<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/NCT04432142</url>
  </required_header>
  <id_info>
    <org_study_id>IPON-1</org_study_id>
    <nct_id>NCT04432142</nct_id>
  </id_info>
  <brief_title>Immune Profiling of Stage III Non-small Cell Lung Cancer Patients Treated With Concurrent Chemoradiation and Adjuvant Durvalumab: A Prospective Observational Phase II Trial</brief_title>
  <acronym>IPON-1</acronym>
  <official_title>Immune Profiling of Stage III Non-small Cell Lung Cancer Patients Treated With Concurrent Chemoradiation and Adjuvant Durvalumab: A Prospective Observational Phase II Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht Radiation Oncology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Maastricht Radiation Oncology</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>
      Currently, there is only limited data available on the functional immune changes after&#xD;
      concurrent chemoradiation in NSCLC (non-small cell lung cancer) patients. Identifying the&#xD;
      effect of the treatment on immune cells and what their functional consequences are is an&#xD;
      essential first step to come to prognostic and predictive biomarkers.&#xD;
&#xD;
      Many studies investigating the role of immunomodulatory effects of treatment are carried out&#xD;
      in either in vitro or in vivo animal models. However, identified factors frequently hamper&#xD;
      clinical validation. In addition, as mentioned earlier, although several immunogenic factors&#xD;
      have been shown to be released by irradiated tumor cells, so far, only a limited number of&#xD;
      studies searched for potential predictive and prognostic immunological biomarkers.&#xD;
&#xD;
      This will be the first time that the immune effects of both treatment modalities will be&#xD;
      studied, with, in addition, the immune changes during durvalumab treatment, which are also&#xD;
      unknown at present. By getting more insight in the treatment-induced immunomodulatory&#xD;
      effects, ultimately, in subsequent projects, this will allow to determine optimal immune&#xD;
      stimulation and hence improved outcomes of subsequent durvalumab immune therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Even with the addition of durvalumab to concurrent chemoradiation, approximately only half of&#xD;
      the patients are alive at 3 years, and more have progressed already, either locally or&#xD;
      distant. Not much is known regarding to identification of patients that will benefit from&#xD;
      adjuvant durvalumab, or regarding resistance to adjuvant durvalumab after chemoradiation.&#xD;
      Most data on immunotherapy resistance come from metastatic patients treated with monotherapy&#xD;
      PD-(L)1 antagonists. Depending on PD-L1 expression level, 10-44% of patients respond well to&#xD;
      PD-(L)1 antagonists. The majority of patients are either unresponsive, or experience a tumor&#xD;
      recurrence after achieving an initial response. The development of individual immunological&#xD;
      treatment strategies (e.g. selection of best treatment: mono- or combination ICI, ICI&#xD;
      combined with chemotherapy, or the addition of radiotherapy) is hampered by the lack of&#xD;
      knowledge in the best timing, sequencing, and dosing of all modalities and the lack of&#xD;
      optimal biomarkers for monitoring the treatment response. This highlights the need of clear&#xD;
      biomarkers that can be used to select the best treatment for each individual patient and&#xD;
      predict whether patients will benefit from adjuvant immunotherapy. Currently, there is only&#xD;
      limited data available on the functional immune changes after concurrent chemoradiation in&#xD;
      NSCLC patients. Identifying the effect of the treatment on immune cells (e.g. T-, B-,&#xD;
      NK-cells, dendritic cells, macrophages) and what their functional consequences are is an&#xD;
      essential first step to come to prognostic and predictive biomarkers.&#xD;
&#xD;
      Many studies investigating the role of immunomodulatory effects of treatment are carried out&#xD;
      in either in vitro or in vivo animal models. However, identified factors frequently hamper&#xD;
      clinical validation. In addition, as mentioned earlier, although several immunogenic factors&#xD;
      have been shown to be released by irradiated tumor cells, so far, only a limited number of&#xD;
      studies searched for potential predictive and prognostic immunological biomarkers.&#xD;
&#xD;
      This will be the first time that the immune effects of both treatment modalities will be&#xD;
      studied, with, in addition, the immune changes during durvalumab treatment, which are also&#xD;
      unknown at present. By getting more insight in the treatment-induced immunomodulatory&#xD;
      effects, ultimately, in subsequent projects, this will allow to determine optimal immune&#xD;
      stimulation and hence improved outcomes of subsequent durvalumab immune therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 1, 2021</start_date>
  <completion_date type="Anticipated">April 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">April 1, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Immune changes</measure>
    <time_frame>3 months</time_frame>
    <description>Number of patients with immune changes in stage III NSCLC patients receiving concurrent chemoradiation with protons or photons followed by durvalumab.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PFS</measure>
    <time_frame>12 months</time_frame>
    <description>Progression Free Survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS</measure>
    <time_frame>12 months</time_frame>
    <description>Overall survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity chemoradition</measure>
    <time_frame>until 3 months after chemo/radiotherapy</time_frame>
    <description>- Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 during and after concurrent chemoradiation, also in relation to the irradiated bone marrow volume</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 during courses of Durvalumab</measure>
    <time_frame>Until 12 months after chemo/radiotherapy</time_frame>
    <description>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 of durvalumab and chemoradiation treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>Incidence and severity of adverse events (Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 and patient reported outcome (PRO)-CTCAE)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune changes compared</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>Number of patients with immune changes that are distinct for proton therapy compared with photon therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac function</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>Troponins</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac function</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>ECG QT Interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac function</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac function</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>BNP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function test</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>MOS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function test</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>Controlled oral word association</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function test</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>Trail making test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive function test</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>HVALT-R test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor material</measure>
    <time_frame>Until 12 months after chemoradiation</time_frame>
    <description>Obtaining tumor material from standard diagnostic material for translational purposes</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Carcinoma, Non-Small-Cell Lung</condition>
  <arm_group>
    <arm_group_label>Proton</arm_group_label>
    <description>Patients receiving proton therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Photon</arm_group_label>
    <description>Patients receiving photon therapy in 4 fractions or less</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      At five timepoints 60ml of blood will be drawn for biobanking of plasma, serum, and buffy&#xD;
      coat samples.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with stage III NSCLC who are eligible for curative intent concurrent chemotherapy&#xD;
        and radiotherapy will be enrolled in the study. They receive standard radiotherapy (60 Gy&#xD;
        in 30 fractions of 2 Gy) with protons or photons according to the standard of care.&#xD;
        Eligible patients will thereafter receive standard durvalumab immune therapy for 12 months.&#xD;
        Eligibility criteria for this study are therefore similar to those for standard of care&#xD;
        treatment.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pathological diagnosis of adequately staged (according to standard practice using&#xD;
             chest-CT, FDG-PET, brain imaging MRI/CT) NSCLC&#xD;
&#xD;
          -  Participant is willing and able to give informed consent for participation in the&#xD;
             trial&#xD;
&#xD;
          -  Male or female, aged 18 years or above&#xD;
&#xD;
          -  Scheduled to receive one of the following two therapeutic strategies:&#xD;
&#xD;
               -  Concurrent chemotherapy and radiotherapy with photons (60 Gy in 30 fractions of 2&#xD;
                  Gy) in patients with stage III NSCLC&#xD;
&#xD;
               -  Concurrent chemotherapy and radiotherapy with protons (60 Gy in 30 fractions of 2&#xD;
                  Gy) in patients with stage III NSCLC&#xD;
&#xD;
          -  Is able and willing to comply with all trial requirement&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Mixed non-small cell lung cancer with other histologies such as small cell lung cancer&#xD;
&#xD;
          -  Not able to comply with the study protocol&#xD;
&#xD;
          -  Less than 18 years' old&#xD;
&#xD;
          -  Pregnancy or not able to comply with adequate contraception in women with child baring&#xD;
             potential&#xD;
&#xD;
          -  Previous radiotherapy to the chest for benign or malignant conditions, including&#xD;
             radiation for breast cancer&#xD;
&#xD;
          -  Previous malignancy treated with chemotherapy, immune therapy or radiotherapy&#xD;
             (irrespective of when this happened)&#xD;
&#xD;
          -  Previous malignancies treated with surgery only are allowed if 2 years or more before&#xD;
             inclusion in the present study&#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>Dirk De Ruysscher, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Maastro</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Chantal Overhof</last_name>
    <phone>+31 88 44 55 686</phone>
    <email>chantal.overhof@maastro.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sylvie Canisius</last_name>
    <phone>+31 88 44 55 686</phone>
    <email>sylvie.canisius@maastro.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Maastricht Radiation Oncology (MAASTRO clinic)</name>
      <address>
        <city>Maastricht</city>
        <zip>6229 ET</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dirk De Ruysscher, Dr.</last_name>
      <phone>31-88-445-5666</phone>
      <email>dirk.deruysscher@maastro.nl</email>
    </contact>
    <investigator>
      <last_name>Dirk De Ruysscher, Dr.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 9, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>August 22, 2023</last_update_submitted>
  <last_update_submitted_qc>August 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 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>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04432142
org study id: IPON-1
nct id: NCT04432142
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Currently, there is only limited data available on the functional immune changes after
      concurrent chemoradiation in NSCLC (non-small cell lung cancer) patients. Identifying the
      effect of the treatment on immune cells and what their functional consequences are is an
      essential first step to come to prognostic and predictive biomarkers.

      Many studies investigating the role of immunomodulatory effects of treatment are carried out
      in either in vitro or in vivo animal models. However, identified factors frequently hamper
      clinical validation. In addition, as mentioned earlier, although several immunogenic factors
      have been shown to be released by irradiated tumor cells, so far, only a limited number of
      studies searched for potential predictive and prognostic immunological biomarkers.

      This will be the first time that the immune effects of both treatment modalities will be
      studied, with, in addition, the immune changes during durvalumab treatment, which are also
      unknown at present. By getting more insight in the treatment-induced immunomodulatory
      effects, ultimately, in subsequent projects, this will allow to determine optimal immune
      stimulation and hence improved outcomes of subsequent durvalumab immune therapy.
Even with the addition of durvalumab to concurrent chemoradiation, approximately only half of
      the patients are alive at 3 years, and more have progressed already, either locally or
      distant. Not much is known regarding to identification of patients that will benefit from
      adjuvant durvalumab, or regarding resistance to adjuvant durvalumab after chemoradiation.
      Most data on immunotherapy resistance come from metastatic patients treated with monotherapy
      PD-(L)1 antagonists. Depending on PD-L1 expression level, 10-44% of patients respond well to
      PD-(L)1 antagonists. The majority of patients are either unresponsive, or experience a tumor
      recurrence after achieving an initial response. The development of individual immunological
      treatment strategies (e.g. selection of best treatment: mono- or combination ICI, ICI
      combined with chemotherapy, or the addition of radiotherapy) is hampered by the lack of
      knowledge in the best timing, sequencing, and dosing of all modalities and the lack of
      optimal biomarkers for monitoring the treatment response. This highlights the need of clear
      biomarkers that can be used to select the best treatment for each individual patient and
      predict whether patients will benefit from adjuvant immunotherapy. Currently, there is only
      limited data available on the functional immune changes after concurrent chemoradiation in
      NSCLC patients. Identifying the effect of the treatment on immune cells (e.g. T-, B-,
      NK-cells, dendritic cells, macrophages) and what their functional consequences are is an
      essential first step to come to prognostic and predictive biomarkers.

      Many studies investigating the role of immunomodulatory effects of treatment are carried out
      in either in vitro or in vivo animal models. However, identified factors frequently hamper
      clinical validation. In addition, as mentioned earlier, although several immunogenic factors
      have been shown to be released by irradiated tumor cells, so far, only a limited number of
      studies searched for potential predictive and prognostic immunological biomarkers.

      This will be the first time that the immune effects of both treatment modalities will be
      studied, with, in addition, the immune changes during durvalumab treatment, which are also
      unknown at present. By getting more insight in the treatment-induced immunomodulatory
      effects, ultimately, in subsequent projects, this will allow to determine optimal immune
      stimulation and hence improved outcomes of subsequent durvalumab immune therapy.
observational model: Cohort
time perspective: Prospective
measure: Immune changes
time frame: 3 months
description: Number of patients with immune changes in stage III NSCLC patients receiving concurrent chemoradiation with protons or photons followed by durvalumab.
measure: PFS
time frame: 12 months
description: Progression Free Survival
measure: OS
time frame: 12 months
description: Overall survival
measure: Toxicity chemoradition
time frame: until 3 months after chemo/radiotherapy
description: - Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 during and after concurrent chemoradiation, also in relation to the irradiated bone marrow volume
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 during courses of Durvalumab
time frame: Until 12 months after chemo/radiotherapy
description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 of durvalumab and chemoradiation treatment
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
time frame: Until 12 months after chemoradiation
description: Incidence and severity of adverse events (Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 and patient reported outcome (PRO)-CTCAE)
measure: Immune changes compared
time frame: Until 12 months after chemoradiation
description: Number of patients with immune changes that are distinct for proton therapy compared with photon therapy
measure: Cardiac function
time frame: Until 12 months after chemoradiation
description: Troponins
measure: Cardiac function
time frame: Until 12 months after chemoradiation
description: ECG QT Interval
measure: Cardiac function
time frame: Until 12 months after chemoradiation
description: blood pressure
measure: Cardiac function
time frame: Until 12 months after chemoradiation
description: BNP
measure: Neurocognitive function test
time frame: Until 12 months after chemoradiation
description: MOS
measure: Neurocognitive function test
time frame: Until 12 months after chemoradiation
description: Controlled oral word association
measure: Neurocognitive function test
time frame: Until 12 months after chemoradiation
description: Trail making test
measure: Neurocognitive function test
time frame: Until 12 months after chemoradiation
description: HVALT-R test
measure: Tumor material
time frame: Until 12 months after chemoradiation
description: Obtaining tumor material from standard diagnostic material for translational purposes
arm group label: Proton
description: Patients receiving proton therapy
arm group label: Photon
description: Patients receiving photon therapy in 4 fractions or less
At five timepoints 60ml of blood will be drawn for biobanking of plasma, serum, and buffy
      coat samples.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dirk De Ruysscher, MD, PhD
role: Principal Investigator
affiliation: Maastro
last name: Chantal Overhof
phone: +31 88 44 55 686
email: chantal.overhof@maastro.nl
last name: Sylvie Canisius
phone: +31 88 44 55 686
email: sylvie.canisius@maastro.nl
facility: 
status: Recruiting
contact: 
investigator: 
country: Netherlands
responsible party type: Sponsor
mesh term: Carcinoma, Non-Small-Cell Lung
sharing ipd: No