<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/NCT03255018</url>
  </required_header>
  <id_info>
    <org_study_id>170149</org_study_id>
    <secondary_id>17-C-0149</secondary_id>
    <nct_id>NCT03255018</nct_id>
  </id_info>
  <brief_title>Pembrolizumab in Relapsed and Refractory Gray-Zone Lymphoma (GZL), Primary Central Nervous System Lymphoma (PCNSL), and Other Extranodal Diffuse Large B-cell Lymphomas</brief_title>
  <official_title>Phase 2 Trial of Pembrolizumab in Relapsed and Refractory Gray-Zone Lymphoma (GZL), Primary Central Nervous System Lymphoma (PCNSL),and Other Extranodal Diffuse Large B-cell Lymphomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      B-cell lymphoma is a cancer of white blood cells that are found in lymph nodes. Some kinds of&#xD;
      these cancers, such as gray-zone and extra-nodal, are rare and often aggressive. They are&#xD;
      usually resistant to current treatments. Researchers want to see if a drug called&#xD;
      pembrolizumab may treat these types of lymphoma.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To collect data to see if it may be effective to give pembrolizumab to people with certain&#xD;
      types of rare, aggressive B-cell lymphomas.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People ages 18 and older who have a B-cell lymphoma, including gray-zone lymphoma or&#xD;
      extra-nodal lymphoma&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with:&#xD;
&#xD;
      Medical history&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Blood and urine tests&#xD;
&#xD;
      Scans. They will lie in a machine that takes images.&#xD;
&#xD;
      A tissue sample from a previous procedure will be tested.&#xD;
&#xD;
      The study will be done in 21-day cycles. During the study, participants:&#xD;
&#xD;
      Will repeat the screening tests.&#xD;
&#xD;
      Will get the study drug as an infusion into a vein over about 30 minutes.&#xD;
&#xD;
      Will have a cheek swab and/or saliva sample collected.&#xD;
&#xD;
      May have a bone marrow aspiration. A needle will be put into the hipbone, and a small amount&#xD;
      of bone marrow will be taken out.&#xD;
&#xD;
      May have a lumbar puncture. If cerebrospinal fluid is collected, researchers will study it.&#xD;
&#xD;
      May have an eye exam.&#xD;
&#xD;
      May provide tissue samples.&#xD;
&#xD;
      May have tumor samples taken.&#xD;
&#xD;
      Participants will have a visit about 30 days after the last dose of the study drug. They will&#xD;
      then have 4 visits in year 1, 2 visits a year in years 2-5, and once each year thereafter.&#xD;
      They will also be contacted by phone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Gray-zone lymphomas (GZL) are rare, aggressive lymphomas that share clinical and&#xD;
           biological features of diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma&#xD;
&#xD;
        -  Standard upfront therapy for GZL is dose-intensive chemotherapy, though disease is often&#xD;
           resistant; consolidative radiation therapy reserved for patients who are relapsed or&#xD;
           refractory, and patients who fail radiation therapy have a poor prognosis&#xD;
&#xD;
        -  Primary central nervous system lymphoma (PCNSL), primary testicular lymphoma (PTL),&#xD;
           primary breast lymphoma (PBL), primary cutaneous DLBCL, leg-type, and intravascular&#xD;
           B-cell lymphoma (IVBCL) are rare, aggressive extranodal subsets of DLBCL that usually&#xD;
           have gene expression signatures of activated B-cell (ABC) DLBCL&#xD;
&#xD;
        -  ABC-DLBCL has cure rates below 40% after standard therapy, and is associated with late&#xD;
           recurrences, often involving the CNS where treatment options are limited by chemotherapy&#xD;
           resistance and an inability of many agents to cross the blood-brain barrier&#xD;
&#xD;
        -  Molecular biology studies of GZL and extranodal DLBCL have identified potentially&#xD;
           targetable genetic features involving the programmed death-1 (PD-1) signaling pathway&#xD;
&#xD;
        -  A high proportion of GZL, PCNSL, and PTL cases have copy number alterations or&#xD;
           chromosomal rearrangements involving the PD-1 ligands, PD-L1 and PD-L2&#xD;
&#xD;
        -  Pembrolizumab, a humanized IgG4 monoclonal antibody that targets the PD-1 receptor, is a&#xD;
           rational therapeutic target for patients with relapsed and refractory GZL, PCNSL, PTL,&#xD;
           and other extranodal DLBCL&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      -To determine the best overall response rate of pembrolizumab in patients with relapsed and&#xD;
      refractory GZL and extranodal DLBCL&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Confirmed diagnosis of B-cell lymphoma, relapsed from or refractory to prior:&#xD;
&#xD;
             -  Cohort 1: B-cell lymphoma, unclassifiable, with features intermediate between&#xD;
                diffuse large B-cell lymphoma and classical Hodgkin lymphoma (i.e., Gray-zone&#xD;
                lymphoma or GZL)&#xD;
&#xD;
             -  Cohort 2: Extranodal diffuse large B-cell lymphoma involving one or more of the&#xD;
                specified extranodal sites (i.e., extranodal DLBCL)&#xD;
&#xD;
        -  Adequate bone marrow and organ function defined&#xD;
&#xD;
        -  Age greater than or equal to 18 years&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Phase 2 study of patients with relapsed and refractory GZL and extranodal DLBCL&#xD;
&#xD;
        -  Patients will be treated with pembrolizumab 200 mg (flat dose) IV every 3 weeks provided&#xD;
           they have clinical benefit and no unacceptable toxicity; patients who achieve a complete&#xD;
           response (CR) will have the option stop after 1 year of therapy.&#xD;
&#xD;
        -  All responding patients (CR, PR, or SD with clinical benefit) who subsequently relapse&#xD;
           or progress within 1 year after discontinuation of study drug are eligible for&#xD;
           re-treatment.&#xD;
&#xD;
        -  At least 20 evaluable patients each with GZL and DLBCL will be evaluated on this&#xD;
           protocol for the primary endpoint (overall accrual ceiling of 52 patients)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 15, 2018</start_date>
  <completion_date type="Anticipated">July 1, 2023</completion_date>
  <primary_completion_date type="Actual">October 22, 2022</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>Best overall response rate of pembrolizumab in patients with relapsed/refractory gray-zone lymphomas (GZL) and extra-nodal diffuse large B-cell lymphomas (DLBCL)</measure>
    <time_frame>24 months</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>toxicity profile of pembrolizumab in patients with GZL and extra-nodal DLBCL</measure>
    <time_frame>every 3 weeks</time_frame>
    <description>The type, grade and frequency of toxicities will be reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>best overall response rate according to the 5-point Lugano classification for interpreting FDG-PET scans</measure>
    <time_frame>every 3-6 months for 24 months</time_frame>
    <description>The response rate will be will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of response for patients who respond to pembrolizumab</measure>
    <time_frame>every 3-6 months for 24 months</time_frame>
    <description>The duration of response (DOR; beginning at the date clinical response is first identified) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>progression-free survival (PFS)</measure>
    <time_frame>every 3-6 months for 24 months</time_frame>
    <description>The progression free survival (PFS) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>event-free survival (EFS)</measure>
    <time_frame>every 3-6 months for 5 years</time_frame>
    <description>The event free survival (EFS) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival (OS)</measure>
    <time_frame>every 3-6 months for 5 years</time_frame>
    <description>The overall survival (OS) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Non-Hodgkin Lymphoma</condition>
  <condition>Lymphoma</condition>
  <condition>Diffuse Large B-Cell Lymphoma</condition>
  <condition>Gray-zone Lymphoma</condition>
  <condition>Primary Central Nervous System Lymphoma</condition>
  <arm_group>
    <arm_group_label>1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects with gray-zone lymphoma (GZL) or extranodal DLBCL relapsed from or refractory to prior therapy with an anthracycline-based regimen</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Administered intravenously (IV) at a fixed dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity; treatment may continue indefinitely if clinical benefit with options for treatment interruption if responding disease and re-treatment upon relapse.</description>
    <arm_group_label>1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients must have a diagnosis of B-cell lymphoma confirmed by Laboratory of&#xD;
             Pathology, NCI, that is relapsed from or refractory to prior therapy as follows:&#xD;
&#xD;
               -  Cohort 1: B-cell lymphoma, unclassifiable, with features intermediate between&#xD;
                  diffuse large B-cell lymphoma and classical Hodgkin lymphoma (i.e., Gray-zone&#xD;
                  lymphoma or GZL)&#xD;
&#xD;
               -  Cohort 2: Extranodal diffuse large B-cell lymphoma involving one or more of the&#xD;
                  specified extranodal sites (i.e., extranodal DLBCL). The following subtypes are&#xD;
                  included (they do not have to be confirmed as non-GCB subtype for study entry):&#xD;
&#xD;
                    -  Primary CNS lymphoma (PCNSL)&#xD;
&#xD;
                    -  Primary testicular lymphoma (PTL)&#xD;
&#xD;
                    -  Primary breast lymphoma (PBL)&#xD;
&#xD;
                    -  Primary cutaneous DLBCL, leg-type&#xD;
&#xD;
                    -  Intravascular large B-cell lymphoma (IVBCL)&#xD;
&#xD;
                    -  Diffuse large B-cell, NOS, activated B-cell type, involving 1 or more&#xD;
                       extranodal site&#xD;
&#xD;
        NOTE: For GZL, diagnosis will be in accordance with the 2016 World Health Organization&#xD;
        classification of lymphoid malignancies. Patients diagnosed with other extranodal DLBCL&#xD;
        subtypes or that are not otherwise specified (NOS) must involved at least 1 extranodal site&#xD;
        and must be considered non-GCB by local immunohistochemistry algorithms. Cases that are&#xD;
        non-GCB by the Hans criteria are considered eligible as well as cases of DLBCL that are&#xD;
        both CD10+ and MUM1+.&#xD;
&#xD;
          -  Evaluable disease by clinical exam (i.e., palpable lymphadenopathy, measurable skin&#xD;
             lesions, etc.), laboratory assessment (i.e., lymphoma involvement of bone marrow or&#xD;
             peripheral blood by morphology, cytology or flow cytometry), and/or imaging&#xD;
             (measurable lymph nodes or masses on CT or MRI and/or evaluable FDG-avid lesions on&#xD;
             PET)&#xD;
&#xD;
          -  Adequate tumor tissue (archival or fresh) must be available for correlative studies.&#xD;
             NOTE: Tumor tissue may be from any previously collected tissue and adequacy is at the&#xD;
             discretion of the Principal Investigator. If prior tissue is not available, patient&#xD;
             must be willing to undergo baseline tumor biopsy.&#xD;
&#xD;
          -  Be 18 years of age or older on day of signing informed consent&#xD;
&#xD;
          -  Adequate performance status (PS) as follows:&#xD;
&#xD;
               -  Patients greater than or equal to 18 years must have ECOG 0-1 (and Karnofsky&#xD;
                  greater than or equal to 60%)&#xD;
&#xD;
        NOTE: Patients greater than or equal to 18 years with an ECOG PS of 2 and Karnofsky greater&#xD;
        than or equal to 60 will be considered eligible at the discretion of the Principal&#xD;
        Investigator if decreased ECOG performance status is felt to be related to residual&#xD;
        neurologic deficits caused by CNS disease involvement that are not progressive or&#xD;
        anticipated to cause clinical managemnt problems during study participation.&#xD;
&#xD;
        - Adequate organ function as evidenced by the following laboratory parameters (unless&#xD;
        related to lymphoma infiltration at the discretion of the investigator):&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) greater than or equal to 750 /mcL&#xD;
&#xD;
          -  Platelets greater than or equal to 50,000 / mcL (transfusions not permitted)&#xD;
&#xD;
          -  Hemoglobin greater than or equal to 9 g/dL (transfusions permitted)&#xD;
&#xD;
          -  Serum creatinine: Adults: less than or equal to 1.5 times upper limit of normal (ULN).&#xD;
             Children: age greater than or equal to 14: less than or equal to 1.5 mg/dL OR Measured&#xD;
             or calculated creatinine clearance (GFR can also be used in place of creatinine or&#xD;
             CrCl):&#xD;
&#xD;
        Greater than or equal to 30 mL/min/1.73 m(2) for subject with creatinine levels &gt; 1.5 times&#xD;
        institutional ULN (CrCl should be calculated per institutional standard)&#xD;
&#xD;
        --Serum total bilirubin less than or equal to 1.5 times ULN&#xD;
&#xD;
        OR&#xD;
&#xD;
        Direct bilirubin less than or equal to ULN for patients with total bilirubin levels &gt; 1.5&#xD;
        ULN&#xD;
&#xD;
          -  AST (SGOT) and ALT (SGPT) less than or equal to 3 times ULN (less than or equal to 5 X&#xD;
             ULN if liver involvement)&#xD;
&#xD;
             - The effects of pembrolizumab on the developing human fetus are unknown. For this&#xD;
             reason, the following measures apply:&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             within 72 hours prior to the first dose of pembrolizumab.&#xD;
&#xD;
          -  Men and women of childbearing potential (WOCBP) who are sexually active must agree to&#xD;
             adequate contraception (hormonal or barrier method of birth control; abstinence) prior&#xD;
             to study entry, for the duration of study participation, and for at least 120 days&#xD;
             after the last dose of pembrolizumab. Should a woman become pregnant or suspect she is&#xD;
             pregnant while she or her partner is participating in this study, she should inform&#xD;
             her treating physician immediately.&#xD;
&#xD;
          -  Participants must not be planning to conceive or father children within the projected&#xD;
             duration of the trial, starting with the pre-screening/screening visit through 120&#xD;
             days after the last dose of pembrolizumab.&#xD;
&#xD;
          -  WOCBP is defined as any female who has experienced menarche and who has not undergone&#xD;
             successful surgical sterilization or who is not postmenopausal.&#xD;
&#xD;
               -  Ability of patient or Legally Authorized Representative (LAR) to understand and&#xD;
                  the willingness to sign a written informed consent document&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients with DLBCL who best fit the criteria of EBV+ DLBCL, NOS are not eligible&#xD;
&#xD;
          -  Current or prior anti-cancer treatment prior to the first dose of pembrolizumab as&#xD;
             defined below:&#xD;
&#xD;
               -  Chemotherapy, targeted small molecule therapy, or other anti-cancer treatment not&#xD;
                  otherwise specified below within 2 weeks&#xD;
&#xD;
               -  Radiation therapy within 2 weeks&#xD;
&#xD;
               -  Anti-cancer monoclonal antibody (mAb) treatment within 4 weeks&#xD;
&#xD;
               -  Use of an investigational agent (e.g., biologic, drug, or other) within 4 weeks&#xD;
&#xD;
               -  Allogeneic stem cell transplant within 100 days&#xD;
&#xD;
               -  Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent at any time&#xD;
&#xD;
          -  No current use of systemic corticosteroids at physiologic doses &gt; 10 mg/day of&#xD;
             dexamethasone or equivalent are permitted. Patients receiving current systemic&#xD;
             steroids must be on a stable steroid dose (i.e., less than or equal to 10 mg/day of&#xD;
             dexamethasone or equivalent at the same dose for at least 7 days). Patients who&#xD;
             recently discontinued systemic steroids must have completed them at least 7 days prior&#xD;
             to entry.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to the following that may&#xD;
             limit interpretation of results or that could increase risk to the patient at the&#xD;
             discretion of the investigator:&#xD;
&#xD;
               -  Active autoimmune disease that has required systemic treatment in the past 2&#xD;
                  years (i.e., with use of disease modifying agents, corticosteroids or&#xD;
                  immunosuppressive drugs). NOTE: Replacement therapy (e.g., thyroxine, insulin, or&#xD;
                  physiologic corticosteroid replacement therapy for adrenal or pituitary&#xD;
                  insufficiency, etc.) is not considered a form of systemic treatment.&#xD;
&#xD;
               -  History of (non-infectious) pneumonitis that required steroids, evidence of&#xD;
                  interstitial lung disease or active, non-infectious pneumonitis.&#xD;
&#xD;
          -  Clinically significant history of liver disease, including viral or other hepatitis,&#xD;
             current alcohol abuse, or cirrhosis; as well as active infection with HBV or HCV:&#xD;
&#xD;
             ---Patients with occult or prior HBV infection (defined as positive total hepatitis B&#xD;
             core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable.&#xD;
&#xD;
               -  Uncontrolled and/or symptomatic thyroid disease&#xD;
&#xD;
               -  Active graft-vs-host disease (GVHD) requiring treatment or any history of greater&#xD;
                  than or equal to grade II acute GVHD&#xD;
&#xD;
               -  Seizure activity within the past 4 weeks&#xD;
&#xD;
               -  Known mental or physical illness that would interfere with cooperation with the&#xD;
                  requirements of the trial or confound the results or interpretation of the&#xD;
                  results of the trial and, in the opinion of the treating investigator, would make&#xD;
                  the patient inappropriate for entry into the study.&#xD;
&#xD;
          -  Because there is an unknown but potential risk for adverse events in nursing infants&#xD;
             secondary to treatment of the mother with pembrolizumab, breastfeeding must be&#xD;
             discontinued if the mother is treated with pembrolizumab&#xD;
&#xD;
          -  Received a live vaccine within 30 days of planned start of study therapy. NOTE:&#xD;
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and&#xD;
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist ) are live&#xD;
             attenuated vaccines, and are not allowed.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to pembrolizumab unless felt to be in the best interests of the patient in&#xD;
             the opinion of the investigator&#xD;
&#xD;
          -  Known additional malignancy that requires active systemic treatment&#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>Mark J Roschewski, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2017-C-0149.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>October 3, 2022</verification_date>
  <study_first_submitted>August 18, 2017</study_first_submitted>
  <study_first_submitted_qc>August 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 21, 2017</study_first_posted>
  <last_update_submitted>November 4, 2022</last_update_submitted>
  <last_update_submitted_qc>November 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Monoclonal Antibody</keyword>
  <keyword>PD-1 Receptor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>.All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@All large scale genomic sequencing data will be shared with subscribers to dbGaP.</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>Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.</ipd_access_criteria>
  </patient_data>
  <pending_results>
    <submitted>September 8, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03255018
org study id: 170149
secondary id: 17-C-0149
nct id: NCT03255018
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      B-cell lymphoma is a cancer of white blood cells that are found in lymph nodes. Some kinds of
      these cancers, such as gray-zone and extra-nodal, are rare and often aggressive. They are
      usually resistant to current treatments. Researchers want to see if a drug called
      pembrolizumab may treat these types of lymphoma.

      Objective:

      To collect data to see if it may be effective to give pembrolizumab to people with certain
      types of rare, aggressive B-cell lymphomas.

      Eligibility:

      People ages 18 and older who have a B-cell lymphoma, including gray-zone lymphoma or
      extra-nodal lymphoma

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Blood and urine tests

      Scans. They will lie in a machine that takes images.

      A tissue sample from a previous procedure will be tested.

      The study will be done in 21-day cycles. During the study, participants:

      Will repeat the screening tests.

      Will get the study drug as an infusion into a vein over about 30 minutes.

      Will have a cheek swab and/or saliva sample collected.

      May have a bone marrow aspiration. A needle will be put into the hipbone, and a small amount
      of bone marrow will be taken out.

      May have a lumbar puncture. If cerebrospinal fluid is collected, researchers will study it.

      May have an eye exam.

      May provide tissue samples.

      May have tumor samples taken.

      Participants will have a visit about 30 days after the last dose of the study drug. They will
      then have 4 visits in year 1, 2 visits a year in years 2-5, and once each year thereafter.
      They will also be contacted by phone.
Background:

        -  Gray-zone lymphomas (GZL) are rare, aggressive lymphomas that share clinical and
           biological features of diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma

        -  Standard upfront therapy for GZL is dose-intensive chemotherapy, though disease is often
           resistant; consolidative radiation therapy reserved for patients who are relapsed or
           refractory, and patients who fail radiation therapy have a poor prognosis

        -  Primary central nervous system lymphoma (PCNSL), primary testicular lymphoma (PTL),
           primary breast lymphoma (PBL), primary cutaneous DLBCL, leg-type, and intravascular
           B-cell lymphoma (IVBCL) are rare, aggressive extranodal subsets of DLBCL that usually
           have gene expression signatures of activated B-cell (ABC) DLBCL

        -  ABC-DLBCL has cure rates below 40% after standard therapy, and is associated with late
           recurrences, often involving the CNS where treatment options are limited by chemotherapy
           resistance and an inability of many agents to cross the blood-brain barrier

        -  Molecular biology studies of GZL and extranodal DLBCL have identified potentially
           targetable genetic features involving the programmed death-1 (PD-1) signaling pathway

        -  A high proportion of GZL, PCNSL, and PTL cases have copy number alterations or
           chromosomal rearrangements involving the PD-1 ligands, PD-L1 and PD-L2

        -  Pembrolizumab, a humanized IgG4 monoclonal antibody that targets the PD-1 receptor, is a
           rational therapeutic target for patients with relapsed and refractory GZL, PCNSL, PTL,
           and other extranodal DLBCL

      Objectives:

      -To determine the best overall response rate of pembrolizumab in patients with relapsed and
      refractory GZL and extranodal DLBCL

      Eligibility:

        -  Confirmed diagnosis of B-cell lymphoma, relapsed from or refractory to prior:

             -  Cohort 1: B-cell lymphoma, unclassifiable, with features intermediate between
                diffuse large B-cell lymphoma and classical Hodgkin lymphoma (i.e., Gray-zone
                lymphoma or GZL)

             -  Cohort 2: Extranodal diffuse large B-cell lymphoma involving one or more of the
                specified extranodal sites (i.e., extranodal DLBCL)

        -  Adequate bone marrow and organ function defined

        -  Age greater than or equal to 18 years

      Design:

        -  Phase 2 study of patients with relapsed and refractory GZL and extranodal DLBCL

        -  Patients will be treated with pembrolizumab 200 mg (flat dose) IV every 3 weeks provided
           they have clinical benefit and no unacceptable toxicity; patients who achieve a complete
           response (CR) will have the option stop after 1 year of therapy.

        -  All responding patients (CR, PR, or SD with clinical benefit) who subsequently relapse
           or progress within 1 year after discontinuation of study drug are eligible for
           re-treatment.

        -  At least 20 evaluable patients each with GZL and DLBCL will be evaluated on this
           protocol for the primary endpoint (overall accrual ceiling of 52 patients)
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Best overall response rate of pembrolizumab in patients with relapsed/refractory gray-zone lymphomas (GZL) and extra-nodal diffuse large B-cell lymphomas (DLBCL)
time frame: 24 months
description: The response rate will be determined and reported along with a 95% confidence interval.
measure: toxicity profile of pembrolizumab in patients with GZL and extra-nodal DLBCL
time frame: every 3 weeks
description: The type, grade and frequency of toxicities will be reported.
measure: best overall response rate according to the 5-point Lugano classification for interpreting FDG-PET scans
time frame: every 3-6 months for 24 months
description: The response rate will be will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.
measure: duration of response for patients who respond to pembrolizumab
time frame: every 3-6 months for 24 months
description: The duration of response (DOR; beginning at the date clinical response is first identified) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.
measure: progression-free survival (PFS)
time frame: every 3-6 months for 24 months
description: The progression free survival (PFS) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.
measure: event-free survival (EFS)
time frame: every 3-6 months for 5 years
description: The event free survival (EFS) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.
measure: overall survival (OS)
time frame: every 3-6 months for 5 years
description: The overall survival (OS) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.
arm group label: 1
arm group type: Experimental
description: Subjects with gray-zone lymphoma (GZL) or extranodal DLBCL relapsed from or refractory to prior therapy with an anthracycline-based regimen
intervention type: Biological
intervention name: Pembrolizumab
description: Administered intravenously (IV) at a fixed dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity; treatment may continue indefinitely if clinical benefit with options for treatment interruption if responding disease and re-treatment upon relapse.
arm group label: 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark J Roschewski, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2017-C-0149.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
mesh term: Pembrolizumab
sharing ipd: Yes
ipd description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@All large scale genomic sequencing data will be shared with subscribers to dbGaP.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
ipd access criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.
submitted: September 8, 2023