<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/NCT03018405</url>
  </required_header>
  <id_info>
    <org_study_id>CYAD-N2T-002</org_study_id>
    <nct_id>NCT03018405</nct_id>
  </id_info>
  <brief_title>A Dose Escalation Phase I Study to Assess the Safety and Clinical Activity of Multiple Cancer Indications</brief_title>
  <acronym>THINK</acronym>
  <official_title>A Multi-national, Open-label, Dose Escalation Phase I Study to Assess the Safety and Clinical Activity of Multiple Administrations of NKR-2 in Patients With Different Metastatic Tumor Types (THINK - THerapeutic Immunotherapy With NKR-2)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Celyad Oncology SA</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Celyad Oncology SA</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      THINK (THerapeutic Immunotherapy with NKR-2) is a multinational (EU/US) open-label Phase I&#xD;
      study to assess the safety and clinical activity of multiple administrations of autologous&#xD;
      NKR-2 cells in seven refractory cancers, including five solid tumors (colorectal, ovarian,&#xD;
      bladder, triple-negative breast and pancreatic cancers) and two hematological tumors (acute&#xD;
      myeloid leukemia and multiple myeloma).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This open-label Phase I study aims at assessing the safety and clinical activity of the NKR-2&#xD;
      treatment administered 3 times with a 2-week interval between each administration in&#xD;
      different tumor types. In absence of progressive disease at the first tumor assessment&#xD;
      following NKR-2 administratio, the patient will receive a new cycle of 3 administrations&#xD;
      maximum with a 2-week interval. The study will contain two consecutive segments: a Phase I&#xD;
      dose escalation and a Phase I expansion segment.&#xD;
&#xD;
      The Phase I dose escalation segment will include 2 arms, one in solid tumors and one in&#xD;
      hematological tumors. The dose escalation design will include 3 dose levels: The dose&#xD;
      escalation phase will consist of 3 cohorts (Cohorts 1-3) for the solid tumors, and 3 cohorts&#xD;
      (Cohorts 4-6) for the hematological tumors; with each set of 3 cohorts receiving escalating&#xD;
      doses of the NKR-2 therapy.&#xD;
&#xD;
      Two additional cohorts will be added in each dose escalation arm with the aim to provide a&#xD;
      more intense treatment during the induction treatment. These additional cohorts in both the&#xD;
      solid arm (cohort 8-9 - only in CRC) and in the hematological arm of the study (cohort 10-11&#xD;
      - only in AML/MDS) will therefore evaluate a tighter schedule of NKR-2 injections with the&#xD;
      three first injections within the induction cycle separated by a 1-week interval followed two&#xD;
      weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2&#xD;
      injections. These cohorts will each enroll 3 patients in case of no DLT. Based on safety and&#xD;
      early clinical data from these cohorts, the specific schedule of cohorts 8-11 might be&#xD;
      selected for the expansion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">August 2021</completion_date>
  <primary_completion_date type="Anticipated">May 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>The maximum number of patients to be enrolled is 146:&#xD;
36 in the dose escalation segment (cohorts 1-6, 18 per arm),&#xD;
24 in the additional cohorts 8-11 (12 per arm),&#xD;
86 patients in the Phase I expansion segment (note that the analysis of this segment will also include a maximum of 12 additional patients from the dose escalation segment).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of NKR-2 infusion</measure>
    <time_frame>24 months</time_frame>
    <description>Safety defined by Occurrence of adverse events (AEs) and serious adverse events (SAEs) during the study treatment until 30 days after the last study treatment administration.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical activity of the treatment in each tumor type</measure>
    <time_frame>24 months</time_frame>
    <description>Clinical activity of the treatment in each tumor type</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">146</enrollment>
  <condition>Acute Myeloid Leukemia/Myelodysplastic Syndrome</condition>
  <condition>Multiple Myeloma (MM)</condition>
  <arm_group>
    <arm_group_label>Hematological tumors</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The dose escalation arm for hematological tumors will use a 3 +3 design to determine the maximum tolerated dose. Two additional cohorts will be added in this dose escalation arm with the aim to provide a more intense treatment during the induction treatment (cycle 1 of injection). Cohort 10-11 (only in AML/MDS) will evaluate a tighter schedule of NKR-2 injections at 1x109 or potentially 3x109 NKR-2 per injection with the three first injections within the induction cycle (cycle 1) separated by a 1-week interval followed two weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2 injections.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Solid Tumors</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The dose escalation arm for solid tumors will use a 3 +3 design to determine the maximum tolerated dose. Two additional cohorts will be added in this dose escalation arm with the aim to provide a more intense treatment during the induction treatment (cycle 1 of injection). Cohort cohort 8-9 ( only in CRC) will evaluate a tighter schedule of NKR-2 injections at 1x109 or potentially 3x109 NKR-2 per injection with the three first injections within the induction cycle (cycle 1) separated by a 1-week interval followed two weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2 injections.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>NKR-2 cells</intervention_name>
    <description>In cohorts 1-6, the schedule of administration will be 3 NKR-2 doses administered with a 2-week interval. In absence of progressive disease at the first tumor assessment following NKR-2 administration (on Visit D29 for hematological tumors or on Visit D57 for solid tumors), and according to product availability, the patient will receive a new cycle of 3 administrations maximum with a 2-week interval, at a dose of 1x109 NKR-2 cells per injection, or at the same dose of cycle 1 if it was below 1x109 NKR-2 cells.&#xD;
Patients in cohorts 8-9 (solid arm) and 10-11 (hematological arm) of first segment will receive 3 treatment doses at 1x109 NKR-2 (cohorts 8 and 10) or 3x109 NKR-2 (cohorts 9 and 11) per injection, with a 1-week interval between each dose. A second cycle of three NKR-2 injections at the same dose as in 1st cycle will be administered 2 weeks after the third NKR-2 injection, and with a 2-week interval between each dose.</description>
    <arm_group_label>Hematological tumors</arm_group_label>
    <arm_group_label>Solid Tumors</arm_group_label>
    <other_name>NKG2D-CAR construct</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Main inclusion criteria are:&#xD;
&#xD;
          -  Men or women ≥ 18 years old at the time of signing the ICF,&#xD;
&#xD;
          -  Patient with a CRC, epithelial ovarian cell or fallopian tube carcinoma, urothelial&#xD;
             carcinoma, TNBC, pancreatic cancer, AML/MDS or MM,&#xD;
&#xD;
          -  Disease must be measurable according to the corresponding guidelines,&#xD;
&#xD;
          -  Patient with an ECOG performance status 0 or 1, and AML patients with anemia resulting&#xD;
             in an ECOG performance status of 2,&#xD;
&#xD;
          -  Patient with adequate bone marrow reserve, hepatic and renal functions.&#xD;
&#xD;
          -  Patients must have sufficient pulmonary functions with a Forced Expiratory Volume in&#xD;
             the first second (FEV-1)/Forced Vital Capacity (FVC) ≥ 0.7 with FEV-1 ≥ 50% predicted.&#xD;
&#xD;
        Main exclusion criteria are:&#xD;
&#xD;
          -  Patient with a tumor metastasis in the central nervous system,&#xD;
&#xD;
          -  Patients who have received another cancer therapy within 2 weeks before the planned&#xD;
             day for the apheresis (except hydroxyurea for AML patients),&#xD;
&#xD;
          -  Patients who receive or are planned to receive any other investigational product&#xD;
             within the 3 weeks before the planned day for the first NKR-2 administration (except&#xD;
             hydroxyurea for AML patients),&#xD;
&#xD;
          -  Patient is under systemic immunosuppressive drugs, unless specific cases authorized&#xD;
             per protocol,&#xD;
&#xD;
          -  Patients who have received other cell therapies,&#xD;
&#xD;
          -  Patients who underwent major surgery within 4 weeks before the planned day for the&#xD;
             first NKR-2 administration.&#xD;
&#xD;
          -  Patient cannot present with history of idiopathic pulmonary fibrosis, organizing&#xD;
             pneumonia, drug-induced pneumonitis, idiopathic pneumonitis and/or active or acute&#xD;
             exacerbation of chronic obstructive pulmonary disease (COPD).&#xD;
&#xD;
        Detailed disease specific criteria exist and can be discussed with contacts listed below.&#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>Frédéric Lehmann, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Celyad Oncology SA</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Amélie Vanneste</last_name>
    <email>avanneste@celyad.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Anne Flament, MD</last_name>
    <email>aflament@celyad.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jeff Edelman</last_name>
      <phone>813-745-1040</phone>
      <email>Jeffrey.Edelman@moffitt.org</email>
    </contact>
  </location>
  <location>
    <facility>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14263</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amy Whitworth</last_name>
      <phone>877-275-7724</phone>
      <email>ASKRPCI@roswellpark.org</email>
    </contact>
  </location>
  <location>
    <facility>
      <address>
        <city>Brussels</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anne Moxhon</last_name>
      <phone>+32 2 764.42.17</phone>
      <email>anne.moxhon@uclouvain.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <address>
        <city>Brussels</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michel Dubuisson</last_name>
      <phone>+32 (0) 2 541 31 79</phone>
      <email>michel.dubuisson@bordet.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <address>
        <city>Ghent</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jonas Segaert</last_name>
      <phone>32 (0)9 332 4912</phone>
      <email>jonas.segaert@uzgent.be</email>
    </contact>
    <contact_backup>
      <last_name>Liesbeth Delanghe</last_name>
      <email>Liesbeth.delanghe@uzgent.be</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>January 10, 2017</study_first_submitted>
  <study_first_submitted_qc>January 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <last_update_submitted>September 18, 2019</last_update_submitted>
  <last_update_submitted_qc>September 18, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 19, 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>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>October 13, 2022</submitted>
    <returned>November 7, 2022</returned>
  </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/NCT03018405
org study id: CYAD-N2T-002
nct id: NCT03018405
lead sponsor: 
has dmc: Yes
THINK (THerapeutic Immunotherapy with NKR-2) is a multinational (EU/US) open-label Phase I
      study to assess the safety and clinical activity of multiple administrations of autologous
      NKR-2 cells in seven refractory cancers, including five solid tumors (colorectal, ovarian,
      bladder, triple-negative breast and pancreatic cancers) and two hematological tumors (acute
      myeloid leukemia and multiple myeloma).
This open-label Phase I study aims at assessing the safety and clinical activity of the NKR-2
      treatment administered 3 times with a 2-week interval between each administration in
      different tumor types. In absence of progressive disease at the first tumor assessment
      following NKR-2 administratio, the patient will receive a new cycle of 3 administrations
      maximum with a 2-week interval. The study will contain two consecutive segments: a Phase I
      dose escalation and a Phase I expansion segment.

      The Phase I dose escalation segment will include 2 arms, one in solid tumors and one in
      hematological tumors. The dose escalation design will include 3 dose levels: The dose
      escalation phase will consist of 3 cohorts (Cohorts 1-3) for the solid tumors, and 3 cohorts
      (Cohorts 4-6) for the hematological tumors; with each set of 3 cohorts receiving escalating
      doses of the NKR-2 therapy.

      Two additional cohorts will be added in each dose escalation arm with the aim to provide a
      more intense treatment during the induction treatment. These additional cohorts in both the
      solid arm (cohort 8-9 - only in CRC) and in the hematological arm of the study (cohort 10-11
      - only in AML/MDS) will therefore evaluate a tighter schedule of NKR-2 injections with the
      three first injections within the induction cycle separated by a 1-week interval followed two
      weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2
      injections. These cohorts will each enroll 3 patients in case of no DLT. Based on safety and
      early clinical data from these cohorts, the specific schedule of cohorts 8-11 might be
      selected for the expansion.
allocation: Non-Randomized
intervention model: Single Group Assignment
intervention model description: The maximum number of patients to be enrolled is 146:
36 in the dose escalation segment (cohorts 1-6, 18 per arm),
24 in the additional cohorts 8-11 (12 per arm),
86 patients in the Phase I expansion segment (note that the analysis of this segment will also include a maximum of 12 additional patients from the dose escalation segment).
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of NKR-2 infusion
time frame: 24 months
description: Safety defined by Occurrence of adverse events (AEs) and serious adverse events (SAEs) during the study treatment until 30 days after the last study treatment administration.
measure: Clinical activity of the treatment in each tumor type
time frame: 24 months
description: Clinical activity of the treatment in each tumor type
arm group label: Hematological tumors
arm group type: Experimental
description: The dose escalation arm for hematological tumors will use a 3 +3 design to determine the maximum tolerated dose. Two additional cohorts will be added in this dose escalation arm with the aim to provide a more intense treatment during the induction treatment (cycle 1 of injection). Cohort 10-11 (only in AML/MDS) will evaluate a tighter schedule of NKR-2 injections at 1x109 or potentially 3x109 NKR-2 per injection with the three first injections within the induction cycle (cycle 1) separated by a 1-week interval followed two weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2 injections.
arm group label: Solid Tumors
arm group type: Experimental
description: The dose escalation arm for solid tumors will use a 3 +3 design to determine the maximum tolerated dose. Two additional cohorts will be added in this dose escalation arm with the aim to provide a more intense treatment during the induction treatment (cycle 1 of injection). Cohort cohort 8-9 ( only in CRC) will evaluate a tighter schedule of NKR-2 injections at 1x109 or potentially 3x109 NKR-2 per injection with the three first injections within the induction cycle (cycle 1) separated by a 1-week interval followed two weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2 injections.
intervention type: Biological
intervention name: NKR-2 cells
description: In cohorts 1-6, the schedule of administration will be 3 NKR-2 doses administered with a 2-week interval. In absence of progressive disease at the first tumor assessment following NKR-2 administration (on Visit D29 for hematological tumors or on Visit D57 for solid tumors), and according to product availability, the patient will receive a new cycle of 3 administrations maximum with a 2-week interval, at a dose of 1x109 NKR-2 cells per injection, or at the same dose of cycle 1 if it was below 1x109 NKR-2 cells.
Patients in cohorts 8-9 (solid arm) and 10-11 (hematological arm) of first segment will receive 3 treatment doses at 1x109 NKR-2 (cohorts 8 and 10) or 3x109 NKR-2 (cohorts 9 and 11) per injection, with a 1-week interval between each dose. A second cycle of three NKR-2 injections at the same dose as in 1st cycle will be administered 2 weeks after the third NKR-2 injection, and with a 2-week interval between each dose.
arm group label: Hematological tumors
arm group label: Solid Tumors
other name: NKG2D-CAR construct
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Frédéric Lehmann, MD
role: Principal Investigator
affiliation: Celyad Oncology SA
last name: Amélie Vanneste
email: avanneste@celyad.com
last name: Anne Flament, MD
email: aflament@celyad.com
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
country: Belgium
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Myelodysplastic Syndromes
sharing ipd: No
submitted: October 13, 2022
returned: November 7, 2022