<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/NCT03788083</url>
  </required_header>
  <id_info>
    <org_study_id>TriMix-Breast</org_study_id>
    <nct_id>NCT03788083</nct_id>
  </id_info>
  <brief_title>Intratumoral TriMix Injections in Early Breast Cancer Patients</brief_title>
  <acronym>TMBA</acronym>
  <official_title>A Phase I Study on the Safety and Immune-modulatory Effect of Intratumoral (i.t.) Administration of mRNA (Messenger RNA) Encoding Dendritic Cell Activating Proteins in Patients With Early, Resectable Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universitair Ziekenhuis Brussel</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>eTheRNA immunotherapies</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Universitair Ziekenhuis Brussel</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with early breast cancer and accessible tumor lesions (1.00 to 10 ml volume) that&#xD;
      are eligible to either surgical removal of their tumor or neoadjuvant chemotherapy will be&#xD;
      injected with the IMP. Patients will be either treated with placebo (buffer alone, 12&#xD;
      patients) or with TriMix mRNA at three dose levels [8 at dose level I (1mg/ml), 8 at dose&#xD;
      level II (3mg/ml), and 8 at dose level III (6mg/ml). The volume injected in this group will&#xD;
      be adjusted to the tumour volume to ensure a perfusion of around 33% of the tumour volume&#xD;
      (33% +/- 5%). Therefore, depending on the patients' tumour size, 500, 1000 or 2000 µl of&#xD;
      TriMix mRNA solution or placebo solution will be injected into each tumor. Each patient will&#xD;
      receive three administrations of TriMix prior to start of general treatment (surgery or&#xD;
      neoadjuvant chemotherapy) separated by one week (7 days +/- 2 days) interval. The last&#xD;
      administration will be performed 2 days preoperatively or start of neoadjuvant chemotherapy.&#xD;
&#xD;
      The tumor and peripheral blood samples will be analyzed for immunological changes. If it is&#xD;
      decided by the multidisciplinary team that neoadjuvant therapy is more appropriate for the&#xD;
      patient, a second tumor biopsy (instead of surgical resection) will be taken 2 days after&#xD;
      third administration of TriMix mRNA to assess immunological changes within the tumor.&#xD;
      Similarly, patients that refuses to undergo surgery or to receive neoadjuvant chemotherapy&#xD;
      can be enrolled into the trial, if they accept three administrations of TriMix followed by a&#xD;
      second tumor biopsy.&#xD;
&#xD;
      The study will start with recruitment of the placebo group. The enrollment of the first three&#xD;
      patients in each cohort with Trimix mRNA will be staggered with at least one day between the&#xD;
      first dose of each individual patient. One week after the third patient of a cohort received&#xD;
      the third TriMix mRNA administration, an overall evaluation of the safety and tolerability of&#xD;
      this cohort will be done by the principal investigator. The results will be reviewed by an&#xD;
      in-house dose evaluation committee overseeing the safety and tolerability of TriMix mRNA.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 12, 2018</start_date>
  <completion_date type="Anticipated">December 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Subjects will not know whether an active or non-active substance is being injected. The choice for TriMix or placebo will take place according to the predefined schedule and can not be influenced by the patient or the investigator. Only after the comparison of the tumour tissue before (the initial biopsy where the diagnosis was made) and after (obtained at second biopsy or surgery) the intratumoral injection, it will be known whether mRNA or non-active product was used for the injection.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v5.0</measure>
    <time_frame>2 years</time_frame>
    <description>Number of patients with adverse events, total number of adverse events, dose limiting toxicities</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tumor microenvironment changes induced by intratumoral TriMix mRNA</measure>
    <time_frame>30 days</time_frame>
    <description>Tumor microenvironment changes induced by intratumoral TriMix mRNA administration from diagnostic biopsy to day 21 (visit 5) assessed by immunohistochemistry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor microenvironment changes induced by intratumoral TriMix mRNA</measure>
    <time_frame>30 days</time_frame>
    <description>Tumor microenvironment changes induced by intratumoral TriMix mRNA administration from diagnostic biopsy to day 21 (visit 5) assessed by nanoString gene profiling</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TriMix mRNA induced T-cell responses</measure>
    <time_frame>30 days</time_frame>
    <description>TriMix mRNA induced T-cell responses assessed by immunoassays in situ and in peripheral blood</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>Breast Cancer Female</condition>
  <condition>Early-stage Breast Cancer</condition>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>TriMix</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trimix</intervention_name>
    <description>Intratumoral TriMix injection</description>
    <arm_group_label>TriMix</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Intratumoral placebo injection</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age greater than or equal to 18 years and less than or equal to 85 yrs&#xD;
&#xD;
          2. Histologically proven breast cancer eligible for curative surgery (with or without the&#xD;
             need for neoadjuvant chemotherapy) with one or more injection-accessible (allowing&#xD;
             ultrasound guidance) nodal tumors.&#xD;
&#xD;
          3. Injectable tumor lesions must have a volume between 1.00 and 10 ml, only one lesion&#xD;
             per patient will be injected&#xD;
&#xD;
          4. ECOG performance status of 0 or 1&#xD;
&#xD;
          5. Willing to give informed consent in writing&#xD;
&#xD;
          6. Willing and able to attend the scheduled study visits and to comply with the study&#xD;
             procedures&#xD;
&#xD;
          7. No prior therapy for ipsilateral breast cancer&#xD;
&#xD;
          8. Normal lab parameters: white cell count ≥ 3,000/mm3, hemoglobin ≥ 10mg/dl, platelet&#xD;
             count ≥ 100,000/mm3, serum creatinine ≤ 1.5 x institutional ULN, bilirubin ≤ 2.0 mg/dl&#xD;
             aspartate aminotransferase/alanine aminotransferase/ alkaline phosphatase ≤ 2 x the&#xD;
             upper normal limit (AST&lt; 72 U/l, ALT &lt; 104 U/l, AP &lt; 252 U/l)&#xD;
&#xD;
          9. Adequate Coagulation Parameters with: Prothrombin INR &lt; 1.5; Partial Thromboplastin&#xD;
             Time &lt; 1.5 x 34.4 sec (51.6 sec)&#xD;
&#xD;
         10. Female patients of childbearing potential should have a negative serum pregnancy test&#xD;
             at screening visit and should use a highly efficient method of birth control for the&#xD;
             duration of treatment and until the first menses after a 4 week period after the last&#xD;
             dose of study medication. Highly effective birth control methods include:&#xD;
&#xD;
               -  combined (estrogen and progestogen containing) hormonal contraception associated&#xD;
                  with inhibition of ovulation administered oral, intravaginal or transdermal.&#xD;
&#xD;
               -  progestogen-only hormonal contraception associated with inhibition of ovulation&#xD;
                  administered oral, as an injectable or implantable formulation.&#xD;
&#xD;
               -  intrauterine device&#xD;
&#xD;
               -  intrauterine hormone-releasing system&#xD;
&#xD;
               -  bilateral tubal occlusion&#xD;
&#xD;
               -  vasectomised partner&#xD;
&#xD;
               -  abstinence from sexual intercourse&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Male patients&#xD;
&#xD;
          2. Patients with stage III-IV breast cancer (AJCC 8th edition)&#xD;
&#xD;
          3. Patients with highly vascularized tumor or important post-biopsy hematoma&#xD;
&#xD;
          4. Previous chemotherapy for breast cancer or other types of cancer within the last five&#xD;
             years&#xD;
&#xD;
          5. Other malignancies other than non-melanoma skin cancer, or controlled superficial&#xD;
             bladder cancer. In the event of prior malignancies treated surgically, the patient&#xD;
             must be considered NED (no evidence of disease) for a minimum of 3 years prior to&#xD;
             enrolment&#xD;
&#xD;
          6. Patients with a history of autoimmune disease (inflammatory bowel disease, systemic&#xD;
             lupus erythematosus, ankylosing spondylitis, scleroderma, rheumatoid arthritis or&#xD;
             multiple sclerosis) other auto-immune or debilitating diseases. Vitiligo is not an&#xD;
             exclusion criterion.&#xD;
&#xD;
          7. Patients with serious intercurrent chronic or acute illness such as pulmonary [asthma&#xD;
             or chronic obstructive pulmonary disease (COPD)] or cardiac (NYHA class III or IV) or&#xD;
             hepatic disease or other illness considered by the P.I. to constitute an unwarranted&#xD;
             high risk for investigational drug treatment&#xD;
&#xD;
          8. Patients with significant psychiatric disabilities or seizure disorders&#xD;
&#xD;
          9. Legal incapacity or limited legal capacity&#xD;
&#xD;
         10. Patients on steroid therapy &gt; 10 mg prednisone (or equivalent) or other&#xD;
             immunosuppressive agents such as azathioprine or cyclosporine A are excluded on the&#xD;
             basis of potential immune suppression. Patients must have had 8 weeks of&#xD;
             discontinuation of any steroid therapy exceeding &gt; 10 mg prednisone (or equivalent)&#xD;
             prior to enrolment&#xD;
&#xD;
         11. Presence of an active acute or chronic infection, including symptomatic urinary tract&#xD;
             infection, HIV (as determined by ELISA and confirmed by Western Blot) or viral&#xD;
             hepatitis (as determined by HBsAg and Hepatitis C serology)&#xD;
&#xD;
         12. Patient is pregnant or is currently breast-feeding&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marian Vanhoeij, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitair Ziekenhuis Brussel</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>UZ Brussel</last_name>
    <phone>+32 2 477 6015</phone>
    <email>borstkliniek@uzbrussel.be</email>
  </overall_contact>
  <location>
    <facility>
      <name>UZ Brussel</name>
      <address>
        <city>Jette</city>
        <state>Brussel</state>
        <zip>1090</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>UZ Brussel</last_name>
      <phone>+32 2 477 6015</phone>
      <email>borstkliniek@uzbrussel.be</email>
    </contact>
    <investigator>
      <last_name>Marian Vanhoeij, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>November 16, 2018</study_first_submitted>
  <study_first_submitted_qc>December 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 27, 2018</study_first_posted>
  <last_update_submitted>May 18, 2022</last_update_submitted>
  <last_update_submitted_qc>May 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 19, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>immune therapy</keyword>
  <keyword>dendritic cells</keyword>
  <keyword>immune priming</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <pending_results>
    <submitted>March 22, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03788083
org study id: TriMix-Breast
nct id: NCT03788083
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Patients with early breast cancer and accessible tumor lesions (1.00 to 10 ml volume) that
      are eligible to either surgical removal of their tumor or neoadjuvant chemotherapy will be
      injected with the IMP. Patients will be either treated with placebo (buffer alone, 12
      patients) or with TriMix mRNA at three dose levels [8 at dose level I (1mg/ml), 8 at dose
      level II (3mg/ml), and 8 at dose level III (6mg/ml). The volume injected in this group will
      be adjusted to the tumour volume to ensure a perfusion of around 33% of the tumour volume
      (33% +/- 5%). Therefore, depending on the patients' tumour size, 500, 1000 or 2000 µl of
      TriMix mRNA solution or placebo solution will be injected into each tumor. Each patient will
      receive three administrations of TriMix prior to start of general treatment (surgery or
      neoadjuvant chemotherapy) separated by one week (7 days +/- 2 days) interval. The last
      administration will be performed 2 days preoperatively or start of neoadjuvant chemotherapy.

      The tumor and peripheral blood samples will be analyzed for immunological changes. If it is
      decided by the multidisciplinary team that neoadjuvant therapy is more appropriate for the
      patient, a second tumor biopsy (instead of surgical resection) will be taken 2 days after
      third administration of TriMix mRNA to assess immunological changes within the tumor.
      Similarly, patients that refuses to undergo surgery or to receive neoadjuvant chemotherapy
      can be enrolled into the trial, if they accept three administrations of TriMix followed by a
      second tumor biopsy.

      The study will start with recruitment of the placebo group. The enrollment of the first three
      patients in each cohort with Trimix mRNA will be staggered with at least one day between the
      first dose of each individual patient. One week after the third patient of a cohort received
      the third TriMix mRNA administration, an overall evaluation of the safety and tolerability of
      this cohort will be done by the principal investigator. The results will be reviewed by an
      in-house dose evaluation committee overseeing the safety and tolerability of TriMix mRNA.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Single (Participant)
masking description: Subjects will not know whether an active or non-active substance is being injected. The choice for TriMix or placebo will take place according to the predefined schedule and can not be influenced by the patient or the investigator. Only after the comparison of the tumour tissue before (the initial biopsy where the diagnosis was made) and after (obtained at second biopsy or surgery) the intratumoral injection, it will be known whether mRNA or non-active product was used for the injection.
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
time frame: 2 years
description: Number of patients with adverse events, total number of adverse events, dose limiting toxicities
measure: Tumor microenvironment changes induced by intratumoral TriMix mRNA
time frame: 30 days
description: Tumor microenvironment changes induced by intratumoral TriMix mRNA administration from diagnostic biopsy to day 21 (visit 5) assessed by immunohistochemistry.
measure: Tumor microenvironment changes induced by intratumoral TriMix mRNA
time frame: 30 days
description: Tumor microenvironment changes induced by intratumoral TriMix mRNA administration from diagnostic biopsy to day 21 (visit 5) assessed by nanoString gene profiling
measure: TriMix mRNA induced T-cell responses
time frame: 30 days
description: TriMix mRNA induced T-cell responses assessed by immunoassays in situ and in peripheral blood
arm group label: placebo
arm group type: Placebo Comparator
arm group label: TriMix
arm group type: Active Comparator
intervention type: Drug
intervention name: Trimix
description: Intratumoral TriMix injection
arm group label: TriMix
intervention type: Drug
intervention name: Placebo
description: Intratumoral placebo injection
arm group label: placebo
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Marian Vanhoeij, MD
role: Principal Investigator
affiliation: Universitair Ziekenhuis Brussel
last name: UZ Brussel
phone: +32 2 477 6015
email: borstkliniek@uzbrussel.be
facility: 
status: Recruiting
contact: 
investigator: 
country: Belgium
responsible party type: Sponsor
mesh term: Breast Neoplasms
submitted: March 22, 2023