<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/NCT03242603</url>
  </required_header>
  <id_info>
    <org_study_id>NKEXPGD2</org_study_id>
    <nct_id>NCT03242603</nct_id>
  </id_info>
  <brief_title>Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells</brief_title>
  <acronym>NKEXPGD2</acronym>
  <official_title>Pilot Study of Anti-GD2 and Expanded, Activated Natural Killer Cell Infusion for Neuroblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National University Hospital, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National University Hospital, Singapore</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>
      Neuroblastoma is a neoplasm of the sympathetic nervous system which affects mostly children&#xD;
      younger than 5 years of age. It is a heterogeneous disease, with nearly 50% of patients&#xD;
      presenting with a high-risk phenotype. After standard treatment, the 2-year event-free&#xD;
      survival (EFS) for high risk neuroblastoma (EFS) is only about 50%. Immunotherapy with&#xD;
      anti-GD2 antibodies has been shown to improve EFS in Children's Oncology Group and SIOPEN&#xD;
      trials.&#xD;
&#xD;
      The anti-GD2 antibody mediates neuroblastoma cell killing primarily through&#xD;
      antibody-dependent cell-mediated cytotoxicity (ADCC). Natural killer (NK) cells are the main&#xD;
      effectors of ADCC. We postulate that infusion of expanded activated NK cells from healthy&#xD;
      haploidentical donors along with anti-GD2 antibody will enhance neuroblastoma killing.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Adoptive transfer of haploidentical NK cells has been shown to be safe in clinical trials at&#xD;
      NUH. There is experience combining antibody infusion with autologous NK cells in the clinical&#xD;
      trial with good safety data.&#xD;
&#xD;
      The proposed trial is a phase I/II study to determine the safety and efficacy of expanded&#xD;
      activated haploidentical NK cells in combination with anti-GD2 (ch14.18/CHO). We plan to&#xD;
      enrol patients with high risk or relapsed neuroblastoma with evidence of residual disease who&#xD;
      are at high risk of recurrence or progression on current treatment.&#xD;
&#xD;
      In the proposed protocol , we plan to infuse NK cells at escalating dose levels to find the&#xD;
      optimum dose tolerated by the patients in combination with anti-GD2 (ch14.18/CHO) . There are&#xD;
      3 NK cell dose levels :&#xD;
&#xD;
      Dose level 1 (1 x 10^6/kg) , Dose level 2 (1 x 10^7/kg) , Dose level 3 (1 x 10^8/kg)&#xD;
&#xD;
      If a partial response or stable disease is observed, further infusions of NK cells can be&#xD;
      administered. There will be intra- and inter - patient dose escalation.&#xD;
&#xD;
      The donor will be either parent, based on the best NK cell donor as determined by the study&#xD;
      team. The donor will be harvested and NK cells expanded prior to infusion into the patient&#xD;
      along with anti-GD2 (ch14.18/CHO).&#xD;
&#xD;
      The study aims to study safety and efficacy of a combination of NK cells and anti-GD2&#xD;
      (ch14.18/CHO).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 3, 2017</start_date>
  <completion_date type="Anticipated">August 15, 2020</completion_date>
  <primary_completion_date type="Anticipated">August 15, 2019</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>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>To determine the feasibility, safety and effectiveness of anti-GD2 in combination with expanded, activated NK cells in research participants with Neuroblastoma</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To measure tumor response after infusion of expanded activated haploidentical NK cells with anti-GD2. Response will be assessed as defined by Revised International Neuroblastoma Response Criteria 2017.</measure>
    <time_frame>2 years</time_frame>
    <description>Disease status at primary and metastatic soft tissue sites will be assessed using MIBG scans or PET scan as applicable. RECIST and Curie scoring systems will be used to assess response. Metastatic bone disease will be assessed using MIBG or PET scan. Bone marrow will be assessed by histology or flow cytometry. Disease response will be defined as Complete response/remission (CR), Partial response (PR), Minor response, Stable disease (SD), or Progressive disease(PD).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To measure the numbers of infused NK cells in peripheral blood at specific time-points after NK cell infusion</measure>
    <time_frame>2 years</time_frame>
    <description>NK cells will be identified by flow cytometry in peripheral blood and their percentages and absolute numbers will be calculated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To measure cytokine levels in plasma at specific time-points after NK cell infusion</measure>
    <time_frame>2 years</time_frame>
    <description>Cytokine panel to assess levels of IL15 serially post lymphodepletion regimen</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">5</enrollment>
  <condition>Neuroblastoma Recurrent</condition>
  <arm_group>
    <arm_group_label>Anti-GD2 in combination with NK cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a single arm study. Patients with high risk neuroblastoma who have residual measurable disease will receive a combination of 5 days of anti-GD2 with expanded activated NK cells.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Anti-GD2 in combination with NK cells</intervention_name>
    <description>Haploidentical donor NK cells will be expanded over 10 days and infused in combination with anti-GD2. Anti-GD2 will be given as daily infusion for 5 days ; D-1, 0,+1, +2 and +3. NK cells will be infused at single dose on day 0. The patient will receive cyclophosphamide 60mg/kg on day -3 and day -2 prior to the NK cell infusion. IL- 2 will be given subcutaneously for 6 doses every alternate day starting on day -1, for NK cell survival.</description>
    <arm_group_label>Anti-GD2 in combination with NK cells</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        -&#xD;
&#xD;
        A) Inclusion criteria for activated NK cell Recipient:&#xD;
&#xD;
          1. Age 6 months to 25 years old.&#xD;
&#xD;
          2. Patients with high risk or relapsed neuroblastoma who have measurable residual disease&#xD;
             (based on imaging findings with Curie scoring or MIBG or PET imaging criteria) after&#xD;
             receiving or has refused to receive standard therapy.&#xD;
&#xD;
               1. High risk will be defined as stage IV disease with poor response to chemotherapy.&#xD;
                  Residual disease after surgery or prior to autologous stem cell rescue which is&#xD;
                  part of Standard of Care. Infants with nMYC amplification will not automatically&#xD;
                  qualify for the protocol unless they have residual disease after surgery.&#xD;
&#xD;
               2. Recurrence after completion of standard treatment.&#xD;
&#xD;
          3. Shortening fraction greater than or equal to 25% or Left ventricular ejection fraction&#xD;
             (LVEF) greater than or equal to 40%.&#xD;
&#xD;
          4. Glomerular filtration rate greater than or equal to 60 ml/min/1.73 m2.&#xD;
&#xD;
          5. Pulse oximetry greater than or equal to 92% on room air.&#xD;
&#xD;
          6. Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L).&#xD;
&#xD;
          7. Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal.&#xD;
&#xD;
          8. Aspartate transaminases (AST) is no more than 2 times the upper limit of normal.&#xD;
&#xD;
          9. Karnofsky or Lansky performance score of greater than or equal to 50.&#xD;
&#xD;
         10. Does not have a current pleural or pericardial effusion.&#xD;
&#xD;
         11. Has a suitable adult family member donor available for NK cell donation.&#xD;
&#xD;
         12. Has recovered from all acute NCI Common Terminology Criteria for Adverse Events&#xD;
             (CTCAE) grade II-IV non-hematologic acute toxicities resulting from prior therapy per&#xD;
             the judgment of the PI.&#xD;
&#xD;
         13. At least two weeks since receipt of any biological therapy, systemic chemotherapy,&#xD;
             and/or radiation therapy.&#xD;
&#xD;
         14. Is not receiving more than the equivalent of prednisone 10 mg daily.&#xD;
&#xD;
         15. Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days&#xD;
             prior to enrollment).&#xD;
&#xD;
         16. Not lactating.&#xD;
&#xD;
        B) Inclusion criteria for NK cell Donor:&#xD;
&#xD;
          1. First and second degree relative acceptable.&#xD;
&#xD;
          2. 18 years of age or above.&#xD;
&#xD;
          3. Not lactating.&#xD;
&#xD;
          4. Greater than or equal to 3 of 6 HLA match to recipient.&#xD;
&#xD;
          5. .Meets eligibility and suitability criteria for hematopoietic cells donation as per&#xD;
             institutional guidelines.&#xD;
&#xD;
          6. Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days&#xD;
             prior to enrollment).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Failure to meet any of the above criteria&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>25 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Miriam Kimpo, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National University Hospital, Singapore</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Dario Campana, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National University Singapore, Singapore</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Miriam Kimpo, MD</last_name>
    <phone>+65 8494 3914</phone>
    <email>miriam_kimpo@nuhs.edu.sg</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Chetan Dhamne, MBBS, MS, MD</last_name>
    <phone>+65 6772 3361</phone>
    <email>chetan_dhamne@nuhs.edu.sg</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National University Hospital</name>
      <address>
        <city>Singapore</city>
        <zip>119074</zip>
        <country>Singapore</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Miriam Kimpo, MD</last_name>
      <phone>(+65) 8494 3914</phone>
      <email>miriam_kimpo@nuhs.edu.sg</email>
    </contact>
    <contact_backup>
      <last_name>Chetan Dhamne, MBBS, MS, MD</last_name>
      <phone>(+65) 6772 3361</phone>
      <email>chetan_dhamne@nuhs.edu.sg</email>
    </contact_backup>
    <investigator>
      <last_name>Dr. Miriam Kimpo, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Dr.Chetan Dhamne, MBBS, MS. MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <reference>
    <citation>Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.</citation>
    <PMID>20879881</PMID>
  </reference>
  <reference>
    <citation>Cho D, Shook DR, Shimasaki N, Chang YH, Fujisaki H, Campana D. Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res. 2010 Aug 1;16(15):3901-9. doi: 10.1158/1078-0432.CCR-10-0735. Epub 2010 Jun 11.</citation>
    <PMID>20542985</PMID>
  </reference>
  <reference>
    <citation>Tarek N, Le Luduec JB, Gallagher MM, Zheng J, Venstrom JM, Chamberlain E, Modak S, Heller G, Dupont B, Cheung NK, Hsu KC. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J Clin Invest. 2012 Sep;122(9):3260-70. doi: 10.1172/JCI62749. Epub 2012 Aug 6.</citation>
    <PMID>22863621</PMID>
  </reference>
  <verification_date>June 2017</verification_date>
  <study_first_submitted>July 13, 2017</study_first_submitted>
  <study_first_submitted_qc>August 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 8, 2017</study_first_posted>
  <last_update_submitted>March 28, 2018</last_update_submitted>
  <last_update_submitted_qc>March 28, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Relapsed, Refractory, Neuroblastoma</keyword>
  <keyword>Anti-GD2</keyword>
  <keyword>Natural Killer (NK) Cells</keyword>
  <keyword>Immunotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroblastoma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>TBC</ipd_description>
  </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/NCT03242603
org study id: NKEXPGD2
nct id: NCT03242603
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Neuroblastoma is a neoplasm of the sympathetic nervous system which affects mostly children
      younger than 5 years of age. It is a heterogeneous disease, with nearly 50% of patients
      presenting with a high-risk phenotype. After standard treatment, the 2-year event-free
      survival (EFS) for high risk neuroblastoma (EFS) is only about 50%. Immunotherapy with
      anti-GD2 antibodies has been shown to improve EFS in Children's Oncology Group and SIOPEN
      trials.

      The anti-GD2 antibody mediates neuroblastoma cell killing primarily through
      antibody-dependent cell-mediated cytotoxicity (ADCC). Natural killer (NK) cells are the main
      effectors of ADCC. We postulate that infusion of expanded activated NK cells from healthy
      haploidentical donors along with anti-GD2 antibody will enhance neuroblastoma killing.
Adoptive transfer of haploidentical NK cells has been shown to be safe in clinical trials at
      NUH. There is experience combining antibody infusion with autologous NK cells in the clinical
      trial with good safety data.

      The proposed trial is a phase I/II study to determine the safety and efficacy of expanded
      activated haploidentical NK cells in combination with anti-GD2 (ch14.18/CHO). We plan to
      enrol patients with high risk or relapsed neuroblastoma with evidence of residual disease who
      are at high risk of recurrence or progression on current treatment.

      In the proposed protocol , we plan to infuse NK cells at escalating dose levels to find the
      optimum dose tolerated by the patients in combination with anti-GD2 (ch14.18/CHO) . There are
      3 NK cell dose levels :

      Dose level 1 (1 x 10^6/kg) , Dose level 2 (1 x 10^7/kg) , Dose level 3 (1 x 10^8/kg)

      If a partial response or stable disease is observed, further infusions of NK cells can be
      administered. There will be intra- and inter - patient dose escalation.

      The donor will be either parent, based on the best NK cell donor as determined by the study
      team. The donor will be harvested and NK cells expanded prior to infusion into the patient
      along with anti-GD2 (ch14.18/CHO).

      The study aims to study safety and efficacy of a combination of NK cells and anti-GD2
      (ch14.18/CHO).
allocation: N/A
intervention model: Single Group Assignment
intervention model description: To determine the feasibility, safety and effectiveness of anti-GD2 in combination with expanded, activated NK cells in research participants with Neuroblastoma
primary purpose: Treatment
masking: None (Open Label)
measure: To measure tumor response after infusion of expanded activated haploidentical NK cells with anti-GD2. Response will be assessed as defined by Revised International Neuroblastoma Response Criteria 2017.
time frame: 2 years
description: Disease status at primary and metastatic soft tissue sites will be assessed using MIBG scans or PET scan as applicable. RECIST and Curie scoring systems will be used to assess response. Metastatic bone disease will be assessed using MIBG or PET scan. Bone marrow will be assessed by histology or flow cytometry. Disease response will be defined as Complete response/remission (CR), Partial response (PR), Minor response, Stable disease (SD), or Progressive disease(PD).
measure: To measure the numbers of infused NK cells in peripheral blood at specific time-points after NK cell infusion
time frame: 2 years
description: NK cells will be identified by flow cytometry in peripheral blood and their percentages and absolute numbers will be calculated.
measure: To measure cytokine levels in plasma at specific time-points after NK cell infusion
time frame: 2 years
description: Cytokine panel to assess levels of IL15 serially post lymphodepletion regimen
arm group label: Anti-GD2 in combination with NK cells
arm group type: Experimental
description: This is a single arm study. Patients with high risk neuroblastoma who have residual measurable disease will receive a combination of 5 days of anti-GD2 with expanded activated NK cells.
intervention type: Biological
intervention name: Anti-GD2 in combination with NK cells
description: Haploidentical donor NK cells will be expanded over 10 days and infused in combination with anti-GD2. Anti-GD2 will be given as daily infusion for 5 days ; D-1, 0,+1, +2 and +3. NK cells will be infused at single dose on day 0. The patient will receive cyclophosphamide 60mg/kg on day -3 and day -2 prior to the NK cell infusion. IL- 2 will be given subcutaneously for 6 doses every alternate day starting on day -1, for NK cell survival.
arm group label: Anti-GD2 in combination with NK cells
criteria: 
gender: All
minimum age: 6 Months
maximum age: 25 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Miriam Kimpo, MD
role: Principal Investigator
affiliation: National University Hospital, Singapore
last name: Dario Campana, MD, PhD
role: Principal Investigator
affiliation: National University Singapore, Singapore
last name: Miriam Kimpo, MD
phone: +65 8494 3914
email: miriam_kimpo@nuhs.edu.sg
last name: Chetan Dhamne, MBBS, MS, MD
phone: +65 6772 3361
email: chetan_dhamne@nuhs.edu.sg
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: Singapore
citation: Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.
PMID: 20879881
citation: Cho D, Shook DR, Shimasaki N, Chang YH, Fujisaki H, Campana D. Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res. 2010 Aug 1;16(15):3901-9. doi: 10.1158/1078-0432.CCR-10-0735. Epub 2010 Jun 11.
PMID: 20542985
citation: Tarek N, Le Luduec JB, Gallagher MM, Zheng J, Venstrom JM, Chamberlain E, Modak S, Heller G, Dupont B, Cheung NK, Hsu KC. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J Clin Invest. 2012 Sep;122(9):3260-70. doi: 10.1172/JCI62749. Epub 2012 Aug 6.
PMID: 22863621
responsible party type: Sponsor
mesh term: Neuroblastoma
sharing ipd: Undecided
ipd description: TBC