<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/NCT03257241</url>
  </required_header>
  <id_info>
    <org_study_id>PALG-AML1/2016</org_study_id>
    <nct_id>NCT03257241</nct_id>
  </id_info>
  <brief_title>A PALG Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in AML Patients ≤ 60 Years Old</brief_title>
  <acronym>PALG-AML1/2016</acronym>
  <official_title>A PALG Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in AML Patients ≤ 60 Years Old</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Polish Adult Leukemia Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Polish Adult Leukemia Group</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study will include newly-diagnosed AML patients, not suffering acute promyelocytic&#xD;
      leukemia; aged 18-60 years, who are eligible for standard induction chemotherapy. The&#xD;
      patients will be randomized to one standard induction regimen (DAC or DA-90). At day seven&#xD;
      after completion of induction, a bone marrow aspiration with MRD will be performed for an&#xD;
      early evaluation of response to treatment. Patients without bone marrow blast reduction below&#xD;
      10% at day seven after induction will be given a second early induction course. Patients who&#xD;
      do not achieve CR after two induction courses will be randomized to one of the standard&#xD;
      salvage regimens (FLAG-IDA or CLAG-M). Postremission treatment intensity will be adjusted to&#xD;
      risk group based on cytogenetic and molecular risk factors at diagnosis and AML biology&#xD;
      (secondary AML, therapy related AML). Patients with a low risk of relapse will be allocated&#xD;
      to consolidation, with three courses of high doses of Ara-C (HiDAC), or two courses of HiDAC&#xD;
      with subsequent autologous stem cell transplantation. Intermediate- or high-risk patients&#xD;
      will be referred for allogeneic stem cell transplantation, if they have a matched donor.&#xD;
      Until transplantation, consolidation with HiDAC will be continued.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The successful treatment of acute myeloid leukemia (AML) depends on the ability to achieve&#xD;
      complete remission (CR) and to prevent relapse. Both may be affected by the efficacy of&#xD;
      induction chemotherapy. The gold standard for treatment since 1982 has been DA, a regimen of&#xD;
      three days of daunorubicin (DNR) and seven days of cytarabine (Ara-C) which results in&#xD;
      complete remission in 50 to 75% of patients; this is typically administered intravenously,&#xD;
      with daunorubicin administered at a dose of 45 mg per square meter of body-surface area daily&#xD;
      for three days, and cytarabine given at a dose of 100 mg per square meter daily for seven&#xD;
      days. Neither substituting DNR with another anthracycline nor the addition of thioguanine or&#xD;
      etoposide has been demonstrated to improve outcome. Recently it has been proved that&#xD;
      high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of complete&#xD;
      remission (70.6% vs. 57.3%, P&lt;0.001) and improved overall survival (median, 23.7 vs. 15.7&#xD;
      months; P = 0.003) without any increase in serious adverse events, compared with the standard&#xD;
      dose of the drug.&#xD;
&#xD;
      An alternative method to intensify induction treatment is by the addition of the purine&#xD;
      analog cladribine. Cladribine was demonstrated to increase cellular uptake of Ara-C and&#xD;
      accumulation of Ara-CTP in leukemic blasts by 50% to 65% and to have direct antileukemic&#xD;
      activity based on incorporation of metabolites into the DNA of proliferating cells. In two&#xD;
      randomized trials by the Polish Adult Leukemia Group (PALG), the investigators demonstrated&#xD;
      that the combination of cladribine with DNR (60 mg/m2) and Ara-C (DAC) resulted in a&#xD;
      significantly increased CR rate after a single induction course compared with the standard&#xD;
      two-drug induction (DA-60). The DAC arm was found to have a survival advantage over the DA-60&#xD;
      arm for patients aged 50 years or older (P =. 005), those with an initial leukocyte count&#xD;
      above 50G /L (P &lt; .03), and those with an unfavorable karyotype (P &lt; .03). Both induction&#xD;
      protocols have the same level of recommendation by the National Cancer Comprehensive Network&#xD;
      (NCCN) for routine use (level I), and are commonly used for the treatment of newly diagnosed&#xD;
      AML in Poland.&#xD;
&#xD;
      As no randomized comparison of these two standard protocols has yet been performed, the aim&#xD;
      of the proposed study is to compare the efficacy of these two standard induction protocols in&#xD;
      terms of achievement of CR, early leukemia elimination (at day seven, post induction) and&#xD;
      quality of remission measured by minimal residual disease level. Additionally, overall&#xD;
      survival (OS), event-free survival (EFS) and disease-free survival (DFS) will be analyzed. It&#xD;
      is also intended to compare the hematological and non-hematological toxicity of both&#xD;
      regimens.&#xD;
&#xD;
      However, in younger adults with AML treated with standard induction chemotherapy, 20-35% do&#xD;
      not achieve CR and 50-70% with CR may be expected to relapse within three years. Patients&#xD;
      with primary refractory disease and with relapses following CR1 have a significantly poorer&#xD;
      outcome. The optimum strategy at the time of relapse or for patients with refractory disease&#xD;
      remains uncertain. Allogeneic transplantation can be curative for the minority of patients&#xD;
      who achieve second CR (2CR) and for whom a suitable donor is available. For the majority of&#xD;
      patients, additional chemotherapy is given in the hope of achieving remission. Most salvage&#xD;
      therapies utilize high or intermediate doses of arabinoside cytosine (Ara-C) in combination&#xD;
      with other agents to overcome resistance in leukemic cells. Previous studies have shown that&#xD;
      a combination of the purine analog fludarabine (FA) and cytosine arabinoside (Ara-C)&#xD;
      increases the accumulation of Ara-C-5' triphosphate (Ara-CTP) responsible for the cytotoxic&#xD;
      effect in leukemic blasts. This combination of FA plus Ara-C was initially explored in&#xD;
      refractory and relapsed AML patients with satisfactory results. It is also likely that these&#xD;
      results can be improved by the addition of granulocyte-colony stimulating factor (G-CSF).&#xD;
      Such a combination of FA, Ara-C, idarubicin and G-CSF (the FLAG-IDA regimen) has been used in&#xD;
      the treatment of refractory and relapsed AML and poor prognosis myelodysplastic syndromes&#xD;
      (MDS), with CR rates of between 30-80% being reported. Recent studies have shown that another&#xD;
      purine analog, cladribine (2-CdA), is also able to enhance Ara-CTP accumulation in leukemic&#xD;
      blasts and that the combination of 2-Cda with Ara-C exhibited synergistic effect on&#xD;
      inhibition of myeloid leukemic cell proliferation, induction of apoptosis, and on disruption&#xD;
      of mitochondrial membrane potential.&#xD;
&#xD;
      Two previous PALG studies have confirmed that the CLAG-M regimen (a combination of&#xD;
      cladribine, Ara-C, G-CSF and mitoxantrone) has high efficacy and low toxicity in&#xD;
      refractory/relapsed AML patients. This salvage regimen was particularly effective in a very&#xD;
      poor-risk subgroup with primary refractoriness, early relapse or relapse after stem cell&#xD;
      transplantation. Both salvage protocols, CLAG-M and FLAG-Ida, are wildly used in the&#xD;
      treatment of relapsed/refractory AML and both have the highest level of NCCN recommendation.&#xD;
      However, these two standard salvage protocols have yet to be examined as part of any&#xD;
      randomized study. Therefore, the aim of this study is to compare the efficacy of these two&#xD;
      standard reinduction protocols (CLAG-M vs FLAG-IDA) in terms of achievement of CR, and&#xD;
      quality of remission measured by minimal residual disease level. Additionally, the overall&#xD;
      survival (OS), event-free survival (EFS) and disease-free survival (DFS) will be analyzed.&#xD;
      The study will also compare the hematological and non-hematological toxicity of both&#xD;
      regimens.&#xD;
&#xD;
      The study will include newly-diagnosed AML patients, not suffering acute promyelocytic&#xD;
      leukemia; aged 18-60 years, who are eligible for standard induction chemotherapy. The&#xD;
      patients will be randomized to one standard induction regimen (DAC or DA-90). At day seven&#xD;
      after completion of induction, a bone marrow aspiration with MRD will be performed for an&#xD;
      early evaluation of response to treatment. Patients without bone marrow blast reduction below&#xD;
      10% at day seven after induction will be given a second early induction course. Patients who&#xD;
      do not achieve CR after two induction courses will be randomized to one of the standard&#xD;
      salvage regimens (FLAG-IDA or CLAG-M). Postremission treatment intensity will be adjusted to&#xD;
      risk group based on cytogenetic and molecular risk factors at diagnosis and AML biology&#xD;
      (secondary AML, therapy related AML). Patients with a low risk of relapse will be allocated&#xD;
      to consolidation, with three courses of high doses of Ara-C (HiDAC), or two courses of HiDAC&#xD;
      with subsequent autologous stem cell transplantation. Intermediate- or high-risk patients&#xD;
      will be referred for allogeneic stem cell transplantation, if they have a matched donor.&#xD;
      Until transplantation, consolidation with HiDAC will be continued.&#xD;
&#xD;
      The primary end point of the study is CR rate after one and two induction courses. The&#xD;
      secondary end-points are the quality of CR (MRD), OS, DFS, PFS, CR rate after salvage&#xD;
      regimen.&#xD;
&#xD;
      It is planned to include 582 patients with newly-diagnosed AML. This will allow a 10%&#xD;
      difference in CR rate between DAC and DA-90 induction regimens to be confirmed with a power&#xD;
      of 80% and level of significance 0.05.&#xD;
&#xD;
      The study includes neither any experimental drug nor procedures that are not of the standard&#xD;
      of treatment for AML.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 3, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">April 1, 2022</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Comparison of the efficacy of two standard induction treatment protocols (DA-90 and DAC) in patients with newly-diagnosed AML (with the exception of acute promyelocytic leukemia). Comparison of the efficacy of two standard reinduction treatment protocols (CLAG-M and FLAG-IDA) in patients with refractory and relapsed AML.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Induction regimen efficacy (DA-90 vs DAC) - I induction</measure>
    <time_frame>On +7 day after chemotherpay</time_frame>
    <description>Comparison of total remission rates after 1 induction course of DA-90 and DAC.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Induction regimen efficacy (DA-90 vs DAC) - II induction</measure>
    <time_frame>On +28 day after chemotherapy or after complete morphology regeneration (if it occurs before day +28)</time_frame>
    <description>Comparison of total remission rates after II induction course of DA-90 and DAC.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Salvage regimen efficacy (CLAG-M vs FLAG-IDA) - I reinduction</measure>
    <time_frame>On +28 day after chemotherapy or after complete morphology regeneration (if it occurs before day +28)</time_frame>
    <description>Comparison of total remission rates after I reinduction course of CLAG-M and FLAG-IDA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Salvage regimen efficacy (CLAG-M vs FLAG-IDA) - II reinduction</measure>
    <time_frame>On +28 day after chemotherapy or after complete morphology regeneration (if it occurs before day +28)</time_frame>
    <description>Comparison of total remission rates after II reinduction course of CLAG-M and FLAG-IDA</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">582</enrollment>
  <condition>Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>A arm (DA-90)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Induction I:&#xD;
DNR 90 mg/m2 D 1-3 in 30-60 min i.v. infusion&#xD;
Ara-C 100 mg/m2 D 1-7 in 24 h i.v. infusion</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B arm (DAC)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Induction I:&#xD;
DNR 60 mg/m2 D 1-3 in 30-60 min i.v. infusion&#xD;
cladribine 5 mg/m2 D 1-5 in 2 h i.v. infusion prior to Ara-C&#xD;
Ara-C 200 mg/m2 D 1-7 in 22 h i.v. infusion.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>A arm (CLAG-M)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cladribine 5mg/m2 in 2 h i.v. infusion on days (1-5) Ara-C 2 g/m2 in 4 h i.v. infusion, 2 h after cladribine infusion on days (1-5) Mitoxantrone 10 mg/m2 i.v. 1xd on days (1-3) G-CSF 30MU s.c. 1xd from day 0 to 5 of the treatment (6 doses).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B arm (FLAG-IDA)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Fludarabine 30 mg/m2 in 30-min i.v. infusion on days (1-5) Ara-C 2 g/m2 in 4 h i.v. infusion, 2 h after fludarabine infusion on days (1-5). Idarubicin 8 mg/m2 i.v. 1xd on days (1-3) G-CSF 30MU s.c. 1xd from day 0 to 5 of the treatment (6 doses).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>A arm (DA-90)</intervention_name>
    <description>After confirming the diagnosis, assuming the inclusion criteria and exclusion criteria are respected, the patients are randomized to one of two standard induction treatment protocols (A arm: DA-90 vs B arm: DAC). After completing induction I, an early bone marrow assessment is performed on day 14 from the beginning of the treatment (+ day 7 after finishing chemotherapy) using the cytological method and MRD is assessed by the immunophenotyping method. Therapeutic decision is taken on the basis of the cytological assessment. Patients, in whom the percentage of blasts in the bone marrow on day 14 is &gt; 10%, receive early induction II from day 16. An Immunophenotype test is a complementary examination.</description>
    <arm_group_label>A arm (DA-90)</arm_group_label>
    <other_name>Daunorubicin, Cytarabine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>B arm (DAC)</intervention_name>
    <description>After confirming the diagnosis, assuming the inclusion criteria and exclusion criteria are respected, the patients are randomized to one of two standard induction treatment protocols (A arm: DA-90 vs B arm: DAC). After completing induction I, an early bone marrow assessment is performed on day 14 from the beginning of the treatment (+ day 7 after finishing chemotherapy) using the cytological method and MRD is assessed by the immunophenotyping method. Therapeutic decision is taken on the basis of the cytological assessment. Patients, in whom the percentage of blasts in the bone marrow on day 14 is &gt; 10%, receive early induction II from day 16. An Immunophenotype test is a complementary examination.</description>
    <arm_group_label>B arm (DAC)</arm_group_label>
    <other_name>Daunorubicin, Cladribine, Cytarabine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>A arm (CLAG-M)</intervention_name>
    <description>Patients who do not achieve CR after two courses of induction therapy or patients with relapsed leukemia are eligible for emergency treatment (&quot;salvage&quot;) according to the CLAG- M or FLAG-IDA protocol.</description>
    <arm_group_label>A arm (CLAG-M)</arm_group_label>
    <other_name>Cladribine, Cytarabine, Mitoxantrone, G-CSF</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>B arm (FLAG-IDA)</intervention_name>
    <description>Patients who do not achieve CR after two courses of induction therapy or patients with relapsed leukemia are eligible for emergency treatment (&quot;salvage&quot;) according to the CLAG- M or FLAG-IDA protocol.</description>
    <arm_group_label>B arm (FLAG-IDA)</arm_group_label>
    <other_name>Fludarabine, Cytarabine, Idarubicin, G-CSF</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of acute myeloid leukemia (≥20% of blasts in the bone marrow)&#xD;
&#xD;
          2. Previously untreated AML&#xD;
&#xD;
               -  AML de novo&#xD;
&#xD;
               -  AML secondary to the myelodysplastic syndromes (MDS)&#xD;
&#xD;
               -  AML secondary towards used therapies or agents, which can induce leukemia (e.g.,&#xD;
                  irradiation, alkylating drugs, topoisomerase II inhibitors) with a primary tumor&#xD;
                  in remission for at least 2 years.&#xD;
&#xD;
          3. Age ≥ 18 years and ≤60 years while signing a written consent form&#xD;
&#xD;
          4. A clinical condition allowing induction treatment to be performed&#xD;
&#xD;
               -  General state according to the ECOG ≤ 2 scale (Annex 1)&#xD;
&#xD;
               -  Index of comorbidities, HCT-CI ≤ 3, according to Sorror et al. (43) (Annex 2)&#xD;
&#xD;
          5. Normal function of the liver and kidneys defined as:&#xD;
&#xD;
               -  Bilirubin of ≤1.5 of the upper limit of the normal range&#xD;
&#xD;
               -  ALT ≤2.5 x of the upper limit of the normal range&#xD;
&#xD;
               -  AST ≤2.5 x of the upper limit of the normal range&#xD;
&#xD;
               -  Creatinine ≤1.5 of the upper limit of the normal range&#xD;
&#xD;
          6. A negative pregnancy test result in women of reproductive age, or women after&#xD;
             menopause&#xD;
&#xD;
          7. The patient has understood and signed an informed consent form (Annex 3)&#xD;
&#xD;
          8. The patient has given consent to adhere to scheduled appointments in the study and the&#xD;
             remaining protocol requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Diagnosis or suspicion of acute promyelocytic leukemia (APL)&#xD;
&#xD;
          2. Lack of consent for participation in the study&#xD;
&#xD;
          3. Active cancerous disease other than AML (with the exception of carcinoma basocellulare&#xD;
             cutis)&#xD;
&#xD;
          4. Diagnosis of unstable angina pectoris, significant cardiac arrhythmia or class III or&#xD;
             IV congestive heart failure according to the New York Heart Association (NYHA)&#xD;
             functional classification&#xD;
&#xD;
          5. Pregnancy&#xD;
&#xD;
          6. Uncontrolled mycotic, bacterial or viral systemic infection&#xD;
&#xD;
          7. Active HIV, or hepatitis B or C virus infection&#xD;
&#xD;
          8. The use of another form of experimental therapy within 28 days of the commencement of&#xD;
             treatment&#xD;
&#xD;
          9. The presence of another comorbidity or improper study results which could expose the&#xD;
             patient to excessive hazard (HCT-CI&gt;3)&#xD;
&#xD;
         10. Any other serious health disorders, abnormal results of laboratory tests or mental&#xD;
             disorders which would interfere with participation in the study&#xD;
&#xD;
         11. The presence of other comorbidities which would disturb the interpretation of the data&#xD;
             obtained in the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sebastian Giebel, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Polish Adult Leukemia Group</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Agnieszka Wierzbowska, Prof.</last_name>
    <phone>+48426895191</phone>
    <email>agawierzbowska@wp.pl</email>
  </overall_contact>
  <location>
    <facility>
      <name>Weill Cornell Medicine</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10021</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gail Roboz, Prof.</last_name>
    </contact>
    <investigator>
      <last_name>Gail Roboz, Prof.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Medical University of Bialystok Clinical Hospital</name>
      <address>
        <city>Białystok</city>
        <zip>15-276</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jarosław Piszcz, Dr</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Markiewicz Memorial Oncology Center Brzozow</name>
      <address>
        <city>Brzozów</city>
        <zip>36-200</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andrzej Pluta, Dr</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Clinical Centre in Gdansk</name>
      <address>
        <city>Gdańsk</city>
        <zip>80-210</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maria Bieniaszewska, Dr</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Holycross Cancer Center</name>
      <address>
        <city>Kielce</city>
        <zip>25-001</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marzena Wątek, Dr</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Ludwik Rydygier Memorial Specialized Hospital</name>
      <address>
        <city>Kraków</city>
        <zip>30-001</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Małgorzata Raźny, Dr</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Regional Specialised Hospital in Legnica</name>
      <address>
        <city>Legnica</city>
        <zip>59-220</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jadwiga Hołojda</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Independent Public University Hospital No. 1 in Lublin</name>
      <address>
        <city>Lublin</city>
        <zip>20-001</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marek Hus, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Clinical Hospital at the Karol Marcinkowski Medical University in Poznan</name>
      <address>
        <city>Poznań</city>
        <zip>60-355</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>MAciej Kaźmierczak, Dr</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Copernicus Memorial Hospital in Lodz Comprehensive Cancer Center and Traumatology</name>
      <address>
        <city>Łódź</city>
        <zip>93-513</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Agnieszka Wierzbowska, Prof.</last_name>
      <phone>+48426895191</phone>
      <email>agawierzbowska@wp.pl</email>
    </contact>
  </location>
  <location_countries>
    <country>Poland</country>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>August 4, 2017</study_first_submitted>
  <study_first_submitted_qc>August 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 22, 2017</study_first_posted>
  <last_update_submitted>September 30, 2021</last_update_submitted>
  <last_update_submitted_qc>September 30, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Polish Adult Leukemia Group</investigator_affiliation>
    <investigator_full_name>Agnieszka Wierzbowska</investigator_full_name>
    <investigator_title>Study Coordinator</investigator_title>
  </responsible_party>
  <keyword>aml</keyword>
  <keyword>acute myeloid leukemia</keyword>
  <keyword>DAC</keyword>
  <keyword>DA-90</keyword>
  <keyword>FLAG-IDA</keyword>
  <keyword>CLAG-M</keyword>
  <keyword>Ara-C</keyword>
  <keyword>HiDAC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Daunorubicin</mesh_term>
    <mesh_term>Mitoxantrone</mesh_term>
    <mesh_term>Idarubicin</mesh_term>
    <mesh_term>Cladribine</mesh_term>
    <mesh_term>Lenograstim</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/NCT03257241
org study id: PALG-AML1/2016
nct id: NCT03257241
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The study will include newly-diagnosed AML patients, not suffering acute promyelocytic
      leukemia; aged 18-60 years, who are eligible for standard induction chemotherapy. The
      patients will be randomized to one standard induction regimen (DAC or DA-90). At day seven
      after completion of induction, a bone marrow aspiration with MRD will be performed for an
      early evaluation of response to treatment. Patients without bone marrow blast reduction below
      10% at day seven after induction will be given a second early induction course. Patients who
      do not achieve CR after two induction courses will be randomized to one of the standard
      salvage regimens (FLAG-IDA or CLAG-M). Postremission treatment intensity will be adjusted to
      risk group based on cytogenetic and molecular risk factors at diagnosis and AML biology
      (secondary AML, therapy related AML). Patients with a low risk of relapse will be allocated
      to consolidation, with three courses of high doses of Ara-C (HiDAC), or two courses of HiDAC
      with subsequent autologous stem cell transplantation. Intermediate- or high-risk patients
      will be referred for allogeneic stem cell transplantation, if they have a matched donor.
      Until transplantation, consolidation with HiDAC will be continued.
The successful treatment of acute myeloid leukemia (AML) depends on the ability to achieve
      complete remission (CR) and to prevent relapse. Both may be affected by the efficacy of
      induction chemotherapy. The gold standard for treatment since 1982 has been DA, a regimen of
      three days of daunorubicin (DNR) and seven days of cytarabine (Ara-C) which results in
      complete remission in 50 to 75% of patients; this is typically administered intravenously,
      with daunorubicin administered at a dose of 45 mg per square meter of body-surface area daily
      for three days, and cytarabine given at a dose of 100 mg per square meter daily for seven
      days. Neither substituting DNR with another anthracycline nor the addition of thioguanine or
      etoposide has been demonstrated to improve outcome. Recently it has been proved that
      high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of complete
      remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7
      months; P = 0.003) without any increase in serious adverse events, compared with the standard
      dose of the drug.

      An alternative method to intensify induction treatment is by the addition of the purine
      analog cladribine. Cladribine was demonstrated to increase cellular uptake of Ara-C and
      accumulation of Ara-CTP in leukemic blasts by 50% to 65% and to have direct antileukemic
      activity based on incorporation of metabolites into the DNA of proliferating cells. In two
      randomized trials by the Polish Adult Leukemia Group (PALG), the investigators demonstrated
      that the combination of cladribine with DNR (60 mg/m2) and Ara-C (DAC) resulted in a
      significantly increased CR rate after a single induction course compared with the standard
      two-drug induction (DA-60). The DAC arm was found to have a survival advantage over the DA-60
      arm for patients aged 50 years or older (P =. 005), those with an initial leukocyte count
      above 50G /L (P < .03), and those with an unfavorable karyotype (P < .03). Both induction
      protocols have the same level of recommendation by the National Cancer Comprehensive Network
      (NCCN) for routine use (level I), and are commonly used for the treatment of newly diagnosed
      AML in Poland.

      As no randomized comparison of these two standard protocols has yet been performed, the aim
      of the proposed study is to compare the efficacy of these two standard induction protocols in
      terms of achievement of CR, early leukemia elimination (at day seven, post induction) and
      quality of remission measured by minimal residual disease level. Additionally, overall
      survival (OS), event-free survival (EFS) and disease-free survival (DFS) will be analyzed. It
      is also intended to compare the hematological and non-hematological toxicity of both
      regimens.

      However, in younger adults with AML treated with standard induction chemotherapy, 20-35% do
      not achieve CR and 50-70% with CR may be expected to relapse within three years. Patients
      with primary refractory disease and with relapses following CR1 have a significantly poorer
      outcome. The optimum strategy at the time of relapse or for patients with refractory disease
      remains uncertain. Allogeneic transplantation can be curative for the minority of patients
      who achieve second CR (2CR) and for whom a suitable donor is available. For the majority of
      patients, additional chemotherapy is given in the hope of achieving remission. Most salvage
      therapies utilize high or intermediate doses of arabinoside cytosine (Ara-C) in combination
      with other agents to overcome resistance in leukemic cells. Previous studies have shown that
      a combination of the purine analog fludarabine (FA) and cytosine arabinoside (Ara-C)
      increases the accumulation of Ara-C-5' triphosphate (Ara-CTP) responsible for the cytotoxic
      effect in leukemic blasts. This combination of FA plus Ara-C was initially explored in
      refractory and relapsed AML patients with satisfactory results. It is also likely that these
      results can be improved by the addition of granulocyte-colony stimulating factor (G-CSF).
      Such a combination of FA, Ara-C, idarubicin and G-CSF (the FLAG-IDA regimen) has been used in
      the treatment of refractory and relapsed AML and poor prognosis myelodysplastic syndromes
      (MDS), with CR rates of between 30-80% being reported. Recent studies have shown that another
      purine analog, cladribine (2-CdA), is also able to enhance Ara-CTP accumulation in leukemic
      blasts and that the combination of 2-Cda with Ara-C exhibited synergistic effect on
      inhibition of myeloid leukemic cell proliferation, induction of apoptosis, and on disruption
      of mitochondrial membrane potential.

      Two previous PALG studies have confirmed that the CLAG-M regimen (a combination of
      cladribine, Ara-C, G-CSF and mitoxantrone) has high efficacy and low toxicity in
      refractory/relapsed AML patients. This salvage regimen was particularly effective in a very
      poor-risk subgroup with primary refractoriness, early relapse or relapse after stem cell
      transplantation. Both salvage protocols, CLAG-M and FLAG-Ida, are wildly used in the
      treatment of relapsed/refractory AML and both have the highest level of NCCN recommendation.
      However, these two standard salvage protocols have yet to be examined as part of any
      randomized study. Therefore, the aim of this study is to compare the efficacy of these two
      standard reinduction protocols (CLAG-M vs FLAG-IDA) in terms of achievement of CR, and
      quality of remission measured by minimal residual disease level. Additionally, the overall
      survival (OS), event-free survival (EFS) and disease-free survival (DFS) will be analyzed.
      The study will also compare the hematological and non-hematological toxicity of both
      regimens.

      The study will include newly-diagnosed AML patients, not suffering acute promyelocytic
      leukemia; aged 18-60 years, who are eligible for standard induction chemotherapy. The
      patients will be randomized to one standard induction regimen (DAC or DA-90). At day seven
      after completion of induction, a bone marrow aspiration with MRD will be performed for an
      early evaluation of response to treatment. Patients without bone marrow blast reduction below
      10% at day seven after induction will be given a second early induction course. Patients who
      do not achieve CR after two induction courses will be randomized to one of the standard
      salvage regimens (FLAG-IDA or CLAG-M). Postremission treatment intensity will be adjusted to
      risk group based on cytogenetic and molecular risk factors at diagnosis and AML biology
      (secondary AML, therapy related AML). Patients with a low risk of relapse will be allocated
      to consolidation, with three courses of high doses of Ara-C (HiDAC), or two courses of HiDAC
      with subsequent autologous stem cell transplantation. Intermediate- or high-risk patients
      will be referred for allogeneic stem cell transplantation, if they have a matched donor.
      Until transplantation, consolidation with HiDAC will be continued.

      The primary end point of the study is CR rate after one and two induction courses. The
      secondary end-points are the quality of CR (MRD), OS, DFS, PFS, CR rate after salvage
      regimen.

      It is planned to include 582 patients with newly-diagnosed AML. This will allow a 10%
      difference in CR rate between DAC and DA-90 induction regimens to be confirmed with a power
      of 80% and level of significance 0.05.

      The study includes neither any experimental drug nor procedures that are not of the standard
      of treatment for AML.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Comparison of the efficacy of two standard induction treatment protocols (DA-90 and DAC) in patients with newly-diagnosed AML (with the exception of acute promyelocytic leukemia). Comparison of the efficacy of two standard reinduction treatment protocols (CLAG-M and FLAG-IDA) in patients with refractory and relapsed AML.
primary purpose: Treatment
masking: None (Open Label)
measure: Induction regimen efficacy (DA-90 vs DAC) - I induction
time frame: On +7 day after chemotherpay
description: Comparison of total remission rates after 1 induction course of DA-90 and DAC.
measure: Induction regimen efficacy (DA-90 vs DAC) - II induction
time frame: On +28 day after chemotherapy or after complete morphology regeneration (if it occurs before day +28)
description: Comparison of total remission rates after II induction course of DA-90 and DAC.
measure: Salvage regimen efficacy (CLAG-M vs FLAG-IDA) - I reinduction
time frame: On +28 day after chemotherapy or after complete morphology regeneration (if it occurs before day +28)
description: Comparison of total remission rates after I reinduction course of CLAG-M and FLAG-IDA
measure: Salvage regimen efficacy (CLAG-M vs FLAG-IDA) - II reinduction
time frame: On +28 day after chemotherapy or after complete morphology regeneration (if it occurs before day +28)
description: Comparison of total remission rates after II reinduction course of CLAG-M and FLAG-IDA
arm group label: A arm (DA-90)
arm group type: Active Comparator
description: Induction I:
DNR 90 mg/m2 D 1-3 in 30-60 min i.v. infusion
Ara-C 100 mg/m2 D 1-7 in 24 h i.v. infusion
arm group label: B arm (DAC)
arm group type: Active Comparator
description: Induction I:
DNR 60 mg/m2 D 1-3 in 30-60 min i.v. infusion
cladribine 5 mg/m2 D 1-5 in 2 h i.v. infusion prior to Ara-C
Ara-C 200 mg/m2 D 1-7 in 22 h i.v. infusion.
arm group label: A arm (CLAG-M)
arm group type: Active Comparator
description: Cladribine 5mg/m2 in 2 h i.v. infusion on days (1-5) Ara-C 2 g/m2 in 4 h i.v. infusion, 2 h after cladribine infusion on days (1-5) Mitoxantrone 10 mg/m2 i.v. 1xd on days (1-3) G-CSF 30MU s.c. 1xd from day 0 to 5 of the treatment (6 doses).
arm group label: B arm (FLAG-IDA)
arm group type: Active Comparator
description: Fludarabine 30 mg/m2 in 30-min i.v. infusion on days (1-5) Ara-C 2 g/m2 in 4 h i.v. infusion, 2 h after fludarabine infusion on days (1-5). Idarubicin 8 mg/m2 i.v. 1xd on days (1-3) G-CSF 30MU s.c. 1xd from day 0 to 5 of the treatment (6 doses).
intervention type: Drug
intervention name: A arm (DA-90)
description: After confirming the diagnosis, assuming the inclusion criteria and exclusion criteria are respected, the patients are randomized to one of two standard induction treatment protocols (A arm: DA-90 vs B arm: DAC). After completing induction I, an early bone marrow assessment is performed on day 14 from the beginning of the treatment (+ day 7 after finishing chemotherapy) using the cytological method and MRD is assessed by the immunophenotyping method. Therapeutic decision is taken on the basis of the cytological assessment. Patients, in whom the percentage of blasts in the bone marrow on day 14 is > 10%, receive early induction II from day 16. An Immunophenotype test is a complementary examination.
arm group label: A arm (DA-90)
other name: Daunorubicin, Cytarabine
intervention type: Drug
intervention name: B arm (DAC)
description: After confirming the diagnosis, assuming the inclusion criteria and exclusion criteria are respected, the patients are randomized to one of two standard induction treatment protocols (A arm: DA-90 vs B arm: DAC). After completing induction I, an early bone marrow assessment is performed on day 14 from the beginning of the treatment (+ day 7 after finishing chemotherapy) using the cytological method and MRD is assessed by the immunophenotyping method. Therapeutic decision is taken on the basis of the cytological assessment. Patients, in whom the percentage of blasts in the bone marrow on day 14 is > 10%, receive early induction II from day 16. An Immunophenotype test is a complementary examination.
arm group label: B arm (DAC)
other name: Daunorubicin, Cladribine, Cytarabine
intervention type: Drug
intervention name: A arm (CLAG-M)
description: Patients who do not achieve CR after two courses of induction therapy or patients with relapsed leukemia are eligible for emergency treatment ("salvage") according to the CLAG- M or FLAG-IDA protocol.
arm group label: A arm (CLAG-M)
other name: Cladribine, Cytarabine, Mitoxantrone, G-CSF
intervention type: Drug
intervention name: B arm (FLAG-IDA)
description: Patients who do not achieve CR after two courses of induction therapy or patients with relapsed leukemia are eligible for emergency treatment ("salvage") according to the CLAG- M or FLAG-IDA protocol.
arm group label: B arm (FLAG-IDA)
other name: Fludarabine, Cytarabine, Idarubicin, G-CSF
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Sebastian Giebel, Prof.
role: Principal Investigator
affiliation: Polish Adult Leukemia Group
last name: Agnieszka Wierzbowska, Prof.
phone: +48426895191
email: agawierzbowska@wp.pl
facility: 
status: Recruiting
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country: Poland
country: United States
responsible party type: Principal Investigator
investigator affiliation: Polish Adult Leukemia Group
investigator full name: Agnieszka Wierzbowska
investigator title: Study Coordinator
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Cytarabine
mesh term: Fludarabine
mesh term: Daunorubicin
mesh term: Mitoxantrone
mesh term: Idarubicin
mesh term: Cladribine
mesh term: Lenograstim