
  <results_reference>
    <citation>Hjorth-Hansen H, Stentoft J, Richter J, Koskenvesa P, Hoglund M, Dreimane A, Porkka K, Gedde-Dahl T, Gjertsen BT, Gruber FX, Stenke L, Eriksson KM, Markevarn B, Lubking A, Vestergaard H, Udby L, Bjerrum OW, Persson I, Mustjoki S, Olsson-Stromberg U. Safety and efficacy of the combination of pegylated interferon-alpha2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients. Leukemia. 2016 Sep;30(9):1853-60. doi: 10.1038/leu.2016.121. Epub 2016 May 2.</citation>
    <PMID>27133821</PMID>
  </results_reference>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>November 8, 2012</study_first_submitted>
  <study_first_submitted_qc>November 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 12, 2012</study_first_posted>
  <last_update_submitted>September 21, 2017</last_update_submitted>
  <last_update_submitted_qc>September 21, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 25, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>dasatinib</keyword>
  <keyword>Protein Kinase Inhibitors</keyword>
  <keyword>pegylated IFN-alpha 2B</keyword>
  <keyword>Interferon-alpha</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>Dasatinib</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01725204
org study id: NordCML007
secondary id: 2011-005989-38
nct id: NCT01725204
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Patients with newly diagnosed CML have excellent outcomes with tyrosine kinase inhibitors
      (TKI). However, a few patients will be cured with TKIs alone, and thus need continued
      life-long treatment. Some patients achieve complete molecular remission (CMR), and this rate
      is higher with second generation TKIs compared with imatinib. Some experience with drug
      discontinuation in CMR has been derived from a few small studies, most notably the French
      STIM study. Approximately 40 % of patients with a minimum of two years in MR4.5 (4.5 log
      reduction in molecular response) can stop imatinib without relapse, indicating possible cure.
      To increase the non-relapse rate is of major importance. To achieve a permanent "cure"
      without stem cell transplantation is presently the most relevant goal of clinical studies in
      CML.

      The investigators hypothesize that to significantly increase cure rates in CML, therapy
      should eradicate leukemic stem cells and/or induce or restore anti-CML immunity. Second
      generation TKIs may have a more profound effect on the stem cell pool as compared to
      imatinib. This is assessed in our current randomized study with a reduction in leukemic stem
      cell burden as the primary endpoint (NordCML006). Interferon-alpha (IFN) has a prominent
      immunomodulatory and antiproliferative mode of action, and has also activity in stem cells.
      Pegylated IFN in combination with imatinib results in improved therapy responses as compared
      to imatinib monotherapy. This advantage may translate into higher cure rates.

      Dasatinib has a unique dual mechanism of action: it is the most potent of available TKIs and
      induces immunological effects that are different from those of IFN. Both of these drugs may
      have immunological adverse-effects when used as a monotherapy. However, immunological
      adverse-effects may also be markers of anti-leukemia efficacy. A combination of dasatinib and
      pegylated IFN (PegIFN) may have additive or synergistic effects and should be tested in a
      clinical study.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: major molecular response rates
time frame: 1 year
description: defined as ≤0.1% BCR-ABL1 on the MMR International Scale
measure: overall survival
time frame: 2 years
measure: quality of life
time frame: up to 18 months (after 3, 6, 12, 18 months)
measure: Rate of CCgR
time frame: up to 18 months (after 3, 6, 12 and 18 months)
measure: Rate of MR4.0 and MR4.5
time frame: up to 24 months (after 3, 6, 12, 15, 18, and 24 months)
arm group label: Dasatinib + PegIFN
arm group type: Experimental
description: Dasatinib 100mg OD for three months single drug, with subsequent addition of PegIFN 15 μg/ week for 3 months. If well tolerated (less than grade 2 non-hematological or grade 3 hematological AE) the dose should be increased to 25μg weekly for the remaining 9 months on combination treatment. Thereafter dasatinib will be given as monotherapy. Patients will be followed for 24 months totally.
intervention type: Drug
intervention name: Dasatinib + PegIFN
arm group label: Dasatinib + PegIFN
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Henrik Hjorth-Hansen, MD PhD
role: Study Chair
affiliation: Norwegian University of Science and Technology
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Finland
country: Norway
country: Sweden
citation: Hjorth-Hansen H, Stentoft J, Richter J, Koskenvesa P, Hoglund M, Dreimane A, Porkka K, Gedde-Dahl T, Gjertsen BT, Gruber FX, Stenke L, Eriksson KM, Markevarn B, Lubking A, Vestergaard H, Udby L, Bjerrum OW, Persson I, Mustjoki S, Olsson-Stromberg U. Safety and efficacy of the combination of pegylated interferon-alpha2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients. Leukemia. 2016 Sep;30(9):1853-60. doi: 10.1038/leu.2016.121. Epub 2016 May 2.
PMID: 27133821
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: Dasatinib