<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/NCT01703364</url>
  </required_header>
  <id_info>
    <org_study_id>AGMT_CLL-9</org_study_id>
    <secondary_id>2011-004912-43</secondary_id>
    <nct_id>NCT01703364</nct_id>
  </id_info>
  <brief_title>Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide in Untreated CLL</brief_title>
  <official_title>Fludarabine/Rituximab Combined With Escalating Doses of Lenalidomide in Untreated Chronic Lymphocytic Leukemia (CLL) - a Dose-finding Study With Escalating Starting Dose of Lenalidomide and Concomitant Evaluation of Safety and Efficacy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Arbeitsgemeinschaft medikamentoese Tumortherapie</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Celgene</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Arbeitsgemeinschaft medikamentoese Tumortherapie</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a trial in patients with previously untreated CLL. Eligible patients will receive&#xD;
      Lenalidomide with a backbone of Fludarabine and Rituximab for 6 therapy cycles. Lenalidomide&#xD;
      will be increased by dose steps of 5 mg every cycle in the absence of limiting toxicity. If&#xD;
      limiting toxicity ensues the patients will be treated with last tolerable dose for the&#xD;
      remainder of the 6 treatment cycles.&#xD;
&#xD;
      The first 5 patients will start with dose level 5 mg Lenalidomide and further escalating&#xD;
      dose. After the fifth patient is included in the study, enrolment will be interrupted until&#xD;
      this patient has finished his first treatment cycle. A safety board will evaluate the&#xD;
      toxicities of the first 5 patients. If there are more than 2 patients experiencing a dose&#xD;
      limiting toxicity (DLT) in the first treatment cycle, the starting dose will not be escalated&#xD;
      and further 5 patients will be enrolled with a starting dose of 5 mg Lenalidomide. If only 2&#xD;
      or less patients experience a DLT in the first treatment cycle, the next 5 patients will&#xD;
      start the treatment with 10 mg Lenalidomide.&#xD;
&#xD;
      The rational for the higher starting doses stems from the lack of tumor lysis or tumor flare&#xD;
      toxicity in this combination on the one hand and from the observation that the very slow&#xD;
      escalation from 2,5 mg on led to a lack of efficacy in monotherapy trials due to early&#xD;
      progression in a relevant number of cases. The increase of the Lenalidomide dosage should&#xD;
      result in an increased efficacy especially at the beginning and a higher cumulative dose of&#xD;
      Lenalidomide.&#xD;
&#xD;
      The identification of patients intolerant to Lenalidomide by immunophenotyping of the T cells&#xD;
      for validation is also part of this trial, because intolerance seems to be not dose dependent&#xD;
      but may be caused by T cell activation. Therefore, early identification of patients&#xD;
      intolerant to this form of modern immunochemotherapy and establishing efficient Lenalidomide&#xD;
      based combination therapy is an important part of improvement of current CLL treatment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>June 2012</start_date>
  <completion_date type="Actual">October 2015</completion_date>
  <primary_completion_date type="Actual">March 2015</primary_completion_date>
  <phase>Phase 1/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>Tolerability of escalated starting dose</measure>
    <time_frame>12 month, 20 month</time_frame>
    <description>Interim analysis after completion of cylce 1 of the first 5 patients, final analysis after last pastient last visit Metrics: Number of patients experiencing defined dose limiting toxicities during cycle 1</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Establishment of maximal tolerated dose (MTD) of Lenalidomide in combination with FR</measure>
    <time_frame>20 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to MTD</measure>
    <time_frame>20 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety profile of the FRL combination</measure>
    <time_frame>20 month</time_frame>
    <description>Analysis of occuring adverse events during the study treatment according to Common Terminology Criteria for Adverse Events (CTCAE)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response rates in all phases by 4-colour flow cytometric and ASO-PCR MRD analysis</measure>
    <time_frame>20 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Risk factor analysis (FISH cytogenetics, CD38/ZAP-70 expression, mutation status)</measure>
    <time_frame>20 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Longitudinal definition of T cell subsets (including prognostic EM T cells and Treg cells)+/- PD1</measure>
    <time_frame>20 month</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>CLL</condition>
  <condition>Chronic Lymphocytic Leukemia</condition>
  <arm_group>
    <arm_group_label>Lenalidomide/Fludarabine/Rituximab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lenalidomide: day 8-21 of cycle 1 and day 1-21 of cycles 2-6; Starting Dose: 5 mg (first 5 patients) and 10 mg (further 5 patients) increase Lenalidomide dose via dose levels (10)/15/20/25 mg/d every 28 days if no limiting toxicity occurs&#xD;
Fludarabine: 25 mg/m2 iv d1-3 or 40 mg/m2 po d1-3; repeat every 28 days&#xD;
Rituximab: 375 mg/m2 iv day 4 on cycle 1 and 500 mg/m2 iv day 1 on cycles 2-6; repeat every 28 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenalidomide</intervention_name>
    <description>Lenalidomide: day 8-21 of cycle 1 and day 1-21 of cycles 2-6; Starting Dose: 5 mg (first 5 patients) and 10 mg (further 5 patients) increase Lenalidomide dose via dose levels (10)/15/20/25 mg/d every 28 days if no limiting toxicity occurs&#xD;
Fludarabine: 25 mg/m2 iv d1-3 or 40 mg/m2 po d1-3; repeat every 28 days&#xD;
Rituximab: 375 mg/m2 iv day 4 on cycle 1 and 500 mg/m2 iv day 1 on cycles 2-6; repeat every 28 days</description>
    <arm_group_label>Lenalidomide/Fludarabine/Rituximab</arm_group_label>
    <other_name>Revlimid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
          -  Male or female ≥ 18 years of age&#xD;
&#xD;
          -  CLL (as determined by CD23+, CD5+, CD19+)&#xD;
&#xD;
          -  Treatment indication as defined by the NCI Workshop criteria (see appendix 6 and&#xD;
             reference 10)&#xD;
&#xD;
          -  ECOG ≤ 2&#xD;
&#xD;
          -  No previous treatment of the CLL by chemotherapy, radiotherapy (except localized&#xD;
             radiotherapy of 1 lymphatic area) or immunotherapy&#xD;
&#xD;
          -  Life expectancy &gt; 6 months (except prognosis due to high risk CLL)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Active bacterial, viral or fungal infection&#xD;
&#xD;
          -  Positivity for HIV, Hepatitis B or C&#xD;
&#xD;
          -  Patients with known history of thromboembolic events&#xD;
&#xD;
          -  Reduced organ functions and bone marrow dysfunction not due to CLL&#xD;
&#xD;
          -  Creatinine clearance of below 30 ml/min&#xD;
&#xD;
          -  Patients with known history of thromboembolic events&#xD;
&#xD;
          -  Patients with a history of other malignancies within 2 years prior to study entry&#xD;
             (except for adequately treated carcinoma in situ of the cervix; basal or squamous cell&#xD;
             skin cancer; low grade, early stage localized prostate cancer treated surgically with&#xD;
             curative intent; good prognosis DCIS of the breast treated with lumpectomy alone with&#xD;
             curative intent)&#xD;
&#xD;
          -  Patients with medical co-morbid conditions that would require long term use (&gt; 1&#xD;
             month) of systemic corticosteroids during study treatment&#xD;
&#xD;
          -  Patients with a history of severe cardiac disease; e.g. NYHA Functional Class III or&#xD;
             IV heart failure, myocardial infarction within 6 months, ventricular tachyarrhythmias&#xD;
             requiring ongoing treatment, or unstable angina&#xD;
&#xD;
          -  Other known co-morbidity with the potential to dominate survival&#xD;
&#xD;
          -  Transformation to aggressive B-cell malignancy (e.g., large B-cell lymphoma, Richter's&#xD;
             syndrome, or prolymphocytic leukemia (PLL))&#xD;
&#xD;
          -  Hypersensitivity with anaphylactic reaction to humanised monoclonal antibodies or any&#xD;
             of the applied drugs&#xD;
&#xD;
          -  Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not&#xD;
             indicated in the study protocol&#xD;
&#xD;
          -  Administration of any investigational agent(s) within 4 weeks prior to entry&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Medical or psychological condition which in the opinion of the Investigator would not&#xD;
             permit the patient to complete the study or sign meaningful informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Universitätsklinik für Innere Medizin Innsbruck, Klinische Abteilung für Hämatologie und Onkologie</name>
      <address>
        <city>Innsbruck</city>
        <state>Tirol</state>
        <zip>6020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinik der PMU Salzburg, Univ-Klinik für Innere Medizin III</name>
      <address>
        <city>Salzburg</city>
        <zip>5020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <link>
    <url>http://www.agmt.at</url>
    <description>AGMT</description>
  </link>
  <verification_date>May 2016</verification_date>
  <study_first_submitted>October 4, 2012</study_first_submitted>
  <study_first_submitted_qc>October 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <last_update_submitted>May 25, 2016</last_update_submitted>
  <last_update_submitted_qc>May 25, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 26, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CLL</keyword>
  <keyword>Lenalidomide</keyword>
  <keyword>Revlimid</keyword>
  <keyword>AGMT</keyword>
  <keyword>T cell</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lenalidomide</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/NCT01703364
org study id: AGMT_CLL-9
secondary id: 2011-004912-43
nct id: NCT01703364
lead sponsor: 
collaborator: 
has dmc: No
This is a trial in patients with previously untreated CLL. Eligible patients will receive
      Lenalidomide with a backbone of Fludarabine and Rituximab for 6 therapy cycles. Lenalidomide
      will be increased by dose steps of 5 mg every cycle in the absence of limiting toxicity. If
      limiting toxicity ensues the patients will be treated with last tolerable dose for the
      remainder of the 6 treatment cycles.

      The first 5 patients will start with dose level 5 mg Lenalidomide and further escalating
      dose. After the fifth patient is included in the study, enrolment will be interrupted until
      this patient has finished his first treatment cycle. A safety board will evaluate the
      toxicities of the first 5 patients. If there are more than 2 patients experiencing a dose
      limiting toxicity (DLT) in the first treatment cycle, the starting dose will not be escalated
      and further 5 patients will be enrolled with a starting dose of 5 mg Lenalidomide. If only 2
      or less patients experience a DLT in the first treatment cycle, the next 5 patients will
      start the treatment with 10 mg Lenalidomide.

      The rational for the higher starting doses stems from the lack of tumor lysis or tumor flare
      toxicity in this combination on the one hand and from the observation that the very slow
      escalation from 2,5 mg on led to a lack of efficacy in monotherapy trials due to early
      progression in a relevant number of cases. The increase of the Lenalidomide dosage should
      result in an increased efficacy especially at the beginning and a higher cumulative dose of
      Lenalidomide.

      The identification of patients intolerant to Lenalidomide by immunophenotyping of the T cells
      for validation is also part of this trial, because intolerance seems to be not dose dependent
      but may be caused by T cell activation. Therefore, early identification of patients
      intolerant to this form of modern immunochemotherapy and establishing efficient Lenalidomide
      based combination therapy is an important part of improvement of current CLL treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Tolerability of escalated starting dose
time frame: 12 month, 20 month
description: Interim analysis after completion of cylce 1 of the first 5 patients, final analysis after last pastient last visit Metrics: Number of patients experiencing defined dose limiting toxicities during cycle 1
measure: Establishment of maximal tolerated dose (MTD) of Lenalidomide in combination with FR
time frame: 20 month
measure: Time to MTD
time frame: 20 month
measure: Safety profile of the FRL combination
time frame: 20 month
description: Analysis of occuring adverse events during the study treatment according to Common Terminology Criteria for Adverse Events (CTCAE)
measure: Response rates in all phases by 4-colour flow cytometric and ASO-PCR MRD analysis
time frame: 20 month
measure: Risk factor analysis (FISH cytogenetics, CD38/ZAP-70 expression, mutation status)
time frame: 20 month
measure: Longitudinal definition of T cell subsets (including prognostic EM T cells and Treg cells)+/- PD1
time frame: 20 month
arm group label: Lenalidomide/Fludarabine/Rituximab
arm group type: Experimental
description: Lenalidomide: day 8-21 of cycle 1 and day 1-21 of cycles 2-6; Starting Dose: 5 mg (first 5 patients) and 10 mg (further 5 patients) increase Lenalidomide dose via dose levels (10)/15/20/25 mg/d every 28 days if no limiting toxicity occurs
Fludarabine: 25 mg/m2 iv d1-3 or 40 mg/m2 po d1-3; repeat every 28 days
Rituximab: 375 mg/m2 iv day 4 on cycle 1 and 500 mg/m2 iv day 1 on cycles 2-6; repeat every 28 days
intervention type: Drug
intervention name: Lenalidomide
description: Lenalidomide: day 8-21 of cycle 1 and day 1-21 of cycles 2-6; Starting Dose: 5 mg (first 5 patients) and 10 mg (further 5 patients) increase Lenalidomide dose via dose levels (10)/15/20/25 mg/d every 28 days if no limiting toxicity occurs
Fludarabine: 25 mg/m2 iv d1-3 or 40 mg/m2 po d1-3; repeat every 28 days
Rituximab: 375 mg/m2 iv day 4 on cycle 1 and 500 mg/m2 iv day 1 on cycles 2-6; repeat every 28 days
arm group label: Lenalidomide/Fludarabine/Rituximab
other name: Revlimid
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: Austria
url: http://www.agmt.at
description: AGMT
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Lenalidomide