<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/NCT01673308</url>
  </required_header>
  <id_info>
    <org_study_id>RV-MDS-PI-0722</org_study_id>
    <nct_id>NCT01673308</nct_id>
  </id_info>
  <brief_title>Lenalidomide After Failure of Hypomethylating Agents in Myelodysplastic Syndrome</brief_title>
  <acronym>VIOLET</acronym>
  <official_title>Salvage in Patients With Myelodysplastic Syndrome After Failure of Hypomethylating Agents: Lenalidomide as a Second-line Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ulsan University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cooperative Study Group A for Hematology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Ulsan University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase II study to evaluate the efficacy of second-line lenalidomide monotherapy for&#xD;
      myelodysplastic syndrome (MDS) patients who failed to hypomethylating agents.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There is no standard therapy after the failure of hypomethylating agents only providing&#xD;
      supportive cares including transfusion or cytokine therapies. Lenalidomide is the treatment&#xD;
      of choice in case of MDS with 5q deletion. A study of lenalidomide for non-5q deletion MDS&#xD;
      patients showed that transfusion independency rate was 26% which was relatively acceptable&#xD;
      and suggested that lenalidomide could be used for non-5q deletion MDS patients. There is no&#xD;
      datum for second-line lenalidomide therapy after hypomethylating agents. MDS which has highly&#xD;
      complex pathogenesis backgrounds will have distinctive subtype for each therapy and each&#xD;
      treatment drug can have distinctive subgroup for the response. In fact the investigators&#xD;
      don't know which patient will be responsive hypomethylating agents or lenalidomide except for&#xD;
      5q deletion. This suggests that second line therapy after the first line failure in MDS will&#xD;
      be different with other type of relapsed/refractory disease which will be tend to more&#xD;
      resistant to subsequent therapies. In this regard, there is a possibility to have a&#xD;
      relatively high response rate to second line lenalidomide in this selected subset who has&#xD;
      failed to the hypomethylation therapy or some patients will be responsive regardless of&#xD;
      treatment line. Recent data suggested that MDS with JAK2 mutation will be responsive to&#xD;
      lenalidomide. The investigators will analyze the JAK2 mutation status in response evaluation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>August 2012</start_date>
  <completion_date type="Anticipated">November 2016</completion_date>
  <primary_completion_date type="Actual">November 2015</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>Response criteria by international working group (IWG) 2006 criteria</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety</measure>
    <time_frame>2 years</time_frame>
    <description>Safety assessed by national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) version 4.03</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">35</enrollment>
  <condition>Myelodysplastic Syndrome</condition>
  <arm_group>
    <arm_group_label>Treatment arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lenalidomide treatment arm</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenalidomide</intervention_name>
    <description>Lenalidomide 10 mg orally on days 1 to 21 of a 28-day cycle for at least 4 cycles until intolerance or disease progression.</description>
    <arm_group_label>Treatment arm</arm_group_label>
    <other_name>Revlimid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Myelodysplastic syndrome by world health organization (WHO) classification&#xD;
&#xD;
          -  Treatment failure after hypomethylating agents (HMA; azacitidine or decitabine);&#xD;
             Intolerant to hypomethylating agents or Progressive disease after HMA&#xD;
&#xD;
          -  Age over 18 years old&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤2&#xD;
&#xD;
          -  Adequate organ function (serum creatinine ≤ 2.5 mg/dL, serum aspartate transaminase or&#xD;
             alanine transaminase ≤ 3.0 x upper limit of normal (ULN), and serum direct bilirubin ≤&#xD;
             2.0 mg/dL).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous therapy history for MDS except for hypomethylating agents, cytokines&#xD;
             (granulocyte-stimulating agents or erythropoietin) or supportive care.&#xD;
&#xD;
          -  Patients who cannot keep the strict contraception or who willing to be pregnant.&#xD;
&#xD;
          -  Contraindication to lenalidomide: Females who are or may become pregnant; Lenalidomide&#xD;
             is contraindicated in any patients who have demonstrated hypersensitivity to the drug&#xD;
             or its components; Lenalidomide capsules contain lactose. Patients with rare&#xD;
             hereditary problems of galactose intolerance, the Lapp lactase deficiency or&#xD;
             glucose-galactose malabsorption should not take this medicinal product.&#xD;
&#xD;
          -  Patients who cannot take lenalidomide orally&#xD;
&#xD;
          -  Current enrollment to other clinical trial&#xD;
&#xD;
          -  Presence of uncontrolled bleeding&#xD;
&#xD;
          -  Severe or life-threatening other medical conditions&#xD;
&#xD;
          -  Any coexisting major illness or organ failure&#xD;
&#xD;
          -  Patients with psychiatric disorder or mental deficiency severe as to make compliance&#xD;
             with the treatment unlike, and making informed consent impossible&#xD;
&#xD;
          -  History of congenital or acquired coagulopathy unrelated to malignancy&#xD;
&#xD;
          -  History of non-compliance or patient who cannot sign informed consent&#xD;
&#xD;
          -  Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years&#xD;
             following therapy with curative intent (except curatively treated nonmelanoma skin&#xD;
             cancer, in situ carcinoma, or cervical intraepithelial neoplasia)&#xD;
&#xD;
          -  Candidate of hematopoietic stem cell transplantation who cannot complete 4 cycles of&#xD;
             lenalidomide.&#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>Hawk Kim, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ulsan University Hospital, University of Ulsan College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ulsan University Hospital</name>
      <address>
        <city>Ulsan</city>
        <zip>682714</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Prebet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, Dreyfus F, Rauzy OB, Recher C, Ades L, Quesnel B, Beach CL, Fenaux P, Vey N. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011 Aug 20;29(24):3322-7. doi: 10.1200/JCO.2011.35.8135. Epub 2011 Jul 25.</citation>
    <PMID>21788559</PMID>
  </reference>
  <reference>
    <citation>Jabbour E, Garcia-Manero G, Batty N, Shan J, O'Brien S, Cortes J, Ravandi F, Issa JP, Kantarjian H. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010 Aug 15;116(16):3830-4. doi: 10.1002/cncr.25247.</citation>
    <PMID>20564137</PMID>
  </reference>
  <reference>
    <citation>List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. doi: 10.1056/NEJMoa041668.</citation>
    <PMID>15703420</PMID>
  </reference>
  <reference>
    <citation>Ades L, Boehrer S, Prebet T, Beyne-Rauzy O, Legros L, Ravoet C, Dreyfus F, Stamatoullas A, Chaury MP, Delaunay J, Laurent G, Vey N, Burcheri S, Mbida RM, Hoarau N, Gardin C, Fenaux P. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood. 2009 Apr 23;113(17):3947-52. doi: 10.1182/blood-2008-08-175778. Epub 2008 Nov 5.</citation>
    <PMID>18987358</PMID>
  </reference>
  <reference>
    <citation>Jadersten M, Hellstrom-Lindberg E. Myelodysplastic syndromes: biology and treatment. J Intern Med. 2009 Mar;265(3):307-28. doi: 10.1111/j.1365-2796.2008.02052.x. Epub 2008 Dec 17.</citation>
    <PMID>19141095</PMID>
  </reference>
  <reference>
    <citation>Heise C, Carter T, Schafer P, Chopra R. Pleiotropic mechanisms of action of lenalidomide efficacy in del(5q) myelodysplastic syndromes. Expert Rev Anticancer Ther. 2010 Oct;10(10):1663-72. doi: 10.1586/era.10.135.</citation>
    <PMID>20942636</PMID>
  </reference>
  <reference>
    <citation>Nomdedeu M, Maffioli M, Calvo X, Martinez-Trillos A, Baumann T, Diaz-Beya M, Aguilar JL, Rozman M, Costa D, Esteve J, Cervantes F, Colomer D, Nomdedeu B. Efficacy of lenalidomide in a patient with myelodysplastic syndrome with isolated del(5q) and JAK2V617F mutation. Leuk Res. 2011 Sep;35(9):1276-8. doi: 10.1016/j.leukres.2011.06.008. Epub 2011 Jul 20. No abstract available.</citation>
    <PMID>21764129</PMID>
  </reference>
  <reference>
    <citation>Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, Dreisbach L, Schiffer CA, Stone RM, Greenberg PL, Curtin PT, Klimek VM, Shammo JM, Thomas D, Knight RD, Schmidt M, Wride K, Zeldis JB, List AF. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008 Jan 1;111(1):86-93. doi: 10.1182/blood-2007-01-068833. Epub 2007 Sep 24.</citation>
    <PMID>17893227</PMID>
  </reference>
  <reference>
    <citation>Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.</citation>
    <PMID>16609072</PMID>
  </reference>
  <verification_date>May 2016</verification_date>
  <study_first_submitted>August 22, 2012</study_first_submitted>
  <study_first_submitted_qc>August 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2012</study_first_posted>
  <last_update_submitted>May 10, 2016</last_update_submitted>
  <last_update_submitted_qc>May 10, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 11, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Ulsan University Hospital</investigator_affiliation>
    <investigator_full_name>Hawk Kim</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Syndrome</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/NCT01673308
org study id: RV-MDS-PI-0722
nct id: NCT01673308
lead sponsor: 
collaborator: 
has dmc: No
This is a Phase II study to evaluate the efficacy of second-line lenalidomide monotherapy for
      myelodysplastic syndrome (MDS) patients who failed to hypomethylating agents.
There is no standard therapy after the failure of hypomethylating agents only providing
      supportive cares including transfusion or cytokine therapies. Lenalidomide is the treatment
      of choice in case of MDS with 5q deletion. A study of lenalidomide for non-5q deletion MDS
      patients showed that transfusion independency rate was 26% which was relatively acceptable
      and suggested that lenalidomide could be used for non-5q deletion MDS patients. There is no
      datum for second-line lenalidomide therapy after hypomethylating agents. MDS which has highly
      complex pathogenesis backgrounds will have distinctive subtype for each therapy and each
      treatment drug can have distinctive subgroup for the response. In fact the investigators
      don't know which patient will be responsive hypomethylating agents or lenalidomide except for
      5q deletion. This suggests that second line therapy after the first line failure in MDS will
      be different with other type of relapsed/refractory disease which will be tend to more
      resistant to subsequent therapies. In this regard, there is a possibility to have a
      relatively high response rate to second line lenalidomide in this selected subset who has
      failed to the hypomethylation therapy or some patients will be responsive regardless of
      treatment line. Recent data suggested that MDS with JAK2 mutation will be responsive to
      lenalidomide. The investigators will analyze the JAK2 mutation status in response evaluation.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Response criteria by international working group (IWG) 2006 criteria
time frame: 12 months
measure: Safety
time frame: 2 years
description: Safety assessed by national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) version 4.03
arm group label: Treatment arm
arm group type: Experimental
description: Lenalidomide treatment arm
intervention type: Drug
intervention name: Lenalidomide
description: Lenalidomide 10 mg orally on days 1 to 21 of a 28-day cycle for at least 4 cycles until intolerance or disease progression.
arm group label: Treatment arm
other name: Revlimid
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Hawk Kim, M.D., Ph.D.
role: Principal Investigator
affiliation: Ulsan University Hospital, University of Ulsan College of Medicine
facility: 
country: Korea, Republic of
citation: Prebet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, Dreyfus F, Rauzy OB, Recher C, Ades L, Quesnel B, Beach CL, Fenaux P, Vey N. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011 Aug 20;29(24):3322-7. doi: 10.1200/JCO.2011.35.8135. Epub 2011 Jul 25.
PMID: 21788559
citation: Jabbour E, Garcia-Manero G, Batty N, Shan J, O'Brien S, Cortes J, Ravandi F, Issa JP, Kantarjian H. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010 Aug 15;116(16):3830-4. doi: 10.1002/cncr.25247.
PMID: 20564137
citation: List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. doi: 10.1056/NEJMoa041668.
PMID: 15703420
citation: Ades L, Boehrer S, Prebet T, Beyne-Rauzy O, Legros L, Ravoet C, Dreyfus F, Stamatoullas A, Chaury MP, Delaunay J, Laurent G, Vey N, Burcheri S, Mbida RM, Hoarau N, Gardin C, Fenaux P. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood. 2009 Apr 23;113(17):3947-52. doi: 10.1182/blood-2008-08-175778. Epub 2008 Nov 5.
PMID: 18987358
citation: Jadersten M, Hellstrom-Lindberg E. Myelodysplastic syndromes: biology and treatment. J Intern Med. 2009 Mar;265(3):307-28. doi: 10.1111/j.1365-2796.2008.02052.x. Epub 2008 Dec 17.
PMID: 19141095
citation: Heise C, Carter T, Schafer P, Chopra R. Pleiotropic mechanisms of action of lenalidomide efficacy in del(5q) myelodysplastic syndromes. Expert Rev Anticancer Ther. 2010 Oct;10(10):1663-72. doi: 10.1586/era.10.135.
PMID: 20942636
citation: Nomdedeu M, Maffioli M, Calvo X, Martinez-Trillos A, Baumann T, Diaz-Beya M, Aguilar JL, Rozman M, Costa D, Esteve J, Cervantes F, Colomer D, Nomdedeu B. Efficacy of lenalidomide in a patient with myelodysplastic syndrome with isolated del(5q) and JAK2V617F mutation. Leuk Res. 2011 Sep;35(9):1276-8. doi: 10.1016/j.leukres.2011.06.008. Epub 2011 Jul 20. No abstract available.
PMID: 21764129
citation: Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, Dreisbach L, Schiffer CA, Stone RM, Greenberg PL, Curtin PT, Klimek VM, Shammo JM, Thomas D, Knight RD, Schmidt M, Wride K, Zeldis JB, List AF. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008 Jan 1;111(1):86-93. doi: 10.1182/blood-2007-01-068833. Epub 2007 Sep 24.
PMID: 17893227
citation: Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.
PMID: 16609072
responsible party type: Principal Investigator
investigator affiliation: Ulsan University Hospital
investigator full name: Hawk Kim
investigator title: Associate Professor
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
mesh term: Syndrome
mesh term: Lenalidomide