<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/NCT04473937</url>
  </required_header>
  <id_info>
    <org_study_id>19-861</org_study_id>
    <nct_id>NCT04473937</nct_id>
  </id_info>
  <brief_title>Radiation Post-CAR T in Refractory Lymphoma</brief_title>
  <official_title>Radiation Therapy To Enhance CAR T Efficacy Early in Post-CAR T Cell Therapy Refractory Lymphoma: A Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is evaluating the safety and efficacy of using radiotherapy in participants who&#xD;
      have refractory lymphoma shortly after receiving CAR T cell therapy (axicel or tisacel).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Pilot Study, which is the first time investigators are examining&#xD;
      this intervention after administration of CAR T cell therapy. This research study looks to&#xD;
      systematically investigate the safety and efficacy of radiotherapy following CAR T cell&#xD;
      therapy (axicel or tisacel) in refractory lymphoma. CAR T cell therapy involves genetically&#xD;
      modifying T cells to target tumor cells for death. Radiotherapy is a standard treatment&#xD;
      offered with refractory lymphoma and uses high-energy x rays, or particles, to destroy or&#xD;
      damage cancer cells. Few have received CAR T cell therapy prior to radiation therapy and this&#xD;
      study aims to gather more information on radiotherapy following CAR T cell therapy as a&#xD;
      treatment option and its potential to improve participants immune system's response to cancer&#xD;
      cells as well as its interaction with CAR T cell therapy to better treat refractory lymphoma.&#xD;
&#xD;
      The research study procedures include screening for eligibility, enrollment, biopsy following&#xD;
      radiation, post-treatment period, and long-term follow-up.&#xD;
&#xD;
        -  Participants will receive radiotherapy at a dose and schedule determined by the study&#xD;
           doctor.&#xD;
&#xD;
        -  Participants will be followed for up to 24 months after completion of study treatment.&#xD;
&#xD;
      It is expected that about 20 people will take part in this research study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">July 2021</start_date>
  <completion_date type="Anticipated">May 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 1, 2022</primary_completion_date>
  <phase>N/A</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>Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0</measure>
    <time_frame>30 days</time_frame>
    <description>Rate and severity of RT-related toxicity as per CTCAE v5.0 criteria during RT or within the first 30 days of completing RT.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>First objective response (which is subsequently confirmed) to disease progression per Lugano criteria or death regardless of cause or up to 2 years</time_frame>
    <description>The competing-risk analysis method will be used to estimate the cumulative incidence of relapse. The cumulative incidence of relapse in the presence of non-disease related mortality (the competing risk) will be estimated along with 2-sided 95% confidence intervals at 3-month intervals.&#xD;
Among subjects who experience an objective response, DOR is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per Lugano criteria or death regardless of cause. Subjects not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR) per IRRC</measure>
    <time_frame>defined as the incidence of either a complete response or a partial response by Lugano criteria or up to 2 years</time_frame>
    <description>ORR per IRRC is defined as the incidence of either a complete response or a partial response by Lugano criteria as determined by the IRRC. All subjects that do not meet the criteria for an objective response by the analysis data cutoff date will be considered non-responders.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>Time from RT completion date to the date of disease progression per Lugano criteria or death from any cause up to 2 years</time_frame>
    <description>Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for progression free survival time. Estimates of the proportion of subjects alive and progression-free at 3-month intervals will be provided.&#xD;
PFS is defined as the time from RT completion date to the date of disease progression per Lugano criteria or death from any cause. Subjects not meeting the criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall All Survival</measure>
    <time_frame>OS is defined as the time from RT completion to the date of death up to 2 years</time_frame>
    <description>Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for OS. Estimates of the proportion of subjects alive at 3-month intervals will be provided</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Hematologic Malignancy</condition>
  <condition>Refractory Lymphoma</condition>
  <arm_group>
    <arm_group_label>Radiotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants must have received CAR-T infusion within the last 90 days prior to completing a study screening and enrollment process.&#xD;
Participants will be enrolled within 28 days after screening is complete and radiotherapy will occur within 14 days after study enrollment.&#xD;
Radiotherapy will be administered based on a dose and schedule pre-determined by the study doctor.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiotherapy</intervention_name>
    <description>Radiotherapy at pre-determined dose and schedule</description>
    <arm_group_label>Radiotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must be able to undergo biopsy. Biopsy will be obtained for patients to&#xD;
             exclude possibility of false negative residual FDG avidity on PET/CT that is not&#xD;
             substantially increased relative to pre-CAR-T PET/CT. Exceptions are allowed for&#xD;
             patients who have clearly progressive disease for whom delaying radiation therapy to&#xD;
             obtain a biopsy may worsen outcome (such as cases of cord compression), and for&#xD;
             patients for whom the risks of biopsy are high (such as patients with evidence for CNS&#xD;
             involvement).&#xD;
&#xD;
          -  Biopsy-confirmed refractory disease within 30-90 days following commercial&#xD;
             axicabtagene ciloleucel or tisagenlecleucel therapy for a hematologic malignancy&#xD;
             (these include relapsed or refractory large B-cell lymphoma after two or more lines of&#xD;
             systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise&#xD;
             specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and&#xD;
             DLBCL arising from follicular lymphoma). Of note, 'refractory' refers to patients who&#xD;
             had early refractory disease after CAR-T cell therapy and not to patients who have&#xD;
             received CAR-T for refractory disease, but had complete response to CAR-T cell&#xD;
             therapy.&#xD;
&#xD;
          -  At least 1 measurable lesion according to the Lugano criteria1. Lesions that have been&#xD;
             previously irradiated will be considered measurable only if progression has been&#xD;
             documented following completion of radiation therapy&#xD;
&#xD;
          -  The following criteria pertain to pattern of progression:&#xD;
&#xD;
               -  Patients may have one refractory lesion without other residual or progressive&#xD;
                  disease as per PET/CT&#xD;
&#xD;
               -  Patients may have more than one refractory lesion, but with evidence for at least&#xD;
                  partial response of at least one other lesion as per PET/CT&#xD;
&#xD;
               -  Patients with more than one site of refractory disease without evidence for at&#xD;
                  least partial response of at least one other lesion are eligible if they are:&#xD;
&#xD;
                    -  A. Symptomatic from a refractory lesion (such as cord compression or focal&#xD;
                       pain) or&#xD;
&#xD;
                    -  B. Have disease that can locally affect the spinal canal or brain if left&#xD;
                       untreated.&#xD;
&#xD;
          -  Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for&#xD;
             clinically non-significant toxicities such as alopecia and prolonged cytopenias that&#xD;
             are not expected to worsen during RT) if there is concern for overlap of anticipated&#xD;
             radiation-related toxicity and toxicity from prior therapy due to where the RT field&#xD;
             is located.&#xD;
&#xD;
          -  Age 18 or older&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to&#xD;
             2.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any medical condition likely to interfere with assessment of safety or efficacy of RT&#xD;
&#xD;
          -  Patients with more than one site of disease without any evidence for response to CAR T&#xD;
             cell therapy who are not focally symptomatic due to progressive disease or do not have&#xD;
             disease that can locally affect the spinal canal or brain if left untreated&#xD;
&#xD;
          -  Women of child-bearing potential who are pregnant because of the potentially dangerous&#xD;
             effects of the preparative chemotherapy on the fetus or infant. Females who have&#xD;
             undergone surgical sterilization or who have been postmenopausal for at least 2 years&#xD;
             are not considered to be of childbearing potential.&#xD;
&#xD;
          -  In the investigators judgment, the subject is unlikely to complete all&#xD;
             protocol-required study visits or procedures, including follow-up visits, or comply&#xD;
             with the study requirements for participation.&#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>Chirayu G Patel, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Chirayu G Patel, MD, MPH</last_name>
    <phone>617-724-2340</phone>
    <email>cpatel@mgh.harvard.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Massachusetts General Hospital Cancer Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
    <contact>
      <last_name>Chirayu G Patel, MD, MPH</last_name>
      <phone>617-724-2340</phone>
      <email>cpatel@mgh.harvard.edu</email>
    </contact>
    <investigator>
      <last_name>Chirayu G Patel, MD, MPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Matthew J Frigault, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>July 13, 2020</study_first_submitted>
  <study_first_submitted_qc>July 13, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 16, 2020</study_first_posted>
  <last_update_submitted>January 19, 2021</last_update_submitted>
  <last_update_submitted_qc>January 19, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 20, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Chirayu G. Patel</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Hematologic Malignancy</keyword>
  <keyword>Refractory Lymphoma</keyword>
  <keyword>CAR T cell therapy</keyword>
  <keyword>Radiotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Hematologic Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Data can be shared no earlier than 1 year following the date of publication</ipd_time_frame>
    <ipd_access_criteria>Contact the Partners Innovations team at http://www.partners.org/innovation</ipd_access_criteria>
  </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/NCT04473937
org study id: 19-861
nct id: NCT04473937
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
This study is evaluating the safety and efficacy of using radiotherapy in participants who
      have refractory lymphoma shortly after receiving CAR T cell therapy (axicel or tisacel).
This research study is a Pilot Study, which is the first time investigators are examining
      this intervention after administration of CAR T cell therapy. This research study looks to
      systematically investigate the safety and efficacy of radiotherapy following CAR T cell
      therapy (axicel or tisacel) in refractory lymphoma. CAR T cell therapy involves genetically
      modifying T cells to target tumor cells for death. Radiotherapy is a standard treatment
      offered with refractory lymphoma and uses high-energy x rays, or particles, to destroy or
      damage cancer cells. Few have received CAR T cell therapy prior to radiation therapy and this
      study aims to gather more information on radiotherapy following CAR T cell therapy as a
      treatment option and its potential to improve participants immune system's response to cancer
      cells as well as its interaction with CAR T cell therapy to better treat refractory lymphoma.

      The research study procedures include screening for eligibility, enrollment, biopsy following
      radiation, post-treatment period, and long-term follow-up.

        -  Participants will receive radiotherapy at a dose and schedule determined by the study
           doctor.

        -  Participants will be followed for up to 24 months after completion of study treatment.

      It is expected that about 20 people will take part in this research study.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0
time frame: 30 days
description: Rate and severity of RT-related toxicity as per CTCAE v5.0 criteria during RT or within the first 30 days of completing RT.
measure: Duration of response (DOR)
time frame: First objective response (which is subsequently confirmed) to disease progression per Lugano criteria or death regardless of cause or up to 2 years
description: The competing-risk analysis method will be used to estimate the cumulative incidence of relapse. The cumulative incidence of relapse in the presence of non-disease related mortality (the competing risk) will be estimated along with 2-sided 95% confidence intervals at 3-month intervals.
Among subjects who experience an objective response, DOR is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per Lugano criteria or death regardless of cause. Subjects not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing.
measure: Objective response rate (ORR) per IRRC
time frame: defined as the incidence of either a complete response or a partial response by Lugano criteria or up to 2 years
description: ORR per IRRC is defined as the incidence of either a complete response or a partial response by Lugano criteria as determined by the IRRC. All subjects that do not meet the criteria for an objective response by the analysis data cutoff date will be considered non-responders.
measure: Progression-free Survival (PFS)
time frame: Time from RT completion date to the date of disease progression per Lugano criteria or death from any cause up to 2 years
description: Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for progression free survival time. Estimates of the proportion of subjects alive and progression-free at 3-month intervals will be provided.
PFS is defined as the time from RT completion date to the date of disease progression per Lugano criteria or death from any cause. Subjects not meeting the criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
measure: Overall All Survival
time frame: OS is defined as the time from RT completion to the date of death up to 2 years
description: Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for OS. Estimates of the proportion of subjects alive at 3-month intervals will be provided
arm group label: Radiotherapy
arm group type: Experimental
description: Participants must have received CAR-T infusion within the last 90 days prior to completing a study screening and enrollment process.
Participants will be enrolled within 28 days after screening is complete and radiotherapy will occur within 14 days after study enrollment.
Radiotherapy will be administered based on a dose and schedule pre-determined by the study doctor.
intervention type: Radiation
intervention name: Radiotherapy
description: Radiotherapy at pre-determined dose and schedule
arm group label: Radiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Chirayu G Patel, MD, MPH
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Chirayu G Patel, MD, MPH
phone: 617-724-2340
email: cpatel@mgh.harvard.edu
facility: 
contact: 
investigator: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Chirayu G. Patel
investigator title: Principal Investigator
mesh term: Lymphoma
mesh term: Neoplasms
mesh term: Hematologic Neoplasms
sharing ipd: Yes
ipd description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Data can be shared no earlier than 1 year following the date of publication
ipd access criteria: Contact the Partners Innovations team at http://www.partners.org/innovation