<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/NCT02261779</url>
  </required_header>
  <id_info>
    <org_study_id>UKM_04_12_TCP_ATRA_AML</org_study_id>
    <secondary_id>2012-002154-23</secondary_id>
    <nct_id>NCT02261779</nct_id>
  </id_info>
  <brief_title>Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible</brief_title>
  <acronym>TCP-AML</acronym>
  <official_title>Phase I/II Pilot Trial of ATRA (Tretinoin) and TCP (Tranylcypromine) in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) and no Intensive Treatment is Possible</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Martin-Luther-Universität Halle-Wittenberg</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Martin-Luther-Universität Halle-Wittenberg</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Longterm disease-free survival (DFS) of older patients with acute myeloid leukemia (AML)&#xD;
      remains poor. The vast majority of AML patients relapses within two years after start of&#xD;
      therapy1,2. In Acute Promyelocytic Leukemia (APL, AML M3), all-trans-retinoic-acid (ATRA;&#xD;
      Tretinoin) induces differentiation and subsequently clinical remission. So far effective&#xD;
      differentiation therapy does not exist in other AML subtypes. Recent preclinical data suggest&#xD;
      that the combinatorial use of ATRA and tranylcypromine (TCP), an irreversible&#xD;
      Monoamine-Oxidase (MAO) and Lysin-specific demethylase (LSD) inhibitor that also inhibits&#xD;
      LSD1 (a histone H3 Lysine 4 demethylase), induces leukemia cell differentiation and leukemic&#xD;
      stem cell exhaustion in vitro and in vivo in non-APL AML subtypes.&#xD;
&#xD;
      In this Phase I/II study the investigators will explore the feasibility, safety, as well as&#xD;
      efficacy and of Tretinoin/TCP treatment in patients with relapsed or refractory AML or in&#xD;
      patients with AML who are not eligible for intensive treatment. Patients will be treated with&#xD;
      daily increasing doses of TCP (initially 10 mg/day, then +10 mg each day up to 80mg/d). After&#xD;
      7 days, ATRA will be added at a fixed dose (45 mg/sqm/day). Overall, 16 evaluable patients&#xD;
      are going to be treated. The primary endpoint is the fraction of patients that achieve CR,&#xD;
      CRp( complete response with incomplete recovery of platelets), CRi (complete response with&#xD;
      incomplete recovery of granulocytes) and PR. Secondary endpoints are tolerability, safety as&#xD;
      well as progression-free survival and overall survival. Serum levels of TCP will be regularly&#xD;
      analyzed. Pharmacodynamic analyses will be performed with analyses of the inhibition of LSD1&#xD;
      by TCP. Further analyses will address the changes in Histone H3 lysine 4 tri demethylase&#xD;
      (H3K4me3) levels in AML blasts and the differentiation status of AML blasts.&#xD;
&#xD;
      Taken together, this Phase I/II study will analyze feasibility, pharmacodynamics and&#xD;
      effectivity of ATRA and TCP as differentiation therapy in AML.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>September 2014</start_date>
  <completion_date type="Anticipated">September 2017</completion_date>
  <primary_completion_date type="Anticipated">September 2017</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>Analysis of the cumulative response rate (CR,CRp, CRi, PR)</measure>
    <time_frame>every 28 day cycle</time_frame>
    <description>Disease status will be assessed by bone marrow analyses</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>number of participants with adverse events as a measure of safety and tolerability</measure>
    <time_frame>one year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>treatment effects of promotor genes</measure>
    <time_frame>2 Years</time_frame>
    <description>To assess the cumulative incidence and degree of histone methylation of promotor genes in AML blasts after treatment with Tretinoin and tranylcpromine</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">16</enrollment>
  <condition>AML</condition>
  <arm_group>
    <arm_group_label>Tretinoin &amp; Tranylcypromine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tretinoin started with 45mg/m2 on day 7 for one year, administered orally as soft capsules, Tranylcypromine started with 10mg/d up to a maximum dose of 60mg/d for on year, administered orally as tablets</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tranylcypromine</intervention_name>
    <arm_group_label>Tretinoin &amp; Tranylcypromine</arm_group_label>
    <other_name>Jatrosom</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tretinoin</intervention_name>
    <arm_group_label>Tretinoin &amp; Tranylcypromine</arm_group_label>
    <other_name>Vesanoid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subjects must provide written informed consent prior to performance of study-specific&#xD;
             procedures or assessments which are not routinely performed for diagnosis or&#xD;
             monitoring of AML, and the subjects must be willing to comply with treatment and to&#xD;
             follow up assessments and procedures&#xD;
&#xD;
          2. Histologically or cytologically confirmed diagnosis of AML relapsed after or&#xD;
             refractory to at least one induction regimen, or patients with AML at initial&#xD;
             diagnosis who are not eligible for allogeneic transplant or intensive induction&#xD;
             chemotherapy (investigator´s choice; for example reduced general state), except for&#xD;
             AML M3 (acute promyelocytic leukemia).&#xD;
&#xD;
          3. Age &gt; 18 years&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 (see Appendix, 3.2)&#xD;
&#xD;
          5. Measurable disease burden (blasts in bonemarrow (BM) and/or peripheral blood (PB),&#xD;
             extramedullary blasts [chloroma])&#xD;
&#xD;
          6. Able to swallow and retain oral medication&#xD;
&#xD;
          7. A life expectancy of at least 4 weeks&#xD;
&#xD;
          8. Adequate contraception methods&#xD;
&#xD;
          9. Adequate organ function&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with more than 20.000/µl leukocytes in the peripheral blood that cannot be&#xD;
             controlled by Hydroxyurea.&#xD;
&#xD;
          2. Patients with a valid option for intensive chemotherapy and/ or stem cell&#xD;
             transplantation. (Patients after allogeneic stem cell transplant must be off&#xD;
             immunosuppressive agents for at least 2 weeks prior to study entry and Graft- versus&#xD;
             host disease must have resolved to Grade &lt;= 2)&#xD;
&#xD;
          3. Patients with less than 30% blasts in the bone marrow at the time of diagnosis. They&#xD;
             should receive Azacytidine monotherapy.&#xD;
&#xD;
          4. History of cancer that according to the Investigator might confound the assessment of&#xD;
             the endpoints of the study&#xD;
&#xD;
          5. Uncontrolled peptic ulcer disease or clinically significant gastrointestinal&#xD;
             abnormalities which interfere with oral dosing or any unstable or serious concurrent&#xD;
             condition (e.g., active uncontrolled infection)&#xD;
&#xD;
          6. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥170&#xD;
             mmHg). Note: Initiation or adjustment of antihypertensive medication is permitted&#xD;
             prior to study entry. BP must be re-assessed on two occasions that are separated by a&#xD;
             minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP/&#xD;
             DBP(diastolic blood pressure) values from each BP assessment must be &lt;140/90 mmHg in&#xD;
             order for a subject to be eligible for he study.&#xD;
&#xD;
          7. Prolongation of corrected QT interval (QTc) &gt; 480 ms&#xD;
&#xD;
          8. History of any one or more of the following cardiovascular conditions within the past&#xD;
             6 months: cardiac angioplasty or stenting, myocardial infarction (MI), unstable&#xD;
             angina, symptomatic peripheral vascular disease, class 3 or 4 congestive heart&#xD;
             failure, as defined by the New York Heart Association (NYHA)&#xD;
&#xD;
          9. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition&#xD;
             (MUGA) scan or echocardiogram (ECHO)&#xD;
&#xD;
         10. History of cerebrovascular infarction or bleeding, pulmonary embolism (PE), or&#xD;
             untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with&#xD;
             recent DVT who have been treated with therapeutic anti- coagulant agents for at least&#xD;
             6 weeks are eligible&#xD;
&#xD;
         11. Evidence of serious active bleeding or bleeding diathesis (except for bleeding or&#xD;
             petechiae due to AML- related thrombocytopenia which will be treated using platelet&#xD;
             transfusions). Also, patients with known endobronchial lesions and/ or lesions&#xD;
             infiltrating major pulmonary vessels will be excluded from the study due to excess&#xD;
             risk of bleeding.&#xD;
&#xD;
         12. Prior major surgery or trauma within 28 days prior to first dose of study drug&#xD;
&#xD;
         13. Treatment with an investigational agent within 21 days or 5 half-life, whichever is&#xD;
             longer prior to the first dose of study drug.&#xD;
&#xD;
         14. Concurrent cytoreductive chemotherapy except hydroxyurea.&#xD;
&#xD;
         15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to Tretinoin,&#xD;
             Retinoids, soya, peanuts or Tranylcypromine.&#xD;
&#xD;
         16. Patients with psychological, familial, sociological, or geographical conditions that&#xD;
             do not permit compliance with the protocol&#xD;
&#xD;
         17. Patients with known epilepsy or patients with known psychiatric affections (bipolar&#xD;
             disorder, schizophrenia, suicidal patients)&#xD;
&#xD;
         18. Pregnant or lactating and actively breastfeeding patients&#xD;
&#xD;
         19. Patients who are indignant to comply with nutritional conditions (see Protocol)&#xD;
&#xD;
         20. Poorly adjusted diabetes mellitus&#xD;
&#xD;
         21. Patients with hereditary Galactose-Intolerance, Lactase-Intolerance or&#xD;
             Glucose-Galactose-Malabsorption&#xD;
&#xD;
         22. Known drug or alcohol abuse&#xD;
&#xD;
         23. Phaeochromocytoma or carcinoid tumor&#xD;
&#xD;
         24. Known cerebral vascular disease or other malformation of vessels (e.g. aneurysma)&#xD;
&#xD;
         25. Diabetes insipidus&#xD;
&#xD;
         26. Patients taking any of the following prohibited medication due to interaction with a)&#xD;
             tretinoin and b) TCP.&#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>Carsten Mueller-Tidow, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Martin-Luther-Universität Halle-Wittenberg</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Carsten Mueller-Tidow, Prof.</last_name>
    <phone>+493455572924</phone>
    <email>carsten.mueller-tidow@uk-halle.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Petra Tschanter, Dr.</last_name>
    <phone>+493455577288</phone>
    <email>petra.tschanter@uk-halle.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Universitaetsklinikum Halle</name>
      <address>
        <city>Halle</city>
        <zip>D-06120</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Contact Person</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>July 2015</verification_date>
  <study_first_submitted>September 23, 2014</study_first_submitted>
  <study_first_submitted_qc>October 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2014</study_first_posted>
  <last_update_submitted>July 6, 2015</last_update_submitted>
  <last_update_submitted_qc>July 6, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 7, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Martin-Luther-Universität Halle-Wittenberg</investigator_affiliation>
    <investigator_full_name>Dr. Petra Tschanter</investigator_full_name>
    <investigator_title>Dr.med.Petra Tschanter</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tretinoin</mesh_term>
    <mesh_term>Tranylcypromine</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/NCT02261779
org study id: UKM_04_12_TCP_ATRA_AML
secondary id: 2012-002154-23
nct id: NCT02261779
lead sponsor: 
has dmc: Yes
Longterm disease-free survival (DFS) of older patients with acute myeloid leukemia (AML)
      remains poor. The vast majority of AML patients relapses within two years after start of
      therapy1,2. In Acute Promyelocytic Leukemia (APL, AML M3), all-trans-retinoic-acid (ATRA;
      Tretinoin) induces differentiation and subsequently clinical remission. So far effective
      differentiation therapy does not exist in other AML subtypes. Recent preclinical data suggest
      that the combinatorial use of ATRA and tranylcypromine (TCP), an irreversible
      Monoamine-Oxidase (MAO) and Lysin-specific demethylase (LSD) inhibitor that also inhibits
      LSD1 (a histone H3 Lysine 4 demethylase), induces leukemia cell differentiation and leukemic
      stem cell exhaustion in vitro and in vivo in non-APL AML subtypes.

      In this Phase I/II study the investigators will explore the feasibility, safety, as well as
      efficacy and of Tretinoin/TCP treatment in patients with relapsed or refractory AML or in
      patients with AML who are not eligible for intensive treatment. Patients will be treated with
      daily increasing doses of TCP (initially 10 mg/day, then +10 mg each day up to 80mg/d). After
      7 days, ATRA will be added at a fixed dose (45 mg/sqm/day). Overall, 16 evaluable patients
      are going to be treated. The primary endpoint is the fraction of patients that achieve CR,
      CRp( complete response with incomplete recovery of platelets), CRi (complete response with
      incomplete recovery of granulocytes) and PR. Secondary endpoints are tolerability, safety as
      well as progression-free survival and overall survival. Serum levels of TCP will be regularly
      analyzed. Pharmacodynamic analyses will be performed with analyses of the inhibition of LSD1
      by TCP. Further analyses will address the changes in Histone H3 lysine 4 tri demethylase
      (H3K4me3) levels in AML blasts and the differentiation status of AML blasts.

      Taken together, this Phase I/II study will analyze feasibility, pharmacodynamics and
      effectivity of ATRA and TCP as differentiation therapy in AML.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Analysis of the cumulative response rate (CR,CRp, CRi, PR)
time frame: every 28 day cycle
description: Disease status will be assessed by bone marrow analyses
measure: number of participants with adverse events as a measure of safety and tolerability
time frame: one year
measure: overall survival
time frame: 2 years
measure: treatment effects of promotor genes
time frame: 2 Years
description: To assess the cumulative incidence and degree of histone methylation of promotor genes in AML blasts after treatment with Tretinoin and tranylcpromine
arm group label: Tretinoin & Tranylcypromine
arm group type: Experimental
description: Tretinoin started with 45mg/m2 on day 7 for one year, administered orally as soft capsules, Tranylcypromine started with 10mg/d up to a maximum dose of 60mg/d for on year, administered orally as tablets
intervention type: Drug
intervention name: Tranylcypromine
arm group label: Tretinoin & Tranylcypromine
other name: Jatrosom
intervention type: Drug
intervention name: Tretinoin
arm group label: Tretinoin & Tranylcypromine
other name: Vesanoid
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Carsten Mueller-Tidow, Prof.
role: Principal Investigator
affiliation: Martin-Luther-Universität Halle-Wittenberg
last name: Carsten Mueller-Tidow, Prof.
phone: +493455572924
email: carsten.mueller-tidow@uk-halle.de
last name: Petra Tschanter, Dr.
phone: +493455577288
email: petra.tschanter@uk-halle.de
facility: 
status: Recruiting
contact: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: Martin-Luther-Universität Halle-Wittenberg
investigator full name: Dr. Petra Tschanter
investigator title: Dr.med.Petra Tschanter
mesh term: Tretinoin
mesh term: Tranylcypromine