<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/NCT03812796</url>
  </required_header>
  <id_info>
    <org_study_id>CCR 4745</org_study_id>
    <nct_id>NCT03812796</nct_id>
  </id_info>
  <brief_title>Epigenetic Modulation of the immunE Response in GastrointEstinal Cancers (EMERGE)</brief_title>
  <acronym>EMERGE</acronym>
  <official_title>Epigenetic Modulation of the immunE Response in GastrointEstinal Cancers (EMERGE)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Royal Marsden NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>4SC AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Merck KGaA, Darmstadt, Germany</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Royal Marsden NHS Foundation Trust</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      A multicenter phase II non-randomised trial assessing the efficacy of domatinostat (4SC-202)&#xD;
      plus avelumab in patients with GI cancer&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      During this phase II non randomised trial patients with microsatellite stable colorectal or&#xD;
      gastroesophageal cancer which has previously been treated with chemotherapy will be treated&#xD;
      with domatinostat plus avelumab.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 11, 2019</start_date>
  <completion_date type="Anticipated">November 30, 2021</completion_date>
  <primary_completion_date type="Anticipated">November 30, 2021</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>
    <intervention_model_description>Non-randomised</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety run-in phase: To establish a safe and tolerable dose of domatinostat in combination with avelumab for use in the main (Phase IIB efficacy) phase of the trial</measure>
    <time_frame>The DLT period is 28 days following the first treatment with domatinostat and avelumab</time_frame>
    <description>Progression through dosing levels will be determined by the occurrence of dose limiting toxicities in the study population.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Main Phase IIB (efficacy) phase: Objective response rate using RECIST 1.1 criteria</measure>
    <time_frame>6 months</time_frame>
    <description>ORR defined as the proportion of patients with either CR or PR (assessed according to RECIST 1.1) by 6 months from combination treatment initiation. The best ORR will be presented as a proportion along side a 95% confidence interval</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with adverse events (according to NCI-CTCAE version 4) as a measure of safety and tolerability</measure>
    <time_frame>Up to 90 days after last dose</time_frame>
    <description>Safety of domatinostat and avelumab will be assessed by summarizing adverse events as a proportion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival according to RECIST 1.1</measure>
    <time_frame>upto 2 years</time_frame>
    <description>PFS will be summarized using Kaplan Meier methods, presenting median survival with 95% confidence intervals. PFS is defined as the time from day of first treatment to disease progression or death from any cause. Patients without an event will be censored on day of last radiological follow up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>upto 2 years</time_frame>
    <description>OS will be summarized using Kaplan Meier methods, presenting median survival with 95% confidence intervals. OS is defined as the time from say of first treatment to death from any cause. Alive patients will be censored at the last follow up date</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate</measure>
    <time_frame>At 6 and 12 months on treatment</time_frame>
    <description>The proportion of patients with best disease control (CR, PR or SD) at 6 months and 12 months from initiation of combination treatment will be presented with a 95% confidence interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of objective response according to RECIST 1.1</measure>
    <time_frame>upto 2 years</time_frame>
    <description>DoOR will be summarized using Kaplan Meier methods. DoOR is defined as the time between the initial response to treatment and subsequent disease progression or relapse. Patients without an event will be censored on day of last radiological assessment</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">75</enrollment>
  <condition>Cancer</condition>
  <condition>GI Cancer</condition>
  <arm_group>
    <arm_group_label>Domatinostat plus Avelumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a multicentre open-label, phase II non-randomised clinical trial domatinostat plus avelumab (two separate cohorts in phase IIB part of trial).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Domatinostat</intervention_name>
    <description>Domatinostat is an oral tablet which will be given at a variable dose during the Phase IIA safety run in phase of the trial.&#xD;
During the Phase IIB efficacy phase of the trial patients will be treated with domatinostat at the safe and tolerated combination dose identified during the Phase IIA safety run in phase.</description>
    <arm_group_label>Domatinostat plus Avelumab</arm_group_label>
    <other_name>4SC-202</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Avelumab</intervention_name>
    <description>Avelumab is a monoclonal antibody which is given via an intravenous infusion at a dose of 10mg/kg every two weeks on the first day of a two week cycle. (Day 1 q 14d) from Cycle 2 onwards.</description>
    <arm_group_label>Domatinostat plus Avelumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
        i. Male/female patients aged ≥18 years ii. Histologically confirmed gastric,&#xD;
        gastro-oesophageal junction or oesophageal adenocarcinoma (referred to as oesophagogastric&#xD;
        adenocarcinoma (OGA) in this protocol) or colorectal adenocarcinoma (referred to as CRC in&#xD;
        this protocol) iii. Agrees to undergo biopsies for translational endpoints iv. Tumour must&#xD;
        be mismatch repair proficient assessed using a validated test such as immunohistochemistry&#xD;
        for mismatch repair proteins or microsatellite instability testing v. Tumours should be&#xD;
        advanced and inoperable or metastatic vi. Patients must have received at least one prior&#xD;
        chemotherapy treatment for their cancer, have no established treatment option, or decides&#xD;
        against an established treatment option.&#xD;
&#xD;
        vii. Adequate bone marrow function:&#xD;
&#xD;
          1. Absolute neutrophil count (ANC) ≥1.5 x109/L&#xD;
&#xD;
          2. White blood count &gt;3x109/L&#xD;
&#xD;
          3. Platelets ≥100x109/L&#xD;
&#xD;
          4. Haemoglobin (Hb) ≥9g/dl (can be post-transfusion) viii. Adequate renal function:&#xD;
             Creatinine Clearance o ≥30ml/min is required. This may be calculated as per local&#xD;
             practice, if calculated CrCl is &lt;60ml/min then EDTA is required to demonstrate CrCl of&#xD;
             ≥30ml/min If available, the EDTA clearance should always take precedence over the&#xD;
             creatinine clearance.&#xD;
&#xD;
        ix. Adequate liver function&#xD;
&#xD;
        a. Serum bilirubin ≤1.5x ULN b. ALT/AST ≤2.5x ULN or ALT/AST ≤5x ULN if metastatic disease&#xD;
        to liver x. Adequate coagulation profile&#xD;
&#xD;
          1. International Normalised Ratio (INR) &lt; 1.5&#xD;
&#xD;
          2. Activated Prothrombin Time (APTT) &lt; 1.5xULN xi. Patients on oral anticoagulation are&#xD;
             advised to change to low molecular weight heparin prior to study entry to be eligible&#xD;
             xii. ECOG performance status 0-1 xiii. Patient is fit to undergo all protocol&#xD;
             investigations and receive all protocol treatment based on the assessment oncology&#xD;
             clinics xiv. Signed and dated informed consent document indicating that the patient&#xD;
             (or legally acceptable representative) has been informed of all the pertinent aspects&#xD;
             of the trial prior to enrolment.&#xD;
&#xD;
        xv. Willingness and ability to comply with the protocol for the duration of the study&#xD;
        including scheduled visits, examinations, investigations and treatment plans xvi. Pregnancy&#xD;
        must be excluded with a negative serum pregnancy test, within 7 days before initiation of&#xD;
        therapy, if the risk of conception exists. Sexually active female patients must be&#xD;
        surgically sterile or be postmenopausal or must agree to use highly effective contraception&#xD;
        which must be used for 10 days before the negative pregnancy test. Sexually active male&#xD;
        patients must be surgically sterile or must agree to use highly effective contraception,&#xD;
        i.e. methods with a failure rate of &lt;1% per year (see section 6.4 for full definition and&#xD;
        examples of highly effective contraception). Highly effective contraception must be agreed&#xD;
        to be used throughout the study and for 30 days after last avelumab treatment if risk of&#xD;
        conception exists. Female patients of child-bearing potential should be strictly advised to&#xD;
        use a highly effective contraceptive measure, from the time of screening to 30 days after&#xD;
        the last dose of trial treatment. If the patient uses a hormonal contraceptive method, the&#xD;
        patient's partner should additionally use a condom. Male patients with partners of child&#xD;
        bearing potential should be strictly advised to use barrier contraception in addition to&#xD;
        having their partner use another method of contraception during the trial and for three&#xD;
        months after the last dose. Male patients should also be advised to abstain from sexual&#xD;
        intercourse with pregnant or lactating women, or to use condoms.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
        i. Any contraindication or known hypersensitivity reaction to any of the study drugs ii.&#xD;
        Persisting toxicity relating to prior therapy of &gt;grade 1 CTCAE version 4.03 except&#xD;
        alopecia of any grade and neuropathy ≤ grade 2, or other grade ≤2 not constituting a safety&#xD;
        risk based on investigators judgement iii. Any prior treatment with immunotherapy including&#xD;
        anti-PD-1or PD-L1 therapy or other immunomodulatory drugs.&#xD;
&#xD;
        iv. All subjects with brain metastases, except those meeting the following criteria:&#xD;
&#xD;
          1. Brain metastases that have been treated locally and are clinically stable for at least&#xD;
             2 weeks prior to enrolment&#xD;
&#xD;
          2. No ongoing neurological symptoms that are related to the brain localization of the&#xD;
             disease (sequelae that are a consequence of the treatment of the brain metastases are&#xD;
             acceptable)&#xD;
&#xD;
          3. Subjects must be either off steroids or on a stable or decreasing dose of &lt;10mg daily&#xD;
             prednisone (or equivalent)&#xD;
&#xD;
        v. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v&#xD;
        4.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of&#xD;
        partially controlled asthma) vi. Patients who have received chemotherapy or radiotherapy&#xD;
        for a previous malignancy in the past 3 years.&#xD;
&#xD;
        vii. Any immunodeficiency disorder viii. Any active, known or suspected autoimmune disease&#xD;
        that might deteriorate when receiving immunostimulatory agent, with the following&#xD;
        exceptions:&#xD;
&#xD;
          1. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not&#xD;
             requiring immunosuppressive treatment are eligible&#xD;
&#xD;
          2. Patients requiring hormone replacement with corticosteroids are eligible if the&#xD;
             steroids are administered only for the purpose of hormonal replacement and at doses&#xD;
             ≤10mg (or equivalent) of prednisolone per day&#xD;
&#xD;
          3. Administration of steroids through a route known to result in minimal systemic&#xD;
             exposure (topical, intranasal, intra-ocular, intra-articular or inhalation) are&#xD;
             acceptable. Steroids as pre-medication for hypersensitivity reactions e.g. CT contrast&#xD;
             are also acceptable.&#xD;
&#xD;
        ix. Prior organ transplantation, including allogeneic stem-cell transplantation x. Active&#xD;
        infection requiring systemic therapy xi. History of inflammatory bowel disease xii.&#xD;
        Patients with a history of interstitial lung disease or radiological evidence of pulmonary&#xD;
        fibrosis xiii. Cerebrovascular disease (including transient ischaemic attacks (TIA) and&#xD;
        strokes) within the previous 6 months xiv. Cardiovascular diseases as follows:&#xD;
&#xD;
          1. Myocardial infarction within the previous 6 months&#xD;
&#xD;
          2. Unstable angina&#xD;
&#xD;
          3. Congestive heart failure ≥NYHA Classification Class II&#xD;
&#xD;
          4. Serious cardiac arrhythmia requiring medication (for example, ventricular tachycardia,&#xD;
             supraventricular tachycardia or atrial fibrillation with a resting heart rate &gt;&#xD;
             110bpm) xv. Current signs or symptoms of any other severe progressive or uncontrolled&#xD;
             hepatic, haematologic, gastrointestinal, endocrine, respiratory or cardiac disease,&#xD;
             which in the opinion of the investigator, might impair the subject's tolerance of&#xD;
             trial treatment or procedures.&#xD;
&#xD;
        xvi. Major surgery, major trauma or open biopsy within 28 days prior to registration (not&#xD;
        including staging laparoscopy) xvii. Evidence of bleeding diathesis or coagulopathy xviii.&#xD;
        Active non-healing wound, ulcer or bone fracture requiring therapy xix. Known positive&#xD;
        tests for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency&#xD;
        syndrome, hepatitis A or C virus, acute or chronic active hepatitis B infection xx. Use of&#xD;
        live attenuated vaccine within 28 days of initiation of study therapy, or anticipation that&#xD;
        a live attenuated vaccine will be required during the study xxi. Current lactation&#xD;
        (patients that discontinue breastfeeding may be eligible) xxii. Other severe acute or&#xD;
        chronic medical conditions or psychiatric conditions including recent (within the past&#xD;
        year) or active suicidal ideation or behaviour; or laboratory abnormalities that may&#xD;
        increase the risk associated with study participation or study treatment administration or&#xD;
        may interfere with the interpretation of study results and, in the judgment of the&#xD;
        investigator, would make the patient inappropriate for entry into this study.&#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>David Cunningham</last_name>
    <role>Principal Investigator</role>
    <affiliation>Consultant Medical Oncologist</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>David Cunningham</last_name>
    <phone>020 8642 6011</phone>
    <phone_ext>4480</phone_ext>
    <email>david.cunningham@rmh.nhs.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Claire Saffery</last_name>
    <phone>020 8642 6011</phone>
    <phone_ext>4480</phone_ext>
    <email>Claire.Saffery@rmh.nhs.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>The Royal Marsden Hospital NHS Foundation Trust</name>
      <address>
        <city>Sutton</city>
        <state>Surrey</state>
        <zip>SM2 5PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Cunningham</last_name>
      <phone>020 8642 6011</phone>
      <email>david.cunningham@rmh.nhs.uk</email>
    </contact>
    <contact_backup>
      <last_name>Claire Saffery</last_name>
      <phone>020 8642 6011</phone>
      <phone_ext>4480</phone_ext>
      <email>Claire.Saffery@rmh.nhs.uk</email>
    </contact_backup>
    <investigator>
      <last_name>David Cunningham</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Royal Marsden Hospital NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SW3 6JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Cunningham</last_name>
      <phone>020 8642 6011</phone>
      <email>david.cunningham@rmh.nhs.uk</email>
    </contact>
    <contact_backup>
      <last_name>Claire Saffery</last_name>
      <phone>020 8642 6011</phone>
      <phone_ext>4480</phone_ext>
      <email>Claire.Saffery@rmh.nhs.uk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>April 9, 2018</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <last_update_submitted>February 1, 2019</last_update_submitted>
  <last_update_submitted_qc>February 1, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 5, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastrointestinal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Avelumab</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/NCT03812796
org study id: CCR 4745
nct id: NCT03812796
lead sponsor: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
A multicenter phase II non-randomised trial assessing the efficacy of domatinostat (4SC-202)
      plus avelumab in patients with GI cancer
During this phase II non randomised trial patients with microsatellite stable colorectal or
      gastroesophageal cancer which has previously been treated with chemotherapy will be treated
      with domatinostat plus avelumab.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Non-randomised
primary purpose: Treatment
masking: None (Open Label)
measure: Safety run-in phase: To establish a safe and tolerable dose of domatinostat in combination with avelumab for use in the main (Phase IIB efficacy) phase of the trial
time frame: The DLT period is 28 days following the first treatment with domatinostat and avelumab
description: Progression through dosing levels will be determined by the occurrence of dose limiting toxicities in the study population.
measure: Main Phase IIB (efficacy) phase: Objective response rate using RECIST 1.1 criteria
time frame: 6 months
description: ORR defined as the proportion of patients with either CR or PR (assessed according to RECIST 1.1) by 6 months from combination treatment initiation. The best ORR will be presented as a proportion along side a 95% confidence interval
measure: Number of patients with adverse events (according to NCI-CTCAE version 4) as a measure of safety and tolerability
time frame: Up to 90 days after last dose
description: Safety of domatinostat and avelumab will be assessed by summarizing adverse events as a proportion
measure: Progression free survival according to RECIST 1.1
time frame: upto 2 years
description: PFS will be summarized using Kaplan Meier methods, presenting median survival with 95% confidence intervals. PFS is defined as the time from day of first treatment to disease progression or death from any cause. Patients without an event will be censored on day of last radiological follow up
measure: Overall survival
time frame: upto 2 years
description: OS will be summarized using Kaplan Meier methods, presenting median survival with 95% confidence intervals. OS is defined as the time from say of first treatment to death from any cause. Alive patients will be censored at the last follow up date
measure: Disease control rate
time frame: At 6 and 12 months on treatment
description: The proportion of patients with best disease control (CR, PR or SD) at 6 months and 12 months from initiation of combination treatment will be presented with a 95% confidence interval
measure: Duration of objective response according to RECIST 1.1
time frame: upto 2 years
description: DoOR will be summarized using Kaplan Meier methods. DoOR is defined as the time between the initial response to treatment and subsequent disease progression or relapse. Patients without an event will be censored on day of last radiological assessment
arm group label: Domatinostat plus Avelumab
arm group type: Experimental
description: This is a multicentre open-label, phase II non-randomised clinical trial domatinostat plus avelumab (two separate cohorts in phase IIB part of trial).
intervention type: Drug
intervention name: Domatinostat
description: Domatinostat is an oral tablet which will be given at a variable dose during the Phase IIA safety run in phase of the trial.
During the Phase IIB efficacy phase of the trial patients will be treated with domatinostat at the safe and tolerated combination dose identified during the Phase IIA safety run in phase.
arm group label: Domatinostat plus Avelumab
other name: 4SC-202
intervention type: Drug
intervention name: Avelumab
description: Avelumab is a monoclonal antibody which is given via an intravenous infusion at a dose of 10mg/kg every two weeks on the first day of a two week cycle. (Day 1 q 14d) from Cycle 2 onwards.
arm group label: Domatinostat plus Avelumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: David Cunningham
role: Principal Investigator
affiliation: Consultant Medical Oncologist
last name: David Cunningham
phone: 020 8642 6011
phone ext: 4480
email: david.cunningham@rmh.nhs.uk
last name: Claire Saffery
phone: 020 8642 6011
phone ext: 4480
email: Claire.Saffery@rmh.nhs.uk
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Gastrointestinal Neoplasms
mesh term: Avelumab
sharing ipd: Undecided