<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/NCT04417660</url>
  </required_header>
  <id_info>
    <org_study_id>200097</org_study_id>
    <secondary_id>20-C-0097</secondary_id>
    <nct_id>NCT04417660</nct_id>
  </id_info>
  <brief_title>Bintrafusp Alfa (M7824) in Subjects With Thymoma and Thymic Carcinoma</brief_title>
  <official_title>A Phase II, Open-Label Trial of Bintrafusp Alfa (M7824) in Subjects With Thymoma and Thymic Carcinoma</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;
      Thymoma and thymic carcinoma are diseases of the thymus. Platinum-based chemotherapy is the&#xD;
      standard treatment for these diseases. But in many cases, the disease returns after&#xD;
      treatment. Researchers want to see if a new drug can help.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To see if bintrafusp alfa (M7824) is an effective treatment for thymoma and thymic carcinoma.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People age 18 and older who have thymoma or thymic cancer and their disease returned or&#xD;
      progressed after treatment with at least one platinum-containing chemotherapy treatment plan.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened under a separate protocol. Their medical, medicine, and&#xD;
      treatment history will be reviewed. They will have a tumor biopsy if they do not have a&#xD;
      sample.&#xD;
&#xD;
      Participants will get the study drug once every 2 weeks as an intravenous infusion. For this,&#xD;
      a small plastic tube is put into an arm vein.&#xD;
&#xD;
      During the study, participants will undergo the following:&#xD;
&#xD;
      Medicine review&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Review of their symptoms and their ability to perform their normal activities&#xD;
&#xD;
      Blood and urine tests&#xD;
&#xD;
      Thigh muscle scan (using MRI)&#xD;
&#xD;
      Tumor assessment (using MRI or CT)&#xD;
&#xD;
      Heart and lung function tests&#xD;
&#xD;
      Thyroid gland test&#xD;
&#xD;
      Skin assessment.&#xD;
&#xD;
      Participants may have tumor biopsies. Some of their blood and biopsy samples will be used for&#xD;
      gene testing.&#xD;
&#xD;
      Participants may take the study drug until their disease worsens or they cannot tolerate&#xD;
      treatment.&#xD;
&#xD;
      Participants will have follow-up visits 2 and 6 weeks after stopping treatment. Then they&#xD;
      will have long-term follow-up visits every 3 months. These may include imaging scans. Visits&#xD;
      may be done by phone, with scans (if needed) done at their doctor s office.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      Platinum-based chemotherapy is the standard of care for advanced unresectable thymic&#xD;
      epithelial tumors (TETs). However more than half of these patients experience disease&#xD;
      recurrence and require second-line therapy.&#xD;
&#xD;
      There are no approved drugs for treatment of recurrent thymoma and thymic carcinoma and new&#xD;
      therapeutic options are needed for patients who have disease progression on or after&#xD;
      platinum-containing therapy.&#xD;
&#xD;
      We have demonstrated the safety and clinical activity of immune checkpoint inhibition in&#xD;
      patients with recurrent TETs. In an ongoing trial (NCT03076554) we have shown that avelumab,&#xD;
      an anti-programmed death ligand-1 (PD-L1) antibody, induces major responses and has an&#xD;
      acceptable safety profile.&#xD;
&#xD;
      Combination immunotherapy is under evaluation for treatment of various cancers but has not&#xD;
      been studied for the treatment of TETs. Immunotherapy targeting the PD-1/PD-L1 axis can be&#xD;
      combined with other immune checkpoint inhibitors, cancer vaccines and anti-cytokine therapy.&#xD;
&#xD;
      Bintrafusp alfa, a bifunctional fusion protein that targets PD-L1 and transforming growth&#xD;
      factor-b (TGF-b) has shown activity against heavily pre-treated solid tumors including&#xD;
      non-small cell lung cancer previously treated with single-agent anti-PD-1/PD-L1 inhibitors.&#xD;
&#xD;
      Retrospective analysis of pre-chemotherapy tissue obtained from 20 patients with stage IV&#xD;
      thymic carcinoma and 13 cases of stage III/IV thymoma, showed TGF-b expression in 65% cases&#xD;
      of thymic carcinoma and 15% cases of thymoma with a lower median survival among patients with&#xD;
      thymic carcinoma (30 months versus 63 months).&#xD;
&#xD;
      As part of a phase I clinical trial, treatment with bintrafusp alfa resulted in a brief&#xD;
      period of disease stabilization and no immune-related adverse events in one patient with&#xD;
      heavily pre-treated, WHO subtype B3 thymoma with a large disease burden&#xD;
&#xD;
      Further investigation of Bintrafusp alfa in patients with recurrent TETs is needed to define&#xD;
      the clinical activity and safety of this drug in patients with TETs.&#xD;
&#xD;
      Primary Objectives&#xD;
&#xD;
      To determine the objective response rate (ORR) to bintrafusp alfa in participants with&#xD;
      relapsed or refractory thymoma and thymic carcinoma.&#xD;
&#xD;
      Eligibility&#xD;
&#xD;
      Participants &gt;= age 18 years with histologically confirmed, unresectable thymoma or thymic&#xD;
      carcinoma who have previously been treated with at least one platinum-containing chemotherapy&#xD;
      regimen with progressive disease prior to study entry.&#xD;
&#xD;
      Progressive and measurable disease prior to enrollment&#xD;
&#xD;
      No history of autoimmune disease, with exception of vitiligo, autoimmune thyroid disease, or&#xD;
      pure red cell aplasia that are adequately managed with medical therapy&#xD;
&#xD;
      Adequate renal, hepatic and hematopoietic function&#xD;
&#xD;
      Design&#xD;
&#xD;
      This will be a single-arm, phase II study to determine the clinical activity of treatment&#xD;
      with Bintrafusp alfa in participants with relapsed or refractory thymoma and thymic&#xD;
      carcinoma.&#xD;
&#xD;
      Bintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two weeks&#xD;
      until disease progression or development of intolerable adverse events. The two-week period&#xD;
      will constitute one cycle.&#xD;
&#xD;
      A Simon optimal two-stage phase II trial design will be used to rule out unacceptably low&#xD;
      response rate of 20% in favor of an improved response rate of 45%&#xD;
&#xD;
      Participants will be enrolled in 2 disease cohorts, thymoma and thymic carcinoma, with up to&#xD;
      17 evaluable participants of each tumor type. Accrual ceiling will be set at 38 participants&#xD;
      to account for inevaluable participants.&#xD;
&#xD;
      Participants who have completed 12 months of treatment with an ongoing response or disease&#xD;
      stability (for &gt;= 6 months) will be given an option of discontinuing active treatment with&#xD;
      the ability to reinstitute treatment on one occasion if radiological or clinical disease&#xD;
      activity is noted during follow-up. All eligibility criteria should be met at the time of&#xD;
      restarting treatment with bintrafusp alfa.&#xD;
&#xD;
      Tumor response will be assessed after completion of every third cycle (6 weeks) using&#xD;
      modified immune-related RECIST criteria. When possible, an optional tumor biopsy will be&#xD;
      conducted pre-treatment, after 3 doses in participants responding to treatment or at 6 weeks,&#xD;
      whichever is sooner, to evaluate treatment-related, intra-tumoral changes.&#xD;
&#xD;
      Exploratory objectives include immune correlative studies to analyze immune cell subsets,&#xD;
      PD-L1 expression and evaluation of soluble factors and intra-tumoral changes before and after&#xD;
      bintrafusp alfa treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 26, 2020</start_date>
  <completion_date type="Anticipated">January 1, 2025</completion_date>
  <primary_completion_date type="Anticipated">January 1, 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>Objective response rate</measure>
    <time_frame>from the start of the treatment until disease progression/recurrence</time_frame>
    <description>overall response rate for M7824 based on RECIST criteria</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of response, progression free survival &amp;amp; overall survival</measure>
    <time_frame>from the start of the treatment until disease progression/recurrence</time_frame>
    <description>To determine duration of response, progression free survival and overall survival in participants with recurrent thymic epithelial TETs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety &amp;amp; tolerability of M7824</measure>
    <time_frame>from the start of the treatment until disease progression/recurrence</time_frame>
    <description>To determine the safety and tolerability of 1200 mg M7824 administered once every 2 weeks in participants with thymoma and thymic carcinoma</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">38</enrollment>
  <condition>Thymic Epithelial Tumor</condition>
  <condition>Recurrent Thymoma</condition>
  <condition>Thymic Cancer</condition>
  <arm_group>
    <arm_group_label>Bintrafusp alfa (M7824)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Bintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two weeks until disease progression or development of intolerable adverse events.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>M7824</intervention_name>
    <description>Bintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two weeks until disease progression or development of intolerable adverse events.</description>
    <arm_group_label>Bintrafusp alfa (M7824)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  IINCLUSION CRITERIA:&#xD;
&#xD;
          -  Participants must have histologically confirmed (by the pathology department/CCR/NCI)&#xD;
             thymoma or thymic carcinoma.&#xD;
&#xD;
          -  Participants must have had at least one prior line of platinum-based chemotherapy.&#xD;
             Progressive disease must be documented prior to study entry and participants must have&#xD;
             advanced, unresectable disease that is not amenable to surgical resection.&#xD;
&#xD;
          -  Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST&#xD;
             1.1.&#xD;
&#xD;
          -  Participants must be aged &gt;=18 years.&#xD;
&#xD;
          -  ECOG performance status &lt;=1.&#xD;
&#xD;
          -  Participants must have adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  absolute neutrophil count: &gt;= 1,500/mm3 OR &gt;= 1.5 x 10(9)/L&#xD;
&#xD;
               -  platelets: &gt;=&gt; 100,000/mm3 OR &gt;= 100 x 10(9)/L&#xD;
&#xD;
               -  hemoglobin: &gt;= 9g/dL (may have been transfused)&#xD;
&#xD;
               -  total bilirubin: &lt;= the upper limit of normal range (ULN) OR &lt;= 3.0 x ULN for&#xD;
                  participants with documented metastatic disease to the liver&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT): &lt;= 1.5 x ULN OR &lt;= 5 x ULN for subjects with documented&#xD;
                  metastatic disease to the liver&#xD;
&#xD;
               -  ALP: &lt;= 2.5 x ULN&#xD;
&#xD;
               -  creatinine clearance: &gt;= 60 mL/min/1.73 m2 calculated by calculated using eGRF in&#xD;
                  the clinical lab&#xD;
&#xD;
               -  INR: normal INR, per institutional guidelines&#xD;
&#xD;
               -  PT: &lt;= 1.5 x ULN&#xD;
&#xD;
               -  aPTT: &lt;= 1.5 x ULN&#xD;
&#xD;
          -  Negative serum or urine pregnancy test at screening for women of childbearing&#xD;
             potential (WOCBP). NOTE: WOCBP is defined as any female who has experienced menarche&#xD;
             and who has not undergone successful surgical sterilization or who is not&#xD;
             postmenopausal. If necessary, to confirm postmenopausal status an FSH level will be&#xD;
             included at screening. The effects of Bintrafusp alfa on the developing human fetus&#xD;
             are unknown. For this reason, women of childbearing potential and men must agree to&#xD;
             use adequate contraception (hormonal or barrier method of birth control; abstinence)&#xD;
             prior to study entry, for the duration of study participation and for at least 2&#xD;
             months after the last dose of the drug.&#xD;
&#xD;
          -  Participants with previously treated brain or CNS metastases are eligible provided&#xD;
             that the subject has recovered from any acute side effects of radiotherapy and does&#xD;
             not require treatment with steroids, and any whole brain radiation therapy was&#xD;
             completed at least 2 weeks prior to enrollment.&#xD;
&#xD;
          -  Ability of subject to understand and the willingness to sign a written informed&#xD;
             consent document.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to bintrafusp alfa.&#xD;
&#xD;
          -  History of anaphylaxis or recent (within 5 months) history of uncontrollable asthma.&#xD;
&#xD;
          -  Prior treatment with PD-1 or PD-L1-directed immune checkpoint blockade is not&#xD;
             permitted. Prior treatment with other immunomodulating drugs such as cancer vaccines&#xD;
             is permitted based on investigators discretion as long as treatment was not&#xD;
             discontinued due to life-threatening adverse events (laboratory abnormalities alone&#xD;
             with prior therapy will not exclude participants from this trial).&#xD;
&#xD;
          -  Concurrent treatment with a non-permitted drug&#xD;
&#xD;
          -  Prior anticancer treatment within 14 days before treatment (e.g., cytoreductive&#xD;
             therapy, radiotherapy [with the exception of palliative bone directed radiotherapy],&#xD;
             immune therapy, or cytokine therapy except for erythropoietin); major surgery within&#xD;
             14 days before treatment (excluding prior diagnostic biopsy); prior systemic therapy&#xD;
             (or 5 half-lives of a drug, whichever is shorter) with immunosuppressive agents within&#xD;
             14 days before treatment; use of hormonal agents for anti-cancer therapy within 7 days&#xD;
             before treatment; or use of any investigational drug within 14 days before treatment.&#xD;
&#xD;
        Note: Subjects receiving bisphosphonate or denosumab are eligible provided treatment was&#xD;
        initiated at least 14 days before treatment.&#xD;
&#xD;
          -  History of previous malignant disease within the last 3 years with the following&#xD;
             exceptions: basal or squamous cell carcinoma in situ of the skin treated with curative&#xD;
             intent, endoscopically resected GI cancers limited to the mucosal layer without&#xD;
             recurrence in &gt; 1 year, cervical carcinoma in situ, ductal carcinoma in situ of the&#xD;
             breast, papillary or follicular thyroid carcinoma, and superficial/non-muscle invasive&#xD;
             bladder cancer.&#xD;
&#xD;
          -  Active brain or CNS metastases causing clinical symptoms or metastases that require&#xD;
             therapeutic intervention.&#xD;
&#xD;
          -  Active or history of autoimmune disease that might deteriorate when receiving an&#xD;
             immune-stimulatory agent, with the exception of diabetes type I, vitiligo, psoriasis,&#xD;
             autoimmune thyroid disease not requiring immunosuppressive treatment, or pure red cell&#xD;
             aplasia that are adequately managed with medical therapy. In addition,&#xD;
             anti-acetylcholine receptor binding antibodies will be checked during screening and&#xD;
             participants will be ineligible if results are positive, even if there is no clinical&#xD;
             history of autoimmune disease.&#xD;
&#xD;
          -  Participants receiving systemic corticosteroids at doses &gt; 10 mg daily prednisone&#xD;
             equivalent will be excluded. However, participants on inhaled steroids and adrenal&#xD;
             replacement steroid doses up to 10 mg daily prednisone equivalents are permitted in&#xD;
             the absence of autoimmune disease&#xD;
&#xD;
          -  Active infection requiring systemic therapy or significant acute or chronic infections&#xD;
             including, among others:&#xD;
&#xD;
               -  Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening&#xD;
                  (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test&#xD;
                  positive).&#xD;
&#xD;
               -  Known history of testing positive for HIV or testing positive for HIV at&#xD;
                  screening or known acquired immunodeficiency syndrome.&#xD;
&#xD;
        HIV-positive TET participants are ineligible because of the risk of developing&#xD;
        opportunistic infections after treatment with an immune checkpoint inhibitor. Additionally,&#xD;
        TET participants are at higher risk of developing opportunistic infections due to&#xD;
        underlying immune defects. Prior cases of disseminated herpes virus, cytomegalovirus and&#xD;
        fungal infections have been documented in this patient population.&#xD;
&#xD;
          -  Prior organ transplantation including allogenic stem-cell transplantation,&#xD;
             Participants who have had prior transplants that do not require immunosuppression are&#xD;
             eligible.&#xD;
&#xD;
          -  Persisting toxicity related to prior therapy (NCI CTCAE v. 5 Grade &gt; 1); however,&#xD;
             alopecia, sensory neuropathy Grade &lt;= 2, or other Grade &lt;= 2 not constituting a safety&#xD;
             risk based on investigator s judgment are acceptable.&#xD;
&#xD;
          -  Participants unwilling to accept blood products as medically indicated.&#xD;
&#xD;
          -  Pregnant or lactating women. Pregnant women are excluded from this study because&#xD;
             Bintrafusp alfa is in the class of agents known as antineoplastics/monoclonal&#xD;
             antibodies with the potential for teratogenic or abortifacient effects. Because there&#xD;
             is an unknown but potential risk for adverse events in nursing infants secondary to&#xD;
             treatment of the mother with Bintrafusp alfa, breastfeeding should be discontinued if&#xD;
             the mother is treated with Bintrafusp alfa.&#xD;
&#xD;
          -  Known alcohol or drug abuse.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic&#xD;
             congestive heart failure, unstable angina pectoris, cardiac arrhythmia, cerebral&#xD;
             vascular accident/stroke &lt; 6 months prior to enrollment, myocardial infarction &lt; 6&#xD;
             months prior to enrollment, or psychiatric illness/social situations that would limit&#xD;
             compliance with study requirements. All other severe acute or chronic medical&#xD;
             conditions including immune colitis, inflammatory bowel disease, immune pneumonitis,&#xD;
             drug-induced pneumonitis requiring oral or IV steroids, interstitial lung disease,&#xD;
             pulmonary fibrosis or psychiatric conditions including recent (within the past year)&#xD;
             or active suicidal ideation or behavior; or laboratory abnormalities that may increase&#xD;
             the risk associated with study participation or study treatment administration or may&#xD;
             interfere with the interpretation of study results and, in the judgment of the&#xD;
             investigator, would make the patient inappropriate for entry into this study.&#xD;
             Participants with history of bleeding diathesis or recent major bleeding events&#xD;
             considered by the Investigator as high risk for investigational drug treatment are&#xD;
             also excluded.&#xD;
&#xD;
          -  Administration of live vaccine within 4 weeks prior to treatment, with the exception&#xD;
             of vaccination against COVID-19&#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>Arun Rajan, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Shannon G Swift, R.N.</last_name>
    <phone>(240) 858-3157</phone>
    <email>shannon.swift@nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Arun Rajan, M.D.</last_name>
    <phone>(240) 760-6236</phone>
    <email>rajana@mail.nih.gov</email>
  </overall_contact_backup>
  <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>
    <status>Recruiting</status>
    <contact>
      <last_name>For more information at the NIH Clinical Center contact National Cancer Institute Referral Office</last_name>
      <phone>888-624-1937</phone>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2020-C-0097.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>September 14, 2023</verification_date>
  <study_first_submitted>June 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <last_update_submitted>September 15, 2023</last_update_submitted>
  <last_update_submitted_qc>September 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Thymoma</keyword>
  <keyword>thymic cancer</keyword>
  <keyword>Immune Checkpoint Inhibition</keyword>
  <keyword>programmed death ligand 1 (PD-L1)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thymoma</mesh_term>
    <mesh_term>Thymus Neoplasms</mesh_term>
  </condition_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. In addition, 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>
  <!-- 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/NCT04417660
org study id: 200097
secondary id: 20-C-0097
nct id: NCT04417660
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Thymoma and thymic carcinoma are diseases of the thymus. Platinum-based chemotherapy is the
      standard treatment for these diseases. But in many cases, the disease returns after
      treatment. Researchers want to see if a new drug can help.

      Objective:

      To see if bintrafusp alfa (M7824) is an effective treatment for thymoma and thymic carcinoma.

      Eligibility:

      People age 18 and older who have thymoma or thymic cancer and their disease returned or
      progressed after treatment with at least one platinum-containing chemotherapy treatment plan.

      Design:

      Participants will be screened under a separate protocol. Their medical, medicine, and
      treatment history will be reviewed. They will have a tumor biopsy if they do not have a
      sample.

      Participants will get the study drug once every 2 weeks as an intravenous infusion. For this,
      a small plastic tube is put into an arm vein.

      During the study, participants will undergo the following:

      Medicine review

      Physical exam

      Review of their symptoms and their ability to perform their normal activities

      Blood and urine tests

      Thigh muscle scan (using MRI)

      Tumor assessment (using MRI or CT)

      Heart and lung function tests

      Thyroid gland test

      Skin assessment.

      Participants may have tumor biopsies. Some of their blood and biopsy samples will be used for
      gene testing.

      Participants may take the study drug until their disease worsens or they cannot tolerate
      treatment.

      Participants will have follow-up visits 2 and 6 weeks after stopping treatment. Then they
      will have long-term follow-up visits every 3 months. These may include imaging scans. Visits
      may be done by phone, with scans (if needed) done at their doctor s office.
Background

      Platinum-based chemotherapy is the standard of care for advanced unresectable thymic
      epithelial tumors (TETs). However more than half of these patients experience disease
      recurrence and require second-line therapy.

      There are no approved drugs for treatment of recurrent thymoma and thymic carcinoma and new
      therapeutic options are needed for patients who have disease progression on or after
      platinum-containing therapy.

      We have demonstrated the safety and clinical activity of immune checkpoint inhibition in
      patients with recurrent TETs. In an ongoing trial (NCT03076554) we have shown that avelumab,
      an anti-programmed death ligand-1 (PD-L1) antibody, induces major responses and has an
      acceptable safety profile.

      Combination immunotherapy is under evaluation for treatment of various cancers but has not
      been studied for the treatment of TETs. Immunotherapy targeting the PD-1/PD-L1 axis can be
      combined with other immune checkpoint inhibitors, cancer vaccines and anti-cytokine therapy.

      Bintrafusp alfa, a bifunctional fusion protein that targets PD-L1 and transforming growth
      factor-b (TGF-b) has shown activity against heavily pre-treated solid tumors including
      non-small cell lung cancer previously treated with single-agent anti-PD-1/PD-L1 inhibitors.

      Retrospective analysis of pre-chemotherapy tissue obtained from 20 patients with stage IV
      thymic carcinoma and 13 cases of stage III/IV thymoma, showed TGF-b expression in 65% cases
      of thymic carcinoma and 15% cases of thymoma with a lower median survival among patients with
      thymic carcinoma (30 months versus 63 months).

      As part of a phase I clinical trial, treatment with bintrafusp alfa resulted in a brief
      period of disease stabilization and no immune-related adverse events in one patient with
      heavily pre-treated, WHO subtype B3 thymoma with a large disease burden

      Further investigation of Bintrafusp alfa in patients with recurrent TETs is needed to define
      the clinical activity and safety of this drug in patients with TETs.

      Primary Objectives

      To determine the objective response rate (ORR) to bintrafusp alfa in participants with
      relapsed or refractory thymoma and thymic carcinoma.

      Eligibility

      Participants >= age 18 years with histologically confirmed, unresectable thymoma or thymic
      carcinoma who have previously been treated with at least one platinum-containing chemotherapy
      regimen with progressive disease prior to study entry.

      Progressive and measurable disease prior to enrollment

      No history of autoimmune disease, with exception of vitiligo, autoimmune thyroid disease, or
      pure red cell aplasia that are adequately managed with medical therapy

      Adequate renal, hepatic and hematopoietic function

      Design

      This will be a single-arm, phase II study to determine the clinical activity of treatment
      with Bintrafusp alfa in participants with relapsed or refractory thymoma and thymic
      carcinoma.

      Bintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two weeks
      until disease progression or development of intolerable adverse events. The two-week period
      will constitute one cycle.

      A Simon optimal two-stage phase II trial design will be used to rule out unacceptably low
      response rate of 20% in favor of an improved response rate of 45%

      Participants will be enrolled in 2 disease cohorts, thymoma and thymic carcinoma, with up to
      17 evaluable participants of each tumor type. Accrual ceiling will be set at 38 participants
      to account for inevaluable participants.

      Participants who have completed 12 months of treatment with an ongoing response or disease
      stability (for >= 6 months) will be given an option of discontinuing active treatment with
      the ability to reinstitute treatment on one occasion if radiological or clinical disease
      activity is noted during follow-up. All eligibility criteria should be met at the time of
      restarting treatment with bintrafusp alfa.

      Tumor response will be assessed after completion of every third cycle (6 weeks) using
      modified immune-related RECIST criteria. When possible, an optional tumor biopsy will be
      conducted pre-treatment, after 3 doses in participants responding to treatment or at 6 weeks,
      whichever is sooner, to evaluate treatment-related, intra-tumoral changes.

      Exploratory objectives include immune correlative studies to analyze immune cell subsets,
      PD-L1 expression and evaluation of soluble factors and intra-tumoral changes before and after
      bintrafusp alfa treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective response rate
time frame: from the start of the treatment until disease progression/recurrence
description: overall response rate for M7824 based on RECIST criteria
measure: Duration of response, progression free survival &amp; overall survival
time frame: from the start of the treatment until disease progression/recurrence
description: To determine duration of response, progression free survival and overall survival in participants with recurrent thymic epithelial TETs
measure: Safety &amp; tolerability of M7824
time frame: from the start of the treatment until disease progression/recurrence
description: To determine the safety and tolerability of 1200 mg M7824 administered once every 2 weeks in participants with thymoma and thymic carcinoma
arm group label: Bintrafusp alfa (M7824)
arm group type: Experimental
description: Bintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two weeks until disease progression or development of intolerable adverse events.
intervention type: Drug
intervention name: M7824
description: Bintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two weeks until disease progression or development of intolerable adverse events.
arm group label: Bintrafusp alfa (M7824)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Arun Rajan, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
last name: Shannon G Swift, R.N.
phone: (240) 858-3157
email: shannon.swift@nih.gov
last name: Arun Rajan, M.D.
phone: (240) 760-6236
email: rajana@mail.nih.gov
facility: 
status: Recruiting
contact: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2020-C-0097.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Thymoma
mesh term: Thymus Neoplasms
sharing ipd: Yes
ipd description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, 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.