<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/NCT02973789</url>
  </required_header>
  <id_info>
    <org_study_id>EF-24</org_study_id>
    <nct_id>NCT02973789</nct_id>
  </id_info>
  <brief_title>Effect of Tumor Treating Fields (TTFields) (150 kHz) Concurrent With Standard of Care Therapies for Treatment of Stage 4 Non-small Cell Lung Cancer (NSCLC) Following Platinum Failure (LUNAR)</brief_title>
  <official_title>LUNAR: Pivotal, Randomized, Open-label Study of Tumor Treating Fields (TTFields) Concurrent With Standard of Care Therapies for Treatment of Stage 4 Non-small Cell Lung Cancer (NSCLC) Following Platinum Failure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NovoCure GmbH</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>NovoCure Ltd.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study is a prospective, randomized controlled phase III trial aimed to test the efficacy&#xD;
      and safety of TTFields, using the NovoTTF-200T device, concurrent with standard therapies for&#xD;
      stage 4 NSCLC patients, following progression while on or after platinum based treatment. The&#xD;
      device is an experimental, portable, battery operated device for chronic administration of&#xD;
      alternating electric fields (termed TTFields or TTF) to the region of the malignant tumor, by&#xD;
      means of surface, insulated electrode arrays.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:&#xD;
&#xD;
      The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in&#xD;
      vitro and in vivo NSCLC pre-clinical models both as a single modality treatment and in&#xD;
      combination with chemotherapies and PD-1 inhibitors. TTFields have been demonstrated to act&#xD;
      synergistically with taxanes and have been shown to be additive when combined with PD-1&#xD;
      inhibitors. In addition, TTFields have shown to inhibit metastatic spread of malignant&#xD;
      melanoma in in vivo experiment.&#xD;
&#xD;
      In a pilot study, 42 patients with advanced NSCLC who had had tumor progression after at&#xD;
      least one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz)&#xD;
      applied to the chest and upper abdomen until disease progression (Pless M., et al., Lung&#xD;
      Cancer 2011). The combination was well tolerated and the only device-related adverse event&#xD;
      was mild to moderate contact dermatitis. Efficacy endpoints were remarkably high compared to&#xD;
      historical data for pemetrexed alone.&#xD;
&#xD;
      In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active&#xD;
      chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active&#xD;
      chemotherapy in extending survival, associated with minimal toxicity, good quality of life,&#xD;
      and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a&#xD;
      phase III trial of Optune® combined with maintenance temozolomide compared to maintenance&#xD;
      temozolomide alone has shown that combined therapy led to a significant improvement in both&#xD;
      progression free survival and overall survival in patients with newly diagnosed glioblastoma&#xD;
      without the addition of high grade toxicity and without decline in quality of life (Stupp R.,&#xD;
      et al., JAMA 2015).&#xD;
&#xD;
      DESCRIPTION OF THE TRIAL:&#xD;
&#xD;
      All patients included in this trial are patients with squamous or non-squamous, stage 4 NSCLC&#xD;
      who had disease progression on or after receiving platinum based chemotherapy. In addition,&#xD;
      all patients must meet all eligibility criteria.&#xD;
&#xD;
      Eligible patients will be randomly assigned to one of two groups:&#xD;
&#xD;
      Patients receive docetaxel or immune checkpoint inhibitor in combination with TTFields using&#xD;
      the NovoTTF-100L System.&#xD;
&#xD;
      Patients receive docetaxel or immune checkpoint inhibitor without TTFields. Patients will be&#xD;
      randomized at a 1:1 ratio. Baseline tests will be performed in patients enrolled in both&#xD;
      arms. If assigned to the NovoTTF-100L group, the patients will be treated continuously with&#xD;
      the device until disease progression in the thorax and/or liver according to RECIST or&#xD;
      irRECIST (Immune-Related Response Evaluation Criteria In Solid Tumors) (depending if the&#xD;
      patient is receiving docetaxel or immune checkpoint inhibitor, respectively).&#xD;
&#xD;
      On both arms, patients who have disease progression according to RECIST or irRECIST&#xD;
      (depending if the patient is receiving docetaxel or immune checkpoint inhibitor,&#xD;
      respectively) will switch to a third line treatment according to local practice.&#xD;
&#xD;
      SCIENTIFIC BACKGROUND:&#xD;
&#xD;
      Electric fields exert forces on electric charges similar to the way a magnet exerts forces on&#xD;
      metallic particles within a magnetic field. These forces cause movement and rotation of&#xD;
      electrically charged biological building blocks, much like the alignment of metallic&#xD;
      particles seen along the lines of force radiating outwards from a magnet.&#xD;
&#xD;
      Electric fields can also cause muscles to twitch and if strong enough may heat tissues.&#xD;
      TTFields are alternating electric fields of low intensity. This means that they change their&#xD;
      direction repetitively many times a second. Since they change direction very rapidly (150&#xD;
      thousand times a second), they do not cause muscles to twitch, nor do they have any effects&#xD;
      on other electrically activated tissues in the body (brain, nerves and heart). Since the&#xD;
      intensities of TTFields in the body are very low, they do not cause heating.&#xD;
&#xD;
      The breakthrough finding made by Novocure was that finely tuned alternating fields of very&#xD;
      low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in&#xD;
      the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are&#xD;
      multiplying, TTFields cause electrically-charged cellular components of these cells to change&#xD;
      their location within the dividing cell, disrupting their normal function and ultimately&#xD;
      leading to cell death. In addition, cancer cells also contain miniature building blocks which&#xD;
      act as tiny motors in moving essential parts of the cells from place to place. TTFields&#xD;
      interfere with the normal orientation of these tiny motors related to other cellular&#xD;
      components since they are electrically-charged as well. As a result of these two effects,&#xD;
      tumor cell division is slowed, results in cellular death or reverses after continuous&#xD;
      exposure to TTFields.&#xD;
&#xD;
      Other cells in the body (normal healthy tissues) are affected much less than cancer cells&#xD;
      since they multiply at a much slower rate if at all. In addition TTFields can be directed to&#xD;
      a certain part of the body, leaving sensitive areas out of their reach. Finally, the&#xD;
      frequency of TTFields applied to each type of cancer is specific and may not damage normally&#xD;
      dividing cells in healthy tissues.&#xD;
&#xD;
      In conclusion, TTFields hold the promise of serving as a brand new treatment for NSCLC with&#xD;
      very few side effects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">September 2023</completion_date>
  <primary_completion_date type="Anticipated">September 2023</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival of patients treated with TTFields + docetaxel or immune checkpoint inhibitors vs. docetaxel or immune checkpoint inhibitors alone (superiority analysis)</measure>
    <time_frame>4 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival of patients treated with TTFields + docetaxel vs. docetaxel alone (superiority analysis)</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival of patients treated with TTFields + immune checkpoint inhibitors vs. immune checkpoint inhibitors alone (superiority)</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival of patients treated with TTFields + docetaxel Vs. immune checkpoint inhibitors alone (non-inferiority analysis)</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival of patients treated with docetaxel or immune checkpoint inhibitors + TTFields vs. docetaxel or immune checkpoint inhibitors alone, based on RECIST Criteria</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall radiological response rate (based on RECIST criteria) of patients treated with docetaxel or Immune checkpoint inhibitors + TTFields vs. docetaxel or immune checkpoint inhibitors alone.</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life using the EORTC QLQ C30 questionnaire with LC13 addendum</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analyses of the effects of NovoTTF-200T with each type of immune checkpoint inhibitor on overall survival and progression free survival</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analysis of the effects of NovoTTF-200T on overall survival and progression free survival within each histological subgroup (squamous and non-squamous)</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effect of treatment compliance with NovoTTF-200T on overall survival and progression free survival outcomes</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events, severity and frequency based on Common Terminology Criteria for Adverse Events (CTCAE) V4.03</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">276</enrollment>
  <condition>Nonsmall Cell Lung Cancer</condition>
  <condition>NSCLC</condition>
  <arm_group>
    <arm_group_label>NovoTTF-200T</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive TTFields using the NovoTTF-200T device together with immune checkpoint inhibitors or docetaxel</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Best Standard of Care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients receive best standard of care with immune checkpoint inhibitors or docetaxel</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>NovoTTF-200T</intervention_name>
    <description>Patients receive continuous TTFields treatment using the NovoTTF-200T device. TTFields treatment will consist of wearing four electrically insulated electrode arrays on the chest. The treatment enables the patient to maintain regular daily routine.&#xD;
Other Name: TTFields&#xD;
Drug: Immune checkpoint inhibitors or docetaxel Patients receive standard of care with Immune checkpoint inhibitors or docetaxel</description>
    <arm_group_label>NovoTTF-200T</arm_group_label>
    <other_name>TTFields</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Immune checkpoint inhibitors or docetaxel</intervention_name>
    <description>Patients receive standard of care with Immune checkpoint inhibitors or docetaxel</description>
    <arm_group_label>Best Standard of Care</arm_group_label>
    <arm_group_label>NovoTTF-200T</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. 22 years of age and older (some regional variations to inclusion age exist)&#xD;
&#xD;
          2. Life expectancy of ≥ 3 months&#xD;
&#xD;
          3. Histological diagnosis of squamous or non-squamous, inoperable, metastatic NSCLC&#xD;
&#xD;
          4. Diagnosis of radiological progression while on or after first platinum-based systemic&#xD;
             therapy administered for advanced or metastatic disease.&#xD;
&#xD;
               1. Patients who received adjuvant or neoadjuvant platinum-based chemotherapy (after&#xD;
                  surgery and/or radiation therapy) and developed metastatic disease within 6&#xD;
                  months of completing therapy are eligible.&#xD;
&#xD;
               2. Patients with metastatic disease more than 6 months after adjuvant or neoadjuvant&#xD;
                  platinum-based chemotherapy, who also subsequently progressed during or after a&#xD;
                  platinum- based regimen given to treat the advanced or metastatic disease, are&#xD;
                  eligible.&#xD;
&#xD;
               3. Patients should not receive any systemic therapy after platinum failure before&#xD;
                  enrollment into the study. Maintenance therapy after platinum based therapy and&#xD;
                  prior to progression is allowed.&#xD;
&#xD;
          5. ECOG Score of 0-2&#xD;
&#xD;
          6. Assigned by the physician to receive either docetaxel or immune checkpoint inhibitor&#xD;
             per standard of care regimen&#xD;
&#xD;
          7. Able to operate the NovoTTF-200T device independently or with the help of a caregiver&#xD;
&#xD;
          8. Signed informed consent for the study protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Metastases to central nervous system (CNS) with clinical symptoms or evidence of new&#xD;
             metastases to CNS during screening. Patients who previously received treatments for&#xD;
             the metastases to CNS, are stable and meet the following requirements are allowed to&#xD;
             be enrolled:&#xD;
&#xD;
               1. The patients are neurologically returned to baseline (except for residual signs&#xD;
                  or symptoms related to CNS treatment).&#xD;
&#xD;
               2. No treatment for the metastases to CNS during the screening period (e.g. surgery,&#xD;
                  radiotherapy, corticosteroid therapy- prednisone &gt; 10 mg/day or equivalent).&#xD;
&#xD;
               3. No progress in CNS lesions as indicated by MRI within 14 days prior to&#xD;
                  randomization.&#xD;
&#xD;
               4. No meningeal metastasis or spinal cord compression.&#xD;
&#xD;
          2. Patients planned to receive immune checkpoint inhibitor with contra-indications to&#xD;
             receive immunotherapy&#xD;
&#xD;
          3. Patients planned to receive docetaxel with contra-indications to receive docetaxel&#xD;
&#xD;
          4. Severe comorbidities:&#xD;
&#xD;
               1. Clinically significant (as determined by the investigator) hematological, hepatic&#xD;
                  and renal dysfunction, defined as: Neutrophil count &lt; 1.5 x 10^9/L and platelet&#xD;
                  count &lt; 100 x 10^9/L; bilirubin &gt; 1.5 x ULN; AST and/or ALT &gt; 2.5 x ULN or &gt; 5 x&#xD;
                  ULN if patient has documented liver metastases; and serum creatinine &gt; 1.5 x ULN&#xD;
&#xD;
               2. History of significant cardiovascular disease unless the disease is well&#xD;
                  controlled. Significant cardiac disease includes second/third degree heart block;&#xD;
                  significant ischemic heart disease; poorly controlled hypertension; congestive&#xD;
                  heart failure of the New York Heart Association (NYHA) Class II or worse (slight&#xD;
                  limitation of physical activity; comfortable at rest, but ordinary activity&#xD;
                  results in fatigue, palpitation or dyspnea)&#xD;
&#xD;
               3. History of arrhythmia that is symptomatic or requires treatment. Patients with&#xD;
                  atrial fibrillation or flutter controlled by medication are not excluded from&#xD;
                  participation in the trial&#xD;
&#xD;
               4. History of pericarditis&#xD;
&#xD;
               5. History of interstitial lung disease&#xD;
&#xD;
               6. History of cerebrovascular accident (CVA) within 6 months prior to randomization&#xD;
                  or that is not stable&#xD;
&#xD;
               7. Active infection or serious underlying medical condition that would impair the&#xD;
                  ability of the patient to received protocol therapy&#xD;
&#xD;
               8. History of any psychiatric condition that might impair patient's ability to&#xD;
                  understand or comply with the requirements of the study or to provide consent&#xD;
&#xD;
               9. Any other malignancy requiring anti-tumor treatment in the past three years,&#xD;
                  excluding treated stage I prostate cancer, in situ cervical cancer, in situ&#xD;
                  breast cancer and non-melanomatous skin cancer&#xD;
&#xD;
          5. Concurrent treatment with other experimental treatments for NSCLC while on the study&#xD;
&#xD;
          6. Implantable electronic medical devices (e.g. pacemaker, defibrillator) in the upper&#xD;
             torso&#xD;
&#xD;
          7. Known allergies to medical adhesives or hydrogel&#xD;
&#xD;
          8. Pregnancy or breast-feeding (patients with reproductive potential must use effective&#xD;
             contraception methods throughout the entire study period, as determined by their&#xD;
             investigator/gynecologist)&#xD;
&#xD;
          9. Admitted to an institution by administrative or court order&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>22 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Central Alabama Research</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ironwood Cancer &amp; Research Center</name>
      <address>
        <city>Chandler</city>
        <state>Arizona</state>
        <zip>85224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cancer Center at St. Joseph Hospital and Medical Center</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85004</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beverly Hills Cancer Center</name>
      <address>
        <city>Beverly Hills</city>
        <state>California</state>
        <zip>90211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>California Cancer Associates for Research and Excellence, Inc. cCARE</name>
      <address>
        <city>Fresno</city>
        <state>California</state>
        <zip>93720</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph Heritage Healthcare</name>
      <address>
        <city>Fullerton</city>
        <state>California</state>
        <zip>92835</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saddleback Memorial Medical Center</name>
      <address>
        <city>Laguna Hills</city>
        <state>California</state>
        <zip>92653</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Redlands Community Hospital (Emad Ibrahim, MD, Inc.)</name>
      <address>
        <city>Redlands</city>
        <state>California</state>
        <zip>92373</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dignity Health - Mercy Cancer Centers</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95186</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sutter Institute for Medical Research</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95816</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Innovative Clinical Research Institute</name>
      <address>
        <city>Whittier</city>
        <state>California</state>
        <zip>90603</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Banner MD Anderson Cancer Center at North Colorado Medical Center</name>
      <address>
        <city>Greeley</city>
        <state>Colorado</state>
        <zip>80631</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Associated Neurologists of Southern CT, P.C.</name>
      <address>
        <city>Fairfield</city>
        <state>Connecticut</state>
        <zip>06824</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington Cancer Institute at MedStar Washington Hospital Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GenesisCare USA</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Medical Center</name>
      <address>
        <city>Miami Beach</city>
        <state>Florida</state>
        <zip>33140</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Miami Cancer Institute</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33176</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AdventHealth Orlando</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32804</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adult Oncology Research</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>BRCR Medical Center INC</name>
      <address>
        <city>Plantation</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Illinois Cancer Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Illinois CancerCare, P.C.</name>
      <address>
        <city>Peoria</city>
        <state>Illinois</state>
        <zip>61615</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southern Illinois University, School of Medicine, Simmons Cancer Institute at SIU</name>
      <address>
        <city>Springfield</city>
        <state>Illinois</state>
        <zip>62702</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Franciscan Health Indianapolis</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46237</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center</name>
      <address>
        <city>Westwood</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norton Cancer Institute</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center, Inc; DBA University of Louisville</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>LSU Health Sciences Center -New Orleans</name>
      <address>
        <city>New Orleans</city>
        <state>Louisiana</state>
        <zip>70112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tulane Cancer Center</name>
      <address>
        <city>New Orleans</city>
        <state>Louisiana</state>
        <zip>70112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRISTUS Health</name>
      <address>
        <city>Shreveport</city>
        <state>Louisiana</state>
        <zip>71105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Maine Medical Center</name>
      <address>
        <city>Lewiston</city>
        <state>Maine</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Maryland School of Medicine</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tufts Medical Center, Division of Hematology and Oncology</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karmanos Cancer Institute</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Oncology Associates</name>
      <address>
        <city>Farmington Hills</city>
        <state>Michigan</state>
        <zip>48336</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Detroit Clinical Research Center</name>
      <address>
        <city>Farmington Hills</city>
        <state>Michigan</state>
        <zip>48336</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Joseph Mercy Health System</name>
      <address>
        <city>Ypsilanti</city>
        <state>Michigan</state>
        <zip>48197</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HealthPartners Institute, Regions Cancer Care Center</name>
      <address>
        <city>Saint Paul</city>
        <state>Minnesota</state>
        <zip>55101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Luke's Cancer Institute</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHI Health Research Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68124</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Hematology West, PC dba Nebraska Cancer Specialists</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska Medical Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>OptumCare Cancer Care</name>
      <address>
        <city>Las Vegas</city>
        <state>Nevada</state>
        <zip>89102</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Renown Regional Medical Center Institute for Cancer</name>
      <address>
        <city>Reno</city>
        <state>Nevada</state>
        <zip>89502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Presbyterian Cancer Center</name>
      <address>
        <city>Albuquerque</city>
        <state>New Mexico</state>
        <zip>87110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New York-Presbyterian/Queens Radiation Oncology</name>
      <address>
        <city>Flushing</city>
        <state>New York</state>
        <zip>11355</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northern Westchester Hospital</name>
      <address>
        <city>Mount Kisco</city>
        <state>New York</state>
        <zip>10549-3417</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stony Brook Cancer Center</name>
      <address>
        <city>Stony Brook</city>
        <state>New York</state>
        <zip>11794</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Specialists of Charlotte</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>W.G. Bill Hefner VA Med Center</name>
      <address>
        <city>Salisbury</city>
        <state>North Carolina</state>
        <zip>28144</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Piedmont Radiation Oncology, PA</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Summa Health</name>
      <address>
        <city>Akron</city>
        <state>Ohio</state>
        <zip>44304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Toledo Clinic Cancer Center</name>
      <address>
        <city>Toledo</city>
        <state>Ohio</state>
        <zip>43623</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vita Medical Associates, P.C.</name>
      <address>
        <city>Bethlehem</city>
        <state>Pennsylvania</state>
        <zip>18015</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Geisinger Cancer Institute</name>
      <address>
        <city>Danville</city>
        <state>Pennsylvania</state>
        <zip>17822</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UT/Erlanger Oncology &amp; Hematology</name>
      <address>
        <city>Chattanooga</city>
        <state>Tennessee</state>
        <zip>37403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology - Amarillo</name>
      <address>
        <city>Amarillo</city>
        <state>Texas</state>
        <zip>79106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology - Arlington</name>
      <address>
        <city>Arlington</city>
        <state>Texas</state>
        <zip>76012</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Christus Health Spohn Ministry</name>
      <address>
        <city>Corpus Christi</city>
        <state>Texas</state>
        <zip>78404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dallas VA Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75216</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology- Baylor Charles A. Sammons Cancer Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75246</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Texas Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Consultants, P.A.</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology-McKinney</name>
      <address>
        <city>McKinney</city>
        <state>Texas</state>
        <zip>75071</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology - Paris</name>
      <address>
        <city>Paris</city>
        <state>Texas</state>
        <zip>75460</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology- Plano West</name>
      <address>
        <city>Plano</city>
        <state>Texas</state>
        <zip>75093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor Scott &amp; White Health/McClinton Cancer Center</name>
      <address>
        <city>Waco</city>
        <state>Texas</state>
        <zip>76712</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology-Waco</name>
      <address>
        <city>Waco</city>
        <state>Texas</state>
        <zip>76712</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Huntsman Cancer Institute/University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Overlake Medical Center &amp; Clinics</name>
      <address>
        <city>Bellevue</city>
        <state>Washington</state>
        <zip>98004</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UW Carbone Cancer Center</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical University Salzburg, State Hospital, University hospital for internal medicine III / PMU</name>
      <address>
        <city>Salzburg</city>
        <zip>5020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Jules Bordet - Department of Intensive Care and Thoracic Oncology</name>
      <address>
        <city>Brussels</city>
        <zip>1000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinique André Renard Herstal Oncologie</name>
      <address>
        <city>Herstal</city>
        <zip>4040</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AZ Sint Maarten</name>
      <address>
        <city>Mechelen</city>
        <zip>2800</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complex Oncology Center (COC) - Plovdiv EOOD,</name>
      <address>
        <city>Plovdiv</city>
        <zip>4004</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McGill University Health Centre</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H4A 3J1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospitalier Universitaire de Sherbrooke (CIUSSS de l'Estrie - CHUS)</name>
      <address>
        <city>Sherbrooke</city>
        <state>Quebec</state>
        <zip>J1H 5N4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allan Blair Cancer Center</name>
      <address>
        <city>Regina</city>
        <state>Saskatchewan</state>
        <zip>S4T 7T1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beijing Cancer Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Affiliated Cancer Hospital of Guangzhou Medical University</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henan Cancer Hospital</name>
      <address>
        <city>Zhengzhou</city>
        <state>Henan</state>
        <zip>450003</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henan Provincial People's Hospital</name>
      <address>
        <city>Zhengzhou</city>
        <state>Henan</state>
        <zip>45003</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>PKUCare Luzhong Hospital</name>
      <address>
        <city>Zibo</city>
        <state>Shandong</state>
        <zip>250014</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sir Run Run Shaw Hospital, Zhejiang University School of Medicine</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <zip>31000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zhejiang Cancer Hospital</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <zip>311000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sun Yat-sen University Cancer Center</name>
      <address>
        <city>Guangzhou</city>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Centre Zagreb</name>
      <address>
        <city>Zagreb</city>
        <zip>10000</zip>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>General University Hospital in Prague</name>
      <address>
        <city>Prague</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Thomayerova Nemocnice Dept. of Pneumology</name>
      <address>
        <city>Prague</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vitkovicka nemocnice</name>
      <address>
        <city>Vitkovice</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier de Beauvais</name>
      <address>
        <city>Beauvais</city>
        <zip>60021</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>INSTITUT BERGONIE Centre Régional de Lutte Contre le Cancer</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Groupe Hospitalier Bretagne Sud</name>
      <address>
        <city>Lorient</city>
        <zip>56100</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Caremeau Service de Pneumologie</name>
      <address>
        <city>Nîmes</city>
        <zip>30029</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AH-HP Hôpital Saint Louis</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier de Saint-Quentin Service de pneumologie</name>
      <address>
        <city>Saint-Quentin</city>
        <zip>21000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Halle - Universitätsklinik und Poliklinik für Innere Medizin IV</name>
      <address>
        <city>Halle (Saale)</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Mary Hospital</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tolna County, Balassa Janos Hospital, Department of oncology</name>
      <address>
        <city>Szekszárd</city>
        <zip>7100</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASL 3, Ospedale Villa Scassi</name>
      <address>
        <city>Genova</city>
        <zip>16132</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)</name>
      <address>
        <city>Meldola</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UOC Oncologia Medica Presidio Ospedaliero di Ravenna AUSL della Romagna</name>
      <address>
        <city>Ravenna</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saronno Hospital</name>
      <address>
        <city>Saronno</city>
        <zip>21047</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Jansdal Ziekenhuis</name>
      <address>
        <city>Harderwijk</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Erasmus Mc</name>
      <address>
        <city>Rotterdam</city>
        <zip>3015</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uniwersyteckie Centrum Kliniczne</name>
      <address>
        <city>Gdansk</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MS Clinsearch Specjalistyczny NZOZ</name>
      <address>
        <city>Lublin</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Hospital of Przemienienia Pańskiego UM in Poznaniu</name>
      <address>
        <city>Poznan</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Samodzielny Publiczny Wojewódzki Szpital Zespolony w Szczecinie</name>
      <address>
        <city>Szczecin</city>
        <zip>70-891</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Terapii Współczesnej</name>
      <address>
        <city>Łódź</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bezanijska kosa Clinical Hospital Center</name>
      <address>
        <city>Belgrade</city>
        <zip>11080</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Clinical Center Kragujevac</name>
      <address>
        <city>Kragujevac</city>
        <zip>34000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Arnau de Vilanova</name>
      <address>
        <city>Lleida</city>
        <state>Catalonia</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Quirón Teknon, Instituto Oncológico Dr. Rosell</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Gregorio Marañón</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Puerta de Hierro</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Regional Universitario Carlos Haya Medical Oncology Department</name>
      <address>
        <city>Málaga</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Virgen de la Salud</name>
      <address>
        <city>Toledo</city>
        <zip>45071</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari i Politécnic La Fe</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kantonsspital Winterthur Tumorzentrum Winterthur</name>
      <address>
        <city>Winterthur</city>
        <zip>8400</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Bulgaria</country>
    <country>Canada</country>
    <country>China</country>
    <country>Croatia</country>
    <country>Czechia</country>
    <country>France</country>
    <country>Germany</country>
    <country>Hong Kong</country>
    <country>Hungary</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Poland</country>
    <country>Serbia</country>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Czech Republic</country>
  </removed_countries>
  <reference>
    <citation>Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004 May 1;64(9):3288-95. doi: 10.1158/0008-5472.can-04-0083.</citation>
    <PMID>15126372</PMID>
  </reference>
  <reference>
    <citation>Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10152-7. doi: 10.1073/pnas.0702916104. Epub 2007 Jun 5.</citation>
    <PMID>17551011</PMID>
  </reference>
  <reference>
    <citation>Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012 Sep;48(14):2192-202. doi: 10.1016/j.ejca.2012.04.011. Epub 2012 May 18.</citation>
    <PMID>22608262</PMID>
  </reference>
  <reference>
    <citation>Pless M, Droege C, von Moos R, Salzberg M, Betticher D. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013 Sep;81(3):445-450. doi: 10.1016/j.lungcan.2013.06.025. Epub 2013 Jul 23.</citation>
    <PMID>23891283</PMID>
  </reference>
  <reference>
    <citation>Kirson ED, Giladi M, Gurvich Z, Itzhaki A, Mordechovich D, Schneiderman RS, Wasserman Y, Ryffel B, Goldsher D, Palti Y. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis. 2009;26(7):633-40. doi: 10.1007/s10585-009-9262-y. Epub 2009 Apr 23.</citation>
    <PMID>19387848</PMID>
  </reference>
  <reference>
    <citation>Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, Cahal S, Shteingauz A, Chaudhry A, Kirson ED, Weinberg U, Palti Y. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells. Sci Rep. 2015 Dec 11;5:18046. doi: 10.1038/srep18046.</citation>
    <PMID>26658786</PMID>
  </reference>
  <reference>
    <citation>Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y. Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol. 2014 Oct;41 Suppl 6:S35-41. doi: 10.1053/j.seminoncol.2014.09.006. Epub 2014 Sep 8.</citation>
    <PMID>25213867</PMID>
  </reference>
  <reference>
    <citation>Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015 Dec 15;314(23):2535-43. doi: 10.1001/jama.2015.16669.</citation>
    <PMID>26670971</PMID>
  </reference>
  <reference>
    <citation>Voloshin T, Kaynan N, Davidi S, Porat Y, Shteingauz A, Schneiderman RS, Zeevi E, Munster M, Blat R, Tempel Brami C, Cahal S, Itzhaki A, Giladi M, Kirson ED, Weinberg U, Kinzel A, Palti Y. Tumor-treating fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. Cancer Immunol Immunother. 2020 Jul;69(7):1191-1204. doi: 10.1007/s00262-020-02534-7. Epub 2020 Mar 6.</citation>
    <PMID>32144446</PMID>
  </reference>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>November 22, 2016</study_first_submitted>
  <study_first_submitted_qc>November 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 25, 2016</study_first_posted>
  <last_update_submitted>September 11, 2023</last_update_submitted>
  <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Non-Small Cell Lung Cancer</keyword>
  <keyword>NSCLC</keyword>
  <keyword>Treatment</keyword>
  <keyword>Minimal Toxicity</keyword>
  <keyword>TTFields</keyword>
  <keyword>TTF</keyword>
  <keyword>Tumor Treating Fields</keyword>
  <keyword>Novocure</keyword>
  <keyword>Docetaxel</keyword>
  <keyword>PD-1 inhibitor</keyword>
  <keyword>PD-L1 inhibitor</keyword>
  <keyword>Immune checkpoint inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Docetaxel</mesh_term>
    <mesh_term>Immune Checkpoint Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT02973789
org study id: EF-24
nct id: NCT02973789
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is unapproved device: Yes
The study is a prospective, randomized controlled phase III trial aimed to test the efficacy
      and safety of TTFields, using the NovoTTF-200T device, concurrent with standard therapies for
      stage 4 NSCLC patients, following progression while on or after platinum based treatment. The
      device is an experimental, portable, battery operated device for chronic administration of
      alternating electric fields (termed TTFields or TTF) to the region of the malignant tumor, by
      means of surface, insulated electrode arrays.
PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:

      The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in
      vitro and in vivo NSCLC pre-clinical models both as a single modality treatment and in
      combination with chemotherapies and PD-1 inhibitors. TTFields have been demonstrated to act
      synergistically with taxanes and have been shown to be additive when combined with PD-1
      inhibitors. In addition, TTFields have shown to inhibit metastatic spread of malignant
      melanoma in in vivo experiment.

      In a pilot study, 42 patients with advanced NSCLC who had had tumor progression after at
      least one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz)
      applied to the chest and upper abdomen until disease progression (Pless M., et al., Lung
      Cancer 2011). The combination was well tolerated and the only device-related adverse event
      was mild to moderate contact dermatitis. Efficacy endpoints were remarkably high compared to
      historical data for pemetrexed alone.

      In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active
      chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active
      chemotherapy in extending survival, associated with minimal toxicity, good quality of life,
      and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a
      phase III trial of Optune® combined with maintenance temozolomide compared to maintenance
      temozolomide alone has shown that combined therapy led to a significant improvement in both
      progression free survival and overall survival in patients with newly diagnosed glioblastoma
      without the addition of high grade toxicity and without decline in quality of life (Stupp R.,
      et al., JAMA 2015).

      DESCRIPTION OF THE TRIAL:

      All patients included in this trial are patients with squamous or non-squamous, stage 4 NSCLC
      who had disease progression on or after receiving platinum based chemotherapy. In addition,
      all patients must meet all eligibility criteria.

      Eligible patients will be randomly assigned to one of two groups:

      Patients receive docetaxel or immune checkpoint inhibitor in combination with TTFields using
      the NovoTTF-100L System.

      Patients receive docetaxel or immune checkpoint inhibitor without TTFields. Patients will be
      randomized at a 1:1 ratio. Baseline tests will be performed in patients enrolled in both
      arms. If assigned to the NovoTTF-100L group, the patients will be treated continuously with
      the device until disease progression in the thorax and/or liver according to RECIST or
      irRECIST (Immune-Related Response Evaluation Criteria In Solid Tumors) (depending if the
      patient is receiving docetaxel or immune checkpoint inhibitor, respectively).

      On both arms, patients who have disease progression according to RECIST or irRECIST
      (depending if the patient is receiving docetaxel or immune checkpoint inhibitor,
      respectively) will switch to a third line treatment according to local practice.

      SCIENTIFIC BACKGROUND:

      Electric fields exert forces on electric charges similar to the way a magnet exerts forces on
      metallic particles within a magnetic field. These forces cause movement and rotation of
      electrically charged biological building blocks, much like the alignment of metallic
      particles seen along the lines of force radiating outwards from a magnet.

      Electric fields can also cause muscles to twitch and if strong enough may heat tissues.
      TTFields are alternating electric fields of low intensity. This means that they change their
      direction repetitively many times a second. Since they change direction very rapidly (150
      thousand times a second), they do not cause muscles to twitch, nor do they have any effects
      on other electrically activated tissues in the body (brain, nerves and heart). Since the
      intensities of TTFields in the body are very low, they do not cause heating.

      The breakthrough finding made by Novocure was that finely tuned alternating fields of very
      low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in
      the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are
      multiplying, TTFields cause electrically-charged cellular components of these cells to change
      their location within the dividing cell, disrupting their normal function and ultimately
      leading to cell death. In addition, cancer cells also contain miniature building blocks which
      act as tiny motors in moving essential parts of the cells from place to place. TTFields
      interfere with the normal orientation of these tiny motors related to other cellular
      components since they are electrically-charged as well. As a result of these two effects,
      tumor cell division is slowed, results in cellular death or reverses after continuous
      exposure to TTFields.

      Other cells in the body (normal healthy tissues) are affected much less than cancer cells
      since they multiply at a much slower rate if at all. In addition TTFields can be directed to
      a certain part of the body, leaving sensitive areas out of their reach. Finally, the
      frequency of TTFields applied to each type of cancer is specific and may not damage normally
      dividing cells in healthy tissues.

      In conclusion, TTFields hold the promise of serving as a brand new treatment for NSCLC with
      very few side effects.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall survival of patients treated with TTFields + docetaxel or immune checkpoint inhibitors vs. docetaxel or immune checkpoint inhibitors alone (superiority analysis)
time frame: 4 years
measure: Overall survival of patients treated with TTFields + docetaxel vs. docetaxel alone (superiority analysis)
time frame: 4 years
measure: Overall survival of patients treated with TTFields + immune checkpoint inhibitors vs. immune checkpoint inhibitors alone (superiority)
time frame: 4 years
measure: Overall Survival of patients treated with TTFields + docetaxel Vs. immune checkpoint inhibitors alone (non-inferiority analysis)
time frame: 4 years
measure: Progression-free survival of patients treated with docetaxel or immune checkpoint inhibitors + TTFields vs. docetaxel or immune checkpoint inhibitors alone, based on RECIST Criteria
time frame: 4 years
measure: Overall radiological response rate (based on RECIST criteria) of patients treated with docetaxel or Immune checkpoint inhibitors + TTFields vs. docetaxel or immune checkpoint inhibitors alone.
time frame: 4 years
measure: Quality of life using the EORTC QLQ C30 questionnaire with LC13 addendum
time frame: 4 years
measure: Analyses of the effects of NovoTTF-200T with each type of immune checkpoint inhibitor on overall survival and progression free survival
time frame: 4 years
measure: Analysis of the effects of NovoTTF-200T on overall survival and progression free survival within each histological subgroup (squamous and non-squamous)
time frame: 4 years
measure: The effect of treatment compliance with NovoTTF-200T on overall survival and progression free survival outcomes
time frame: 4 years
measure: Adverse events, severity and frequency based on Common Terminology Criteria for Adverse Events (CTCAE) V4.03
time frame: 4 years
arm group label: NovoTTF-200T
arm group type: Experimental
description: Patients receive TTFields using the NovoTTF-200T device together with immune checkpoint inhibitors or docetaxel
arm group label: Best Standard of Care
arm group type: Active Comparator
description: Patients receive best standard of care with immune checkpoint inhibitors or docetaxel
intervention type: Device
intervention name: NovoTTF-200T
description: Patients receive continuous TTFields treatment using the NovoTTF-200T device. TTFields treatment will consist of wearing four electrically insulated electrode arrays on the chest. The treatment enables the patient to maintain regular daily routine.
Other Name: TTFields
Drug: Immune checkpoint inhibitors or docetaxel Patients receive standard of care with Immune checkpoint inhibitors or docetaxel
arm group label: NovoTTF-200T
other name: TTFields
intervention type: Drug
intervention name: Immune checkpoint inhibitors or docetaxel
description: Patients receive standard of care with Immune checkpoint inhibitors or docetaxel
arm group label: Best Standard of Care
arm group label: NovoTTF-200T
criteria: 
gender: All
minimum age: 22 Years
maximum age: N/A
healthy volunteers: No
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country: Austria
country: Belgium
country: Bulgaria
country: Canada
country: China
country: Croatia
country: Czechia
country: France
country: Germany
country: Hong Kong
country: Hungary
country: Italy
country: Netherlands
country: Poland
country: Serbia
country: Spain
country: Switzerland
country: United States
country: Czech Republic
citation: Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004 May 1;64(9):3288-95. doi: 10.1158/0008-5472.can-04-0083.
PMID: 15126372
citation: Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10152-7. doi: 10.1073/pnas.0702916104. Epub 2007 Jun 5.
PMID: 17551011
citation: Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012 Sep;48(14):2192-202. doi: 10.1016/j.ejca.2012.04.011. Epub 2012 May 18.
PMID: 22608262
citation: Pless M, Droege C, von Moos R, Salzberg M, Betticher D. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013 Sep;81(3):445-450. doi: 10.1016/j.lungcan.2013.06.025. Epub 2013 Jul 23.
PMID: 23891283
citation: Kirson ED, Giladi M, Gurvich Z, Itzhaki A, Mordechovich D, Schneiderman RS, Wasserman Y, Ryffel B, Goldsher D, Palti Y. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis. 2009;26(7):633-40. doi: 10.1007/s10585-009-9262-y. Epub 2009 Apr 23.
PMID: 19387848
citation: Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, Cahal S, Shteingauz A, Chaudhry A, Kirson ED, Weinberg U, Palti Y. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells. Sci Rep. 2015 Dec 11;5:18046. doi: 10.1038/srep18046.
PMID: 26658786
citation: Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y. Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol. 2014 Oct;41 Suppl 6:S35-41. doi: 10.1053/j.seminoncol.2014.09.006. Epub 2014 Sep 8.
PMID: 25213867
citation: Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015 Dec 15;314(23):2535-43. doi: 10.1001/jama.2015.16669.
PMID: 26670971
citation: Voloshin T, Kaynan N, Davidi S, Porat Y, Shteingauz A, Schneiderman RS, Zeevi E, Munster M, Blat R, Tempel Brami C, Cahal S, Itzhaki A, Giladi M, Kirson ED, Weinberg U, Kinzel A, Palti Y. Tumor-treating fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. Cancer Immunol Immunother. 2020 Jul;69(7):1191-1204. doi: 10.1007/s00262-020-02534-7. Epub 2020 Mar 6.
PMID: 32144446
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Docetaxel
mesh term: Immune Checkpoint Inhibitors
sharing ipd: Undecided