<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/NCT03837899</url>
  </required_header>
  <id_info>
    <org_study_id>D419EC00001</org_study_id>
    <secondary_id>2018-003118-42</secondary_id>
    <nct_id>NCT03837899</nct_id>
  </id_info>
  <brief_title>Durvalumab and Tremelimumab for Pediatric Malignancies</brief_title>
  <official_title>Phase I/II, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of Durvalumab Monotherapy or in Combination With Tremelimumab in Pediatric Patients With Advanced Solid Tumors and Hematological Malignancies.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AstraZeneca</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to determine the recommended dose of durvalumab and tremelimumab&#xD;
      (immunotherapy drugs) in pediatric patients with advanced solid and hematological cancers and&#xD;
      expand in a second phase to test the efficacy of these drugs once this dose is determined.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a first time in pediatrics study primarily designed to evaluate the safety and&#xD;
      tolerability of durvalumab and durvalumab in combination with tremelimumab at increasing&#xD;
      doses in pediatric patients with advanced solid malignancies and hematological malignancies&#xD;
      (including lymphomas) and for whom no standard of care treatments exist. Although treatment&#xD;
      efficacy is not a primary objective of this study given its early phase nature, the patients&#xD;
      screened for this study have no curative options and this study offers the potential of some&#xD;
      benefit.&#xD;
&#xD;
      The study will also characterize the PK of durvalumab and durvalumab in combination with&#xD;
      tremelimumab in children and adolescents and explore potential biological activity and&#xD;
      immunogenicity by assessing pharmacodynamics, anti drug antibody (ADA) levels, and anti-tumor&#xD;
      activity. The results from this trial will form the basis for decisions for potential future&#xD;
      pediatric studies&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 7, 2019</start_date>
  <completion_date type="Anticipated">December 29, 2023</completion_date>
  <primary_completion_date type="Actual">February 28, 2023</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose Finding phase: Recommended Phase 2 Dose</measure>
    <time_frame>15 months</time_frame>
    <description>Endpoints include adult equivalent dose for both durvalumab (administered as monotherapy and in combination) and for tremelimumab, to reflect the RP2D regimen dose for durvalumab monotherapy and for the combination treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety and Tolerability</measure>
    <time_frame>Up to 4 years.</time_frame>
    <description>Evaluated based on adverse events occurring throughout the study</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective Response Rate (dose expansion phase only)</measure>
    <time_frame>up to 4 years.</time_frame>
    <description>Number (%) of patients achieving complete or partial response according to RECIST 1.1. (solid tumors) and disease-specific response criteria.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) of Durvalumab and Tremelimumab</measure>
    <time_frame>15 months.</time_frame>
    <description>Serum concentrations of Durvalumab and Tremelimumab</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Pediatric Cancer</condition>
  <condition>Solid Tumor Pediatric</condition>
  <condition>Hematological Malignancies</condition>
  <arm_group>
    <arm_group_label>Durvalumab / Tremelimumab Combination Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part 1 (dose finding) Durvalumab + tremelimumab Combination Treatment. Durvalumab and tremelimumab are initially administered at dose level 1 and dose escalated based on results from PK modeling and tolerance to determine the RP2D. Both drugs are administered every 4 weeks as intravenous infusions. Tremelimumab is only administered with durvavalumab for 4 doses, from cycles 2-5. (sarcoma, NB and NHL)&#xD;
Part 2 (dose expansion phase) Durvalumab + tremelimumab Combination Treatment. Durvalumab and tremelimumab are administered at the RP2D, every 4 weeks as intravenous infusions. Tremelimumab is only administered with durvalumab for 4 doses, from cycles 1-4. Tremelimumab may be added for 4 doses at time of progressive disease. Cohorts: solid tumors, sarcomas, NHL restricted to PMBCL and ALCL subtypes)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab / Tremelimumab Combination Therapy</intervention_name>
    <description>Starting dose:&#xD;
durvalumab: 20mg/kg tremelimumab: 1mg/kg at cycles 2 to 5 only co-administered with durvalumab. The Recommended Phase 2 dose will be used for the dose expansion phase.</description>
    <arm_group_label>Durvalumab / Tremelimumab Combination Therapy</arm_group_label>
    <other_name>durvalumab: Imfinzi, MEDI4736</other_name>
    <other_name>tremelimumab: CP-675,206</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Max Age =17 years&#xD;
&#xD;
          -  Solid Tumors (except primary central nervous system malignant tumors): Patients must&#xD;
             have a histopathologic confirmation of malignancy. Patients must have progressed or&#xD;
             are refractory to standard therapies, and for whom no standard of care treatments&#xD;
             exist&#xD;
&#xD;
          -  Non-Hodgkin's Lymphoma, limited to primary mediastinal B-cell lymphoma and anaplastic&#xD;
             large cell lymphoma. Patients must have progressed or are refractory to standard&#xD;
             therapies, and for whom no standard of care treatments exist.&#xD;
&#xD;
          -  Provision of diagnostic tumor sample mandated if available&#xD;
&#xD;
          -  Evaluable disease&#xD;
&#xD;
          -  No prior exposure to immune-mediated therapy&#xD;
&#xD;
          -  Adequate organ and marrow function&#xD;
&#xD;
          -  Life expectancy of at least 3 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of allogeneic organ transplantation (exceptions may be allowed for NHL after&#xD;
             discussion with Sponsor). History of autologous bone marrow transplant may be allowed&#xD;
             (after discussion with Sponsor).&#xD;
&#xD;
          -  Active or prior documented autoimmune or inflammatory disorders (exceptions)&#xD;
&#xD;
          -  Uncontrolled intercurrent illness&#xD;
&#xD;
          -  History of primary immunodeficiency&#xD;
&#xD;
          -  Active infection including tuberculosis, hepatitis B, C or HIV&#xD;
&#xD;
          -  Any unresolved toxicity NCI CTCAE version 5.0 Grade ≥2 from previous anticancer&#xD;
             therapy (exceptions)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>0 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ashok Gupta, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>AstraZeneca Global Medicines Development, Academy House</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New Hyde Park</city>
        <state>New York</state>
        <zip>11040</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Lille Cedex</city>
        <zip>59020</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Marseille</city>
        <zip>13385</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Paris Cedex 05</city>
        <zip>75248</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Köln</city>
        <zip>50924</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Genova</city>
        <zip>16100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Milano</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Rome</city>
        <zip>00165</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Torino</city>
        <zip>10126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Utrecht</city>
        <zip>3584 CS</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Madrid</city>
        <zip>28009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Leeds</city>
        <zip>LS1 3EX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>London</city>
        <zip>WC1N 3JH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Sutton</city>
        <zip>SM2 5PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Spain</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>January 24, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>August 25, 2023</last_update_submitted>
  <last_update_submitted_qc>August 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 29, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pediatric, solid tumors, hematological malignancies, durvalumab, tremelimumab, immunotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Hematologic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
    <mesh_term>Tremelimumab</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure</ipd_time_frame>
    <ipd_access_criteria>When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure</ipd_access_criteria>
    <ipd_url>https://astrazenecagroup-dt.pharmacm.com/DT/Home</ipd_url>
  </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/NCT03837899
org study id: D419EC00001
secondary id: 2018-003118-42
nct id: NCT03837899
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of the study is to determine the recommended dose of durvalumab and tremelimumab
      (immunotherapy drugs) in pediatric patients with advanced solid and hematological cancers and
      expand in a second phase to test the efficacy of these drugs once this dose is determined.
This is a first time in pediatrics study primarily designed to evaluate the safety and
      tolerability of durvalumab and durvalumab in combination with tremelimumab at increasing
      doses in pediatric patients with advanced solid malignancies and hematological malignancies
      (including lymphomas) and for whom no standard of care treatments exist. Although treatment
      efficacy is not a primary objective of this study given its early phase nature, the patients
      screened for this study have no curative options and this study offers the potential of some
      benefit.

      The study will also characterize the PK of durvalumab and durvalumab in combination with
      tremelimumab in children and adolescents and explore potential biological activity and
      immunogenicity by assessing pharmacodynamics, anti drug antibody (ADA) levels, and anti-tumor
      activity. The results from this trial will form the basis for decisions for potential future
      pediatric studies
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose Finding phase: Recommended Phase 2 Dose
time frame: 15 months
description: Endpoints include adult equivalent dose for both durvalumab (administered as monotherapy and in combination) and for tremelimumab, to reflect the RP2D regimen dose for durvalumab monotherapy and for the combination treatment
measure: Safety and Tolerability
time frame: Up to 4 years.
description: Evaluated based on adverse events occurring throughout the study
measure: Objective Response Rate (dose expansion phase only)
time frame: up to 4 years.
description: Number (%) of patients achieving complete or partial response according to RECIST 1.1. (solid tumors) and disease-specific response criteria.
measure: Pharmacokinetics (PK) of Durvalumab and Tremelimumab
time frame: 15 months.
description: Serum concentrations of Durvalumab and Tremelimumab
arm group label: Durvalumab / Tremelimumab Combination Therapy
arm group type: Experimental
description: Part 1 (dose finding) Durvalumab + tremelimumab Combination Treatment. Durvalumab and tremelimumab are initially administered at dose level 1 and dose escalated based on results from PK modeling and tolerance to determine the RP2D. Both drugs are administered every 4 weeks as intravenous infusions. Tremelimumab is only administered with durvavalumab for 4 doses, from cycles 2-5. (sarcoma, NB and NHL)
Part 2 (dose expansion phase) Durvalumab + tremelimumab Combination Treatment. Durvalumab and tremelimumab are administered at the RP2D, every 4 weeks as intravenous infusions. Tremelimumab is only administered with durvalumab for 4 doses, from cycles 1-4. Tremelimumab may be added for 4 doses at time of progressive disease. Cohorts: solid tumors, sarcomas, NHL restricted to PMBCL and ALCL subtypes)
intervention type: Drug
intervention name: Durvalumab / Tremelimumab Combination Therapy
description: Starting dose:
durvalumab: 20mg/kg tremelimumab: 1mg/kg at cycles 2 to 5 only co-administered with durvalumab. The Recommended Phase 2 dose will be used for the dose expansion phase.
arm group label: Durvalumab / Tremelimumab Combination Therapy
other name: durvalumab: Imfinzi, MEDI4736
other name: tremelimumab: CP-675,206
criteria: 
gender: All
minimum age: 0 Years
maximum age: 18 Years
healthy volunteers: No
last name: Ashok Gupta, MD, PhD
role: Study Director
affiliation: AstraZeneca Global Medicines Development, Academy House
facility: 
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country: France
country: Germany
country: Italy
country: Netherlands
country: Spain
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Hematologic Neoplasms
mesh term: Durvalumab
mesh term: Tremelimumab
mesh term: Antibodies, Monoclonal
sharing ipd: Yes
ipd description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
ipd access criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
ipd url: https://astrazenecagroup-dt.pharmacm.com/DT/Home