<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/NCT01684241</url>
  </required_header>
  <id_info>
    <org_study_id>RB_0001-01</org_study_id>
    <nct_id>NCT01684241</nct_id>
  </id_info>
  <brief_title>RBL001/RBL002 Phase I Clinical Trial</brief_title>
  <acronym>MERIT</acronym>
  <official_title>Clinical First-in-human Dose Escalation Study Evaluating the Safety and Tolerability of Intranodal Administration of an RNA-based Cancer Vaccine Targeting Two Tumor-associated Antigens in Patients With Advanced Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>BioNTech RNA Pharmaceuticals GmbH</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>BioNTech SE</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Clinical first-in-human dose escalation study evaluating the safety and tolerability of&#xD;
      intranodal administration of an RNA-based cancer vaccine targeting two tumor-associated&#xD;
      antigens in patients with advanced melanoma&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      RBL001/RBL002 are naked ribonucleic acid (RNA) based recombinant vaccines that were optimized&#xD;
      to induce antigen specific CD8+ and CD4+ T cell responses against malignant melanoma target&#xD;
      antigens.&#xD;
&#xD;
      The Targeted antigens are well characterized antigens in melanoma that have been previously&#xD;
      utilized with excellent safety and proven immunogenicity as vaccine targets in a number of&#xD;
      independent clinical trials.&#xD;
&#xD;
      The overall rationale of the study is to determine safety of the novel RNA based vaccine&#xD;
      approach and determine vaccine target antigen directed immune responses as early biomarkers&#xD;
      for clinical mode of action.&#xD;
&#xD;
      The RBL001/RBL002 vaccine is expected to lead to several effects contributing to its&#xD;
      immunological (therapeutic) effect. First, ultrasound guided administration of naked RNA drug&#xD;
      product into lymph nodes is expected to result in rapid uptake of naked RNA by lymph node&#xD;
      resident professional antigen-presenting cells (APCs). Incorporated RNA is known to&#xD;
      translocate to the cytoplasm leading to its translation by the host ribosome complex into the&#xD;
      respective protein antigens. The recombinant vaccine is optimized for immunogenicity and&#xD;
      enables presentation of diverse antigenic epitopes on both HLA-class I as well as HLA-class&#xD;
      II molecules. Consecutively, antigen-specific CD8+ and CD4+ T cell responses will be&#xD;
      triggered by HLA-peptide complexes on the surface of antigen presenting cells. In addition,&#xD;
      RNA administration will also lead to transient activation (change of surface marker&#xD;
      expression and cytokine secretion) of APCs in the targeted lymph nodes particularly via&#xD;
      signaling of TLR 7 and 8 leading to an adjuvant effect, supporting the induction of&#xD;
      target-specific T cell responses with systemic anti-tumor activity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2012</start_date>
  <completion_date type="Actual">July 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of adverse events</measure>
    <time_frame>90 days</time_frame>
    <description>Number of Patients with adverse events, total number of adverse events, dose-limiting toxicities</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Determination of antitumoral immune responses</measure>
    <time_frame>90 days</time_frame>
    <description>Cellular immune responses, cytokines, AB responses, serum biomarkers, and further immunological parameters will be determined once or repeatedly in the course of treatment. In the latter case changes from baseline will be tabulated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Monitoring of Tumor Lesions</measure>
    <time_frame>90 days</time_frame>
    <description>Tumor lesion status as determined by CT or MRI results evaluated by irRC and RECIST.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>RBL001/RBL002 intranodal administration</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants will be treated with RBL001/RBL002 after allocation to one of the four escalating dose cohorts:&#xD;
Cohort-1 50 µg RBL001 and 50 µg RBL002&#xD;
Cohort-2 100 µg RBL001 and 100 µg RBL002&#xD;
Cohort-3 300 µg RBL001 and 300 µg RBL002&#xD;
Cohort-4 600 µg RBL001 and 600 µg RBL002</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>RBL001/RBL002</intervention_name>
    <description>Each participant will receive 8 repeated intranodal administrations of RBL001 and RBL002 during a time frame of 43 to 51 days.</description>
    <arm_group_label>RBL001/RBL002 intranodal administration</arm_group_label>
    <other_name>cancer vaccine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stage IIC, IIIA-C or unresectable stage IV of cutaneous melanoma (AJCC 2009 melanoma&#xD;
             classification)&#xD;
&#xD;
          -  First line therapy for subjects not eligible or declining other first line therapies&#xD;
             after all available treatment options have been transparently disclosed (to be&#xD;
             documented!)&#xD;
&#xD;
          -  Antigen expression confirmed by RT-PCR analysis from FFPE&#xD;
&#xD;
          -  ≥ 18 years of age&#xD;
&#xD;
          -  Written informed consent (part I and part II)&#xD;
&#xD;
          -  ECOG performance status (PS) 0-1 or Karnofsky Index 70-100 %&#xD;
&#xD;
          -  Life expectancy &gt; 3 months&#xD;
&#xD;
          -  WBC ≥ 3x109/L&#xD;
&#xD;
          -  Hemoglobin ≥ 10 g/dl&#xD;
&#xD;
          -  Platelet count ≥ 100,000/mm³&#xD;
&#xD;
          -  LDH level &lt; 2.0 x ULN&#xD;
&#xD;
          -  Negative pregnancy test (measured by β-HCG) for females of childbearing age&#xD;
&#xD;
          -  Suitable lymph nodes for injection using ultrasound guidance&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Primary ocular melanoma&#xD;
&#xD;
          -  Presence of history (&lt; 5 years) of a second malignancy other than squamous or basal&#xD;
             cell carcinoma, non-active prostate cancer or cervical carcinoma in situ&#xD;
&#xD;
          -  Brain metastases&#xD;
&#xD;
          -  Known or symptomatic pleural effusions and/or ascites&#xD;
&#xD;
          -  Known hypersensitivity to the active substance or to any of the excipients&#xD;
&#xD;
          -  A serious local infection (e. g. cellulitis, abscess) or systemic infection (e. g.&#xD;
             pneumonia, septicemia) which requires systemic antibiotic treatment within 2 weeks&#xD;
             prior to the first dose of study medication&#xD;
&#xD;
          -  Acute or chronic active hepatitis B or C infection, EBV or CMV&#xD;
&#xD;
          -  Receipt of allogenic stem cell transplantation&#xD;
&#xD;
          -  Clinically relevant autoimmune disease&#xD;
&#xD;
          -  Systemic immune suppression:&#xD;
&#xD;
          -  HIV disease&#xD;
&#xD;
          -  Use of chronic oral or systemic steroid medication (topical or inhalational steroids&#xD;
             are permitted) Other clinical relevant systemic immune suppression&#xD;
&#xD;
          -  Symptomatic congestive heart failure (NYHA 3 or 4)&#xD;
&#xD;
          -  Unstable angina pectoris&#xD;
&#xD;
          -  Radiotherapy, chemotherapy, major surgery, immunotherapy, vaccination, any other&#xD;
             concurrent anticancer therapy or any investigational drug within 28 days before the&#xD;
             first treatment of this study&#xD;
&#xD;
          -  Minor surgery within 14 days before the first treatment of this study&#xD;
&#xD;
          -  Treatment with Ipilimumab within 84 days before the first treatment of this study&#xD;
&#xD;
          -  Fertile males and females who are unwilling to employ adequate means of contraception&#xD;
             (e. g. condom with spermicide, diaphragm with spermicide, birth control pills,&#xD;
             injections, patches or intrauterine device) during study treatment and 28 days after&#xD;
             the last dose of study treatment&#xD;
&#xD;
          -  Presence of a serious concurrent illness or other condition (e. g. psychological,&#xD;
             family, sociological, or geographical circumstances) that does not permit adequate&#xD;
             follow-up and compliance with the protocol&#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>Ugur Sahin, Prof. Dr.</last_name>
    <role>Study Director</role>
    <affiliation>Ribological GmbH</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Medizinische Universität Wien, Abteilung für Dermatologie</name>
      <address>
        <city>Vienna</city>
        <zip>A-1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medizinische Fakultät der Universität Duisburg-Essen</name>
      <address>
        <city>Essen</city>
        <zip>45122</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universtitätsmedizin der Johannes-Gutenberg Universtität</name>
      <address>
        <city>Mainz</city>
        <zip>55131</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinik Mannheim</name>
      <address>
        <city>Mannheim</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Germany</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>September 10, 2012</study_first_submitted>
  <study_first_submitted_qc>September 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2012</study_first_posted>
  <last_update_submitted>January 14, 2020</last_update_submitted>
  <last_update_submitted_qc>January 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Biontech</keyword>
  <keyword>Biontech RNA Pharmaceuticals GmbH</keyword>
  <keyword>Biontech RNA</keyword>
  <keyword>MERIT</keyword>
  <keyword>RNA</keyword>
  <keyword>Immuno Therapy</keyword>
  <keyword>RB_0001-01</keyword>
  <keyword>Ribological</keyword>
  <keyword>Melanoma</keyword>
  <keyword>RBL001</keyword>
  <keyword>RBL002</keyword>
  <keyword>cancer vaccine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaccines</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01684241
org study id: RB_0001-01
nct id: NCT01684241
lead sponsor: 
has dmc: Yes
Clinical first-in-human dose escalation study evaluating the safety and tolerability of
      intranodal administration of an RNA-based cancer vaccine targeting two tumor-associated
      antigens in patients with advanced melanoma
RBL001/RBL002 are naked ribonucleic acid (RNA) based recombinant vaccines that were optimized
      to induce antigen specific CD8+ and CD4+ T cell responses against malignant melanoma target
      antigens.

      The Targeted antigens are well characterized antigens in melanoma that have been previously
      utilized with excellent safety and proven immunogenicity as vaccine targets in a number of
      independent clinical trials.

      The overall rationale of the study is to determine safety of the novel RNA based vaccine
      approach and determine vaccine target antigen directed immune responses as early biomarkers
      for clinical mode of action.

      The RBL001/RBL002 vaccine is expected to lead to several effects contributing to its
      immunological (therapeutic) effect. First, ultrasound guided administration of naked RNA drug
      product into lymph nodes is expected to result in rapid uptake of naked RNA by lymph node
      resident professional antigen-presenting cells (APCs). Incorporated RNA is known to
      translocate to the cytoplasm leading to its translation by the host ribosome complex into the
      respective protein antigens. The recombinant vaccine is optimized for immunogenicity and
      enables presentation of diverse antigenic epitopes on both HLA-class I as well as HLA-class
      II molecules. Consecutively, antigen-specific CD8+ and CD4+ T cell responses will be
      triggered by HLA-peptide complexes on the surface of antigen presenting cells. In addition,
      RNA administration will also lead to transient activation (change of surface marker
      expression and cytokine secretion) of APCs in the targeted lymph nodes particularly via
      signaling of TLR 7 and 8 leading to an adjuvant effect, supporting the induction of
      target-specific T cell responses with systemic anti-tumor activity.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of adverse events
time frame: 90 days
description: Number of Patients with adverse events, total number of adverse events, dose-limiting toxicities
measure: Determination of antitumoral immune responses
time frame: 90 days
description: Cellular immune responses, cytokines, AB responses, serum biomarkers, and further immunological parameters will be determined once or repeatedly in the course of treatment. In the latter case changes from baseline will be tabulated.
measure: Clinical Monitoring of Tumor Lesions
time frame: 90 days
description: Tumor lesion status as determined by CT or MRI results evaluated by irRC and RECIST.
arm group label: RBL001/RBL002 intranodal administration
arm group type: Experimental
description: All participants will be treated with RBL001/RBL002 after allocation to one of the four escalating dose cohorts:
Cohort-1 50 µg RBL001 and 50 µg RBL002
Cohort-2 100 µg RBL001 and 100 µg RBL002
Cohort-3 300 µg RBL001 and 300 µg RBL002
Cohort-4 600 µg RBL001 and 600 µg RBL002
intervention type: Biological
intervention name: RBL001/RBL002
description: Each participant will receive 8 repeated intranodal administrations of RBL001 and RBL002 during a time frame of 43 to 51 days.
arm group label: RBL001/RBL002 intranodal administration
other name: cancer vaccine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ugur Sahin, Prof. Dr.
role: Study Director
affiliation: Ribological GmbH
facility: 
facility: 
facility: 
facility: 
country: Austria
country: Germany
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Vaccines