<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/NCT02212639</url>
  </required_header>
  <id_info>
    <org_study_id>P130944</org_study_id>
    <secondary_id>2014-001741-24</secondary_id>
    <nct_id>NCT02212639</nct_id>
  </id_info>
  <brief_title>Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi' s Sarcoma</brief_title>
  <acronym>KADIG 01</acronym>
  <official_title>Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi' s Sarcoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Classic and endemic Kaposi's sarcoma (KS) are lymph angio proliferations associated with&#xD;
      human herpes virus 8 (HHV8) which treatment is poorly codified. Chemotherapies give at best&#xD;
      30-60% of transient responses. While interferon responses are frequent, this drug is often&#xD;
      poorly tolerated in elderly patients. Therefore new therapies are needed. Classic KS&#xD;
      represents an ideal model for evaluating new drugs since patients do not receive concomitant&#xD;
      immunosuppressive regimens nor antiviral therapies.&#xD;
&#xD;
      Hypoxia-inducible factor 1(HIF-1 alpha) is a major regulator of solid tumor growth and&#xD;
      therefore a suitable target currently explored in many cancers. Moreover HIF-1 alpha enhances&#xD;
      HHV-8 gene expression in KS and induces lytic replication cycle. Digoxin has anti cancer&#xD;
      effect in vivo through HIF-alpha down regulation in several preclinical tumor models&#xD;
      including KS. The identification of HIF-1 alpha as a key factor in HHV8 replication prompt us&#xD;
      to explore inhibition of HIF-1 alpha by digoxin as a potential therapeutic approach for KS&#xD;
      treatment it has and consequently may down regulate HHV-8 replication in KS. This latter&#xD;
      approach is heightened by recent data suggesting that Digoxin has some efficacy in vitro&#xD;
      against others human herpes virus i.e. Herpes simplex and Cytomegalovirus (8) (9)&#xD;
&#xD;
      In this study the investigators shall evaluate the benefit and safety profile of digoxin in&#xD;
      classic and endemic KS (serum drug concentration of 0.6 to 1.2 ng/ml for patients &lt;75 years&#xD;
      and between 0.5-0.8 ng/ml in patients older than 75 years The participants will take study&#xD;
      drug digoxin, for a total of 6 cycles (4 weeks/cycle).&#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 2019</completion_date>
  <primary_completion_date type="Anticipated">January 2019</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>tumor response</measure>
    <time_frame>at 3 months</time_frame>
    <description>The primary endpoint will be tumor response, at 3 months. Assessed by AIDS Clinical Trials Group (ACTG) criteria ;Complete response (CR) will be defined as the absence of detectable residual disease lasting for at least 4 weeks; patients whose only remaining manifestation of KS are pigmented macules could be classified as having had a complete response if malignant cells are absent on biopsy of at least one lesion. Patients with visceral disease on entry who have complete resolution of cutaneous lesions as described above could be considered to have a CR only if no residual disease was detected on endoscopic or radiographic restaging.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Best overall response during the trial</measure>
    <time_frame>at 6 months</time_frame>
    <description>Best overall response during the trial, defined by the best response recorded from the start of treatment until disease progression/recurrence or treatment interruption for any reason</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response rate at 6 months</measure>
    <time_frame>at 6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of lesions</measure>
    <time_frame>at 3 months</time_frame>
    <description>number of lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>size of target lesions</measure>
    <time_frame>at 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tumor infiltration of target lesions</measure>
    <time_frame>at 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>lymphedema</measure>
    <time_frame>at 3 months</time_frame>
    <description>lymphedema (scale of 0 (absence)-3 (painful or oozing), circumference)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to response</measure>
    <time_frame>at 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to progression</measure>
    <time_frame>at 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>toxicity</measure>
    <time_frame>at 6 months</time_frame>
    <description>Safety and tolerance aspects, they will be assessed in terms of drug toxicity evaluated by clinic and on laboratory parameters and scored according Common Terminology Criteria for Adverse Events v4.0 (CTCAE)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">17</enrollment>
  <condition>Kaposi' s Sarcoma</condition>
  <condition>Classic Kaposi' s Sarcoma</condition>
  <condition>Endemic Kaposi' s Sarcoma</condition>
  <condition>Lymph Angio Proliferations</condition>
  <arm_group>
    <arm_group_label>Digoxin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients will receive Digoxin without interruption. Doses can be modified individually to reach a serum drug concentration of 0.6 to 1.2 ng/ml for patients &lt;75 years and between 0.5-0.8 ng/ml in patients older than 75 years</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>digoxin</intervention_name>
    <description>All patients will receive Digoxin without interruption. Doses can be modified individually to reach a serum drug concentration of 0.6 to 1.2 ng/ml for patients &lt;75 years and between 0.5-0.8 ng/ml in patients older than 75 years</description>
    <arm_group_label>Digoxin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt; 18 years &lt;à 80 years&#xD;
&#xD;
          -  Classic or endemic histologically confirmed Kaposi's Sarcoma (KS)&#xD;
&#xD;
          -  Progressive disease&#xD;
&#xD;
          -  KS with more than 10 lesions or involving more than one limb segment or with&#xD;
             involvement &gt;3% body surface&#xD;
&#xD;
          -  KS with at least 4 lesions ≥5mm&#xD;
&#xD;
          -  Patients should have at least 2 others cutaneous tumor available for repeated&#xD;
             pharmacodynamics evaluation&#xD;
&#xD;
          -  At least 4 weeks wash out for all KS specific therapies including chemotherapy and&#xD;
             immunotherapy&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Symptomatic visceral lesions&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group ( ECOG) performance status &gt; 1&#xD;
&#xD;
          -  Life expectancy of ≤ 6 months&#xD;
&#xD;
          -  Patients already receiving digoxin&#xD;
&#xD;
          -  hepatic dysfunction defined as serum bilirubin&gt;25 µm/l, transaminases &gt; 3.0 times the&#xD;
             upper limit of normal (ULN) (5ULN in cases of liver metastases)&#xD;
&#xD;
          -  bone marrow dysfunction defined as absolute neutrophil count&lt;1500/mcl,&#xD;
             platelets&lt;150000/mcl or hemoglobin&lt;8g/dL&#xD;
&#xD;
          -  renal failure with creatinine clearance&lt; 40ml/mn&#xD;
&#xD;
          -  HIV positive, active infectious hepatitis, type A, B or C&#xD;
&#xD;
          -  Uncontrolled systemic infection&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Presence of any of the following on electrocardiogram (ECG): atrial arrhythmias,&#xD;
             including atrial fibrillation and flutter with Wolff-Parkinson-White syndrome;&#xD;
             auricular ventricular (AV) block; heart rate &lt; 60 beats/minute and &gt; 100 beats/minute;&#xD;
             ventricular fibrillation; ventricular tachycardia; premature ventricular contractions.&#xD;
&#xD;
          -  History of or current cardiac arrythmia including sinus node disease, history of AV&#xD;
             Block, accessory AV pathway (Wolff-Parkinson-White Syndrome), history myocardial&#xD;
             infarction, any significant valvulopathy.&#xD;
&#xD;
          -  Electrolyte imbalance (hypokalemia, hypo- or hypercalcemia, hypomagnesemia)&#xD;
&#xD;
          -  Severe pulmonary disease and hypoxia&#xD;
&#xD;
          -  Medical conditions such as uncontrolled hypertension, uncontrolled diabetes mellitus,&#xD;
             hypothyroidism or hyperthyroidism, which would, in the opinion of the investigator,&#xD;
             make this protocol unreasonably hazardous.&#xD;
&#xD;
          -  Major thoracic or abdominal surgery within the prior 3 weeks.&#xD;
&#xD;
          -  GI tract disease resulting in an inability to take oral medication, malabsorption&#xD;
             syndrome, a requirement for IV alimentation, prior surgical procedures affecting&#xD;
             absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis).&#xD;
&#xD;
          -  Immunosuppressive regimen should not be allowed including corticosteroids&#xD;
&#xD;
          -  Use of any prohibited concomitant medications:&#xD;
&#xD;
               -  the calcium channel blockers diltiazem or verapamil;&#xD;
&#xD;
               -  Class I and III cardiac arrhythmic agents (such as quinidine, amiodarone);&#xD;
&#xD;
               -  beta-blockers (such as atenolol, metoprolol);&#xD;
&#xD;
               -  indomethacin (Indocin);&#xD;
&#xD;
               -  calcium carbonate antacids (e.g., Maalox, Tums, Rolaids);&#xD;
&#xD;
               -  Calcium&#xD;
&#xD;
               -  omeprazole;&#xD;
&#xD;
               -  antidiarrheal adsorbents (kaolin and pectin);&#xD;
&#xD;
               -  antibiotics P450 inhibitors clarithromycin, erythromycin telithromycin and other&#xD;
                  P450 inhibitors./such as Ritonavir)&#xD;
&#xD;
          -  Persistent Grade &gt;2 treatment-related toxicity from prior therapy&#xD;
&#xD;
          -  History of any digoxin-related or drug induced anaphylactic reaction&#xD;
&#xD;
          -  Use of any other investigational agent&#xD;
&#xD;
          -  Patient without health insurance coverage&#xD;
&#xD;
          -  Patient under guardianship&#xD;
&#xD;
          -  Enrollment into a clinical trial within last 4 weeks&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>celeste lebbe, MDPHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>APHP</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Céleste Céleste, MD PHD</last_name>
    <phone>+33 1 42494679</phone>
    <email>celeste.lebbe@sls.aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>matthieu resche-rigon, MD PHD</last_name>
    <phone>+33 1 42 49 97 42</phone>
    <email>matthieu.resche-rigon@paris7.jussieu.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Saint-Louis Hospital</name>
      <address>
        <city>Paris</city>
        <zip>75010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Celeste Lebbe, MD PHD</last_name>
      <phone>+ 33 142494679</phone>
      <email>celeste.lebbe@sls.aphp.fr</email>
    </contact>
    <investigator>
      <last_name>celeste lebbe, MD-PHD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>August 6, 2014</study_first_submitted>
  <study_first_submitted_qc>August 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 8, 2014</study_first_posted>
  <last_update_submitted>July 20, 2018</last_update_submitted>
  <last_update_submitted_qc>July 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 23, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Kaposi' s sarcoma</keyword>
  <keyword>Digoxin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sarcoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Digoxin</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/NCT02212639
org study id: P130944
secondary id: 2014-001741-24
nct id: NCT02212639
lead sponsor: 
has dmc: No
Classic and endemic Kaposi's sarcoma (KS) are lymph angio proliferations associated with
      human herpes virus 8 (HHV8) which treatment is poorly codified. Chemotherapies give at best
      30-60% of transient responses. While interferon responses are frequent, this drug is often
      poorly tolerated in elderly patients. Therefore new therapies are needed. Classic KS
      represents an ideal model for evaluating new drugs since patients do not receive concomitant
      immunosuppressive regimens nor antiviral therapies.

      Hypoxia-inducible factor 1(HIF-1 alpha) is a major regulator of solid tumor growth and
      therefore a suitable target currently explored in many cancers. Moreover HIF-1 alpha enhances
      HHV-8 gene expression in KS and induces lytic replication cycle. Digoxin has anti cancer
      effect in vivo through HIF-alpha down regulation in several preclinical tumor models
      including KS. The identification of HIF-1 alpha as a key factor in HHV8 replication prompt us
      to explore inhibition of HIF-1 alpha by digoxin as a potential therapeutic approach for KS
      treatment it has and consequently may down regulate HHV-8 replication in KS. This latter
      approach is heightened by recent data suggesting that Digoxin has some efficacy in vitro
      against others human herpes virus i.e. Herpes simplex and Cytomegalovirus (8) (9)

      In this study the investigators shall evaluate the benefit and safety profile of digoxin in
      classic and endemic KS (serum drug concentration of 0.6 to 1.2 ng/ml for patients <75 years
      and between 0.5-0.8 ng/ml in patients older than 75 years The participants will take study
      drug digoxin, for a total of 6 cycles (4 weeks/cycle).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: tumor response
time frame: at 3 months
description: The primary endpoint will be tumor response, at 3 months. Assessed by AIDS Clinical Trials Group (ACTG) criteria ;Complete response (CR) will be defined as the absence of detectable residual disease lasting for at least 4 weeks; patients whose only remaining manifestation of KS are pigmented macules could be classified as having had a complete response if malignant cells are absent on biopsy of at least one lesion. Patients with visceral disease on entry who have complete resolution of cutaneous lesions as described above could be considered to have a CR only if no residual disease was detected on endoscopic or radiographic restaging.
measure: Best overall response during the trial
time frame: at 6 months
description: Best overall response during the trial, defined by the best response recorded from the start of treatment until disease progression/recurrence or treatment interruption for any reason
measure: Response rate at 6 months
time frame: at 6 months
measure: number of lesions
time frame: at 3 months
description: number of lesions
measure: size of target lesions
time frame: at 3 months
measure: tumor infiltration of target lesions
time frame: at 3 months
measure: lymphedema
time frame: at 3 months
description: lymphedema (scale of 0 (absence)-3 (painful or oozing), circumference)
measure: Time to response
time frame: at 3 months
measure: Time to progression
time frame: at 3 months
measure: toxicity
time frame: at 6 months
description: Safety and tolerance aspects, they will be assessed in terms of drug toxicity evaluated by clinic and on laboratory parameters and scored according Common Terminology Criteria for Adverse Events v4.0 (CTCAE)
arm group label: Digoxin
arm group type: Experimental
description: All patients will receive Digoxin without interruption. Doses can be modified individually to reach a serum drug concentration of 0.6 to 1.2 ng/ml for patients <75 years and between 0.5-0.8 ng/ml in patients older than 75 years
intervention type: Drug
intervention name: digoxin
description: All patients will receive Digoxin without interruption. Doses can be modified individually to reach a serum drug concentration of 0.6 to 1.2 ng/ml for patients <75 years and between 0.5-0.8 ng/ml in patients older than 75 years
arm group label: Digoxin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: celeste lebbe, MDPHD
role: Principal Investigator
affiliation: APHP
last name: Céleste Céleste, MD PHD
phone: +33 1 42494679
email: celeste.lebbe@sls.aphp.fr
last name: matthieu resche-rigon, MD PHD
phone: +33 1 42 49 97 42
email: matthieu.resche-rigon@paris7.jussieu.fr
facility: 
status: Recruiting
contact: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Sarcoma
mesh term: Digoxin