<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/NCT04417166</url>
  </required_header>
  <id_info>
    <org_study_id>IELSG50</org_study_id>
    <nct_id>NCT04417166</nct_id>
  </id_info>
  <brief_title>Pembrolizumab and Radiotherapy for Patients With NK/T Cell Lymphoma</brief_title>
  <official_title>Pembrolizumab and Radiotherapy for Previously Untreated Patients With Limited Stage NK/T Cell Lymphoma Who Are Not Eligible to Chemotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>International Extranodal Lymphoma Study Group (IELSG)</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>International Extranodal Lymphoma Study Group (IELSG)</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>
      Aim of the trial is to evaluate the activity and tolerability of the anti PD1 agent&#xD;
      Pembrolizumab in combination with RadioTherapy for the initial treatment of previously&#xD;
      untreated patients with limited stage NK/T cell lymphoma who are not eligible to&#xD;
      chemotherapy.&#xD;
&#xD;
      It is planned to enroll 30 patients in chinese sites.&#xD;
&#xD;
      All eligible patients will be treated with standard radiotherapy and concurrent pembrolizumab&#xD;
      administered intravenously every 3 weeks. After 6 cycles of pembrolizumab patients with&#xD;
      complete remission, partial response and stable disease will continue with pembrolizumab&#xD;
      maintenance up to 2 years.&#xD;
&#xD;
      Patients will be followed up to 4 years from treatment start.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an interventional, phase II, open label, single arm, multicentric clinical trial to&#xD;
      be conducted in China.&#xD;
&#xD;
      The primary objective is to test the efficacy of concurrent RT-Pembrolizumab in patients with&#xD;
      limited stage NK/T cell lymphoma and who are not eligible to receive chemotherapy.&#xD;
&#xD;
      The secondary objectives are to further explore the efficacy and safety of a the combination&#xD;
      of RT and Pembrolizumab as initial treatment of the patients population.&#xD;
&#xD;
      All eligible patients will be treated with standard IFRT and concurrent pembrolizumab&#xD;
      administered intravenously, over 30 minutes starting on day 1 of RT (C1D1, at the dose of 200&#xD;
      mg, every 3 weeks). After 6 cycles of pembrolizumab patients will undergo restaging imaging.&#xD;
      Patients with complete remission (CR), partial response (PR) and stable disease (SD) will&#xD;
      continue with pembrolizumab maintenance up to 2 years that will be administered&#xD;
      intravenously, at the dose of 200 mg, over 30 minutes on day 1 every 3 weeks up to 34 cycles.&#xD;
&#xD;
      The follow-up period will last up to 4 years from treatment start.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 11, 2022</start_date>
  <completion_date type="Anticipated">December 2026</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <phase>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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival (PFS) rate at 2 years - The proportion of patients without disease progression after 2 years from treatment start</measure>
    <time_frame>2 years from treatment start</time_frame>
    <description>Response will be assessed using international criteria for response assessment in lymphomas (Cheson 2014) and their update for patients receiving checkpoint inhibitors (Cheson 2016 Lyric)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Complete remission rate (CRR) - Proportion of patients with complete responses</measure>
    <time_frame>After 4 months from treatment start (End of Induction phase), Maintenance Phase:every 4 months during the first year and then every 6 months until end of treatment. Follow up: every 4 months during first year, then every 6 months during second year</time_frame>
    <description>CRR defined according to Cheson 2014 criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>2-year Event-free survival - Proportion of patient without disease related events after 2 years from treatment start</measure>
    <time_frame>2 years from treatment start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment related mortality - Number of treatment related deaths</measure>
    <time_frame>From informed consent signature to 90 days after the last study treatment administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>2-year Overall survival - Proportion of patients alive after 2 years from treatment start</measure>
    <time_frame>2 years from treatment start</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of adverse events - Analysis of incidence, severity and relationship of adverse events</measure>
    <time_frame>From Informed Consent signature to 30 days for AEs or 90 for SAEs after end of treatment</time_frame>
    <description>Adverse Events severity will be classified according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) V. 5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR) - calculated as the sum of the complete and partial remission rates</measure>
    <time_frame>After 4 months from treatment start (End of Induction phase) Maintenance Phase: every 4 months during the first year and then every 6 months until end of treatment. Follow up: every 4 months during first year, then every 6 months during second year</time_frame>
    <description>ORR defined according to Cheson 2014 criteria</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Lymphoma, Extranodal NK-T-Cell</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab and Radiotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Induction Phase:&#xD;
Standard Involved Field Radiation Therapy (IFRT) and pembrolizumab. Pembrolizumab 200 mg IV will be given over 30 minutes on day 1 of each 21 day cycle for a total of 6 cycles. IFRT will start at first cycle of Pembrolizumab and will be delivered concurrently.&#xD;
Patients with complete remission (CR), partial response (PR) and stable disease (SD) after Induction Phase will continue with pembrolizumab maintenance.&#xD;
Maintenance Phase:&#xD;
Pembrolizumab 200 mg IV will be given over 30 minutes on day 1 of each 21 day cycle up to 34 cycles or until disease progression or unaccepted toxicity</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>50 mg powder for concentrate for solution for infusion</description>
    <arm_group_label>Pembrolizumab and Radiotherapy</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Involved Field Radiation Therapy</intervention_name>
    <description>50-54 Gy Involved Field Radiation Therapy (IFRT) as proposed by the International Lymphoma Radiation Oncology Group (ILROG) guidelines. 50 Gy is recommended in patients without primary tumor invasiveness (invasion to adjacent tissue and/or organs), 54 Gy in locally advanced cases (invasion to adjacent tissue and/or organs) or with other risk factors (age &gt; 60 years, stage II, elevated serum LDH levels).&#xD;
Intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) are recommended but not mandatory; 3-dimensional conformal RT (3D-CRT) is allowed.</description>
    <arm_group_label>Pembrolizumab and Radiotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed histological diagnosis of NK/T Cell Lymphoma&#xD;
&#xD;
          -  No previous anti-lymphoma treatment&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Ann Arbor stage I-II&#xD;
&#xD;
          -  At least one measurable/evaluable site after diagnostic biopsy before treatment start&#xD;
&#xD;
          -  At least one of the following high-risk features: age &gt; 60 years, elevated LDH, stage&#xD;
             II, primary tumor invasion&#xD;
&#xD;
          -  Patient ineligible to receive full dose standard chemotherapy&#xD;
&#xD;
          -  ECOG performance status of 0-1&#xD;
&#xD;
          -  Signed Informed consent&#xD;
&#xD;
          -  Ability to comply with the protocol&#xD;
&#xD;
          -  Adequate hematological and organ function;&#xD;
&#xD;
          -  Tumor tissue (fresh preferred, archival tissue is also acceptable)&#xD;
&#xD;
          -  For women of childbearing potential a negative pregnancy test on day 1 of cycle 1 and&#xD;
             agree to adopt an adequate measure to avoid pregnancy during study treatment and for&#xD;
             at least one year from end of treatment&#xD;
&#xD;
          -  For men agreement to remain abstinent or to use barrier contraception&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Advanced stage disease (AA stage III-IV)&#xD;
&#xD;
          -  Extranasal type NKTCL&#xD;
&#xD;
          -  History of autoimmune disease&#xD;
&#xD;
          -  History of other(s) infiltrating cancer(s) in the previous 3 years that were not&#xD;
             treated with curative intent or who are still receiving anticancer therapy (including&#xD;
             hormone therapy for breast or prostate cancer).&#xD;
&#xD;
          -  History of (non-infectious) pneumonitis that required steroids; evidence of&#xD;
             interstitial lung disease or active, non-infectious pneumonitis&#xD;
&#xD;
          -  Active infection requiring systemic therapy&#xD;
&#xD;
          -  Significant cardiovascular disease, myocardial infarction in the previous 3 months,&#xD;
             unstable arrhythmias, or unstable angina.&#xD;
&#xD;
          -  Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent&#xD;
&#xD;
          -  HBsAg, HCV or HIV positivity. Positive serology is admitted for HBV and HCV but&#xD;
             DNA/RNA test must be negative&#xD;
&#xD;
          -  Administration of a live attenuated vaccine within 4 weeks before cyle 1 day 1.&#xD;
             Patients must not receive live, attenuate vaccines, including influenza vaccines at&#xD;
             any time during study.&#xD;
&#xD;
          -  Treatment with systemic immunosuppressive medications, including prednisone,&#xD;
             cyclophosphamide, azathioprine, methotrexate, thalidomide and anti tumor necrosis&#xD;
             factor (anti-TNF) agents within 2 weeks prior to cycle 1 day 1; inhaled&#xD;
             corticosteroids are allowed.&#xD;
&#xD;
          -  Evidence of suspect of CNS disease&#xD;
&#xD;
          -  Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid reactions&#xD;
             to the compound Pembrolizumab itself or to the excipients in its formulation).&#xD;
&#xD;
          -  Has had an allogenic tissue/solid organ transplant&#xD;
&#xD;
          -  Known history of active TB (Bacillus Tuberculosis)&#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>Stefano Luminari, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Ematologia, AUSL IRCCS Reggio Emilia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Weili Zhao, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Shanghai Rui Jin Hospital,Shanghai Jiao Tong University - School of Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Emanuele Zucca, MD</last_name>
    <phone>+41 58 666</phone>
    <phone_ext>7321</phone_ext>
    <email>ielsg@ior.usi.ch</email>
  </overall_contact>
  <location>
    <facility>
      <name>Shanghai Rui-Jin Hospital</name>
      <address>
        <city>Shanghai</city>
        <zip>200025</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Weili Zhao, MD, PhD</last_name>
      <email>zhao.weili@yahoo.com</email>
    </contact>
    <investigator>
      <last_name>Weili Zhao, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>June 2, 2020</study_first_submitted>
  <study_first_submitted_qc>June 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>May 19, 2023</last_update_submitted>
  <last_update_submitted_qc>May 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 22, 2023</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>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, T-Cell</mesh_term>
    <mesh_term>Lymphoma, Extranodal NK-T-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</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/NCT04417166
org study id: IELSG50
nct id: NCT04417166
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Aim of the trial is to evaluate the activity and tolerability of the anti PD1 agent
      Pembrolizumab in combination with RadioTherapy for the initial treatment of previously
      untreated patients with limited stage NK/T cell lymphoma who are not eligible to
      chemotherapy.

      It is planned to enroll 30 patients in chinese sites.

      All eligible patients will be treated with standard radiotherapy and concurrent pembrolizumab
      administered intravenously every 3 weeks. After 6 cycles of pembrolizumab patients with
      complete remission, partial response and stable disease will continue with pembrolizumab
      maintenance up to 2 years.

      Patients will be followed up to 4 years from treatment start.
This is an interventional, phase II, open label, single arm, multicentric clinical trial to
      be conducted in China.

      The primary objective is to test the efficacy of concurrent RT-Pembrolizumab in patients with
      limited stage NK/T cell lymphoma and who are not eligible to receive chemotherapy.

      The secondary objectives are to further explore the efficacy and safety of a the combination
      of RT and Pembrolizumab as initial treatment of the patients population.

      All eligible patients will be treated with standard IFRT and concurrent pembrolizumab
      administered intravenously, over 30 minutes starting on day 1 of RT (C1D1, at the dose of 200
      mg, every 3 weeks). After 6 cycles of pembrolizumab patients will undergo restaging imaging.
      Patients with complete remission (CR), partial response (PR) and stable disease (SD) will
      continue with pembrolizumab maintenance up to 2 years that will be administered
      intravenously, at the dose of 200 mg, over 30 minutes on day 1 every 3 weeks up to 34 cycles.

      The follow-up period will last up to 4 years from treatment start.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival (PFS) rate at 2 years - The proportion of patients without disease progression after 2 years from treatment start
time frame: 2 years from treatment start
description: Response will be assessed using international criteria for response assessment in lymphomas (Cheson 2014) and their update for patients receiving checkpoint inhibitors (Cheson 2016 Lyric)
measure: Complete remission rate (CRR) - Proportion of patients with complete responses
time frame: After 4 months from treatment start (End of Induction phase), Maintenance Phase:every 4 months during the first year and then every 6 months until end of treatment. Follow up: every 4 months during first year, then every 6 months during second year
description: CRR defined according to Cheson 2014 criteria
measure: 2-year Event-free survival - Proportion of patient without disease related events after 2 years from treatment start
time frame: 2 years from treatment start
measure: Treatment related mortality - Number of treatment related deaths
time frame: From informed consent signature to 90 days after the last study treatment administration
measure: 2-year Overall survival - Proportion of patients alive after 2 years from treatment start
time frame: 2 years from treatment start
measure: Rate of adverse events - Analysis of incidence, severity and relationship of adverse events
time frame: From Informed Consent signature to 30 days for AEs or 90 for SAEs after end of treatment
description: Adverse Events severity will be classified according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) V. 5.0
measure: Overall Response Rate (ORR) - calculated as the sum of the complete and partial remission rates
time frame: After 4 months from treatment start (End of Induction phase) Maintenance Phase: every 4 months during the first year and then every 6 months until end of treatment. Follow up: every 4 months during first year, then every 6 months during second year
description: ORR defined according to Cheson 2014 criteria
arm group label: Pembrolizumab and Radiotherapy
arm group type: Experimental
description: Induction Phase:
Standard Involved Field Radiation Therapy (IFRT) and pembrolizumab. Pembrolizumab 200 mg IV will be given over 30 minutes on day 1 of each 21 day cycle for a total of 6 cycles. IFRT will start at first cycle of Pembrolizumab and will be delivered concurrently.
Patients with complete remission (CR), partial response (PR) and stable disease (SD) after Induction Phase will continue with pembrolizumab maintenance.
Maintenance Phase:
Pembrolizumab 200 mg IV will be given over 30 minutes on day 1 of each 21 day cycle up to 34 cycles or until disease progression or unaccepted toxicity
intervention type: Drug
intervention name: Pembrolizumab
description: 50 mg powder for concentrate for solution for infusion
arm group label: Pembrolizumab and Radiotherapy
other name: Keytruda
intervention type: Radiation
intervention name: Involved Field Radiation Therapy
description: 50-54 Gy Involved Field Radiation Therapy (IFRT) as proposed by the International Lymphoma Radiation Oncology Group (ILROG) guidelines. 50 Gy is recommended in patients without primary tumor invasiveness (invasion to adjacent tissue and/or organs), 54 Gy in locally advanced cases (invasion to adjacent tissue and/or organs) or with other risk factors (age > 60 years, stage II, elevated serum LDH levels).
Intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) are recommended but not mandatory; 3-dimensional conformal RT (3D-CRT) is allowed.
arm group label: Pembrolizumab and Radiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Stefano Luminari, MD
role: Study Chair
affiliation: Ematologia, AUSL IRCCS Reggio Emilia
last name: Weili Zhao, MD
role: Study Chair
affiliation: Shanghai Rui Jin Hospital,Shanghai Jiao Tong University - School of Medicine
last name: Emanuele Zucca, MD
phone: +41 58 666
phone ext: 7321
email: ielsg@ior.usi.ch
facility: 
status: Recruiting
contact: 
investigator: 
country: China
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, T-Cell
mesh term: Lymphoma, Extranodal NK-T-Cell
mesh term: Pembrolizumab