<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/NCT03018288</url>
  </required_header>
  <id_info>
    <org_study_id>170034</org_study_id>
    <secondary_id>17-C-0034</secondary_id>
    <nct_id>NCT03018288</nct_id>
  </id_info>
  <brief_title>Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)</brief_title>
  <official_title>A Randomized, Double Blind Phase II Trial of Surgery, Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)</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;
      GBM refers to a specific kind of brain cancer called glioblastoma. The standard treatment for&#xD;
      GBM is radiation plus temozolomide, an oral chemotherapy drug. Pembrolizumab is an immune&#xD;
      therapy that is now used to treat other cancers. The addition of pembrolizumab to the&#xD;
      standard treatment of radiation and temozolomide has been shown to be well tolerated.&#xD;
      Researchers want to see if adding a vaccine made from the person s own tumor will improve the&#xD;
      effect of the pembrolizumab. The vaccine which is developed from fresh tumor taken at the&#xD;
      time of surgery is called HSPPC-96.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      To see if the adding pembrolizumab and HSPPC-96 improves the standard treatment for&#xD;
      glioblastoma multiforme.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Adults at least 18 years old with glioblastoma.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with typical cancer tests:&#xD;
&#xD;
      Brain scan&#xD;
&#xD;
      Medical history&#xD;
&#xD;
      Blood and urine tests&#xD;
&#xD;
      Questions about quality of life and symptoms&#xD;
&#xD;
      These tests will be repeated throughout the study.&#xD;
&#xD;
      Participants will have surgery to remove their tumor. A tissue sample from the tumor will be&#xD;
      sent to a lab. A vaccine will be made from it.&#xD;
&#xD;
      Some participants will get pembrolizumab and vaccine. Some will get pembrolizumab and&#xD;
      placebo. Participants will not know which they get.&#xD;
&#xD;
      Participants will get radiation for 6 weeks.&#xD;
&#xD;
      Participants will take temozolomide by mouth before each treatment.&#xD;
&#xD;
      Participants will get pembrolizumab by IV for 30 minutes 3 times over the radiation cycle.&#xD;
&#xD;
      Participants will keep taking the 2 drugs every few weeks for about a year. Some may take&#xD;
      pembrolizumab for an additional year.&#xD;
&#xD;
      Most participants will get the vaccine or placebo after radiation. They will get it 5 times&#xD;
      over 6 weeks. Some participants will continue to get the vaccine every few weeks for 1 or 2&#xD;
      years.&#xD;
&#xD;
      Participants will repeat the screening tests when they stop study treatment. They will also&#xD;
      have follow-up phone calls.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Malignant gliomas are unfortunately, in most cases, a uniformly fatal tumor. Despite&#xD;
           aggressive surgery, radiation treatment (RT) and chemotherapy at initial diagnosis these&#xD;
           tumors almost always recur.&#xD;
&#xD;
        -  Many clinical trials in glioblastoma (GBM) have evaluated the addition of agent(s) to&#xD;
           standard therapy which consists of concurrent radiation with temozolomide chemotherapy&#xD;
           after maximal surgical resection in patients with newly diagnosed disease and salvage&#xD;
           chemotherapy with either rechallenge with temozolomide or an alternative alkylating&#xD;
           agent such as CCNU or cisplatin. To date, none of the combination strategies have&#xD;
           demonstrated clinical benefit. Furthermore, in subjects with an unmethylated MGMT&#xD;
           (O6-methylguanine-DNA methyltransferase) promoter temozolomide has only modest benefit&#xD;
           and salvage therapies have not demonstrated a significant impact in this subject group&#xD;
           underscoring the need for more research.&#xD;
&#xD;
        -  Immunotherapy offers the promise of improving outcomes for patients with GBM by evoking&#xD;
           specific immune responses that may produce a more sustained and less toxic effect than&#xD;
           conventional therapy. Heat-shock proteins (HSPs), which function as intracellular&#xD;
           chaperones, can be used to deliver a variety of tumor antigens to antigen presenting&#xD;
           cells for immune stimulation.&#xD;
&#xD;
        -  Heat Shock Protein-Peptide Complex-96 (HSPPC-96) consists of the heat shock protein&#xD;
           glycoprotein-96 (HSP gp-96) and a wide array of chaperoned proteins, including&#xD;
           autologous antigenic peptides (aka vaccine ). Heat shock proteins (HSP) are molecules&#xD;
           that respond to cellular stress and counteract abnormal protein folding. They are known&#xD;
           to modulate immune responses, especially the HSP gp-96. In a stressful environment, such&#xD;
           as a tumor, HSPs are upregulated and highly expressed on tumor cells. This protects the&#xD;
           tumor and leads to resistance to therapy. HSP expression is associated with cellular&#xD;
           proliferation, apoptosis evasion, tissue invasion, metastasis, and angiogenesis.&#xD;
&#xD;
        -  Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of&#xD;
           the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its&#xD;
           ligands, PD-L1 and PD-L2. Additionally, pembrolizumab is thought to also have activity&#xD;
           in the peripherally circulating T-effector cells by reversing lymphocyte exhaustion. It&#xD;
           is currently FDA approved for use in patients with unresectable or metastatic melanoma&#xD;
           and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF&#xD;
           inhibitor and NSCLC with elevated PD-L1 in the tumor. recurrent or metastatic HNSCC with&#xD;
           disease progression on or after platinum-containing chemotherapy. It is also FDA&#xD;
           approved for use with advanced (metastatic) non-small cell lung cancer (NSCLC) whose&#xD;
           disease has progressed after other treatments and with tumors that express a protein&#xD;
           called PD-L1 and for the treatment of patients with recurrent or metastatic head and&#xD;
           neck squamous cell carcinoma (HNSCC) with disease progression on or after&#xD;
           platinum-containing chemotherapy&#xD;
&#xD;
        -  This study will be the first to evaluate this combination of vaccine (HSPPC-96) and PD-1&#xD;
           inhibition (pembrolizumab) in newly diagnosed GBM patients whose tumors are MGMT&#xD;
           promoter unmethylated and are isocytrate dehydrogenase (IDH) wildtype; and will provide&#xD;
           important data on immune-modulatory effect of this combination. This may be of&#xD;
           particular value in patients with high peripheral PD-L1 expression, but also the value&#xD;
           of PD-1 added to standard GBM therapy. As vaccine needs to be generated from the patient&#xD;
           s tumor, patients will need to be identified prior to surgery.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  MRI findings consistent with a suspected GBM or histologically confirmed newly diagnosed&#xD;
           GBM that has not been treated and would benefit from further surgical resection.&#xD;
&#xD;
        -  Tumor must be supratentorial.&#xD;
&#xD;
        -  GBM diagnosis must be made by surgical excision (stereotactic biopsy will not be allowed&#xD;
           unless there is plan for second surgery to remove greater than or equal to 80% of the&#xD;
           tumor) and patients tumors must not have MGMT promoter methylation and must be IDH&#xD;
           wildtype.&#xD;
&#xD;
        -  No prior treatment with radiation or chemotherapy for their GBM.&#xD;
&#xD;
        -  Age greater than or equal to 18 years on day of signing informed consent&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - The primary endpoint is to determine whether the one year overall survival (OS) rate is&#xD;
      improved in newly diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and&#xD;
      are IDH wildtype treated with RT + TMZ + Pembrolizumab followed by TMZ + Pembrolizumab +&#xD;
      HSPPC-96 vaccine or Placebo vaccine x 6 cycles (1 cycle is 9 weeks).&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  This will be a randomized, double blind phase II trial of surgery, RT + TMZ +&#xD;
           Pembrolizumab followed by TMZ + Pembrolizumab +/- HSPPC-96 in newly diagnosed GBM&#xD;
           patients whose tumors have an unmethylated MGMT promotor and are IDH wildtype.&#xD;
&#xD;
        -  Subjects will be assigned to intervention based on ability to generate vaccine as&#xD;
           follows:&#xD;
&#xD;
             -  If &gt;= 80 % of tumor removed, &gt;=7 g of tumor is resected but HSPPC-96 cannot be&#xD;
                generated, subjects will be treated on the ancillary arm of RT+TMZ +Pembrolizumab&#xD;
                followed by TMZ+ Pembrolizumab.&#xD;
&#xD;
             -  If&gt;= 80% of contrasting enhanced tumor removed (based on T1 Post contrast MRI using&#xD;
                cross sectional measurement), &gt;= 7 g of tumor is resected and sufficient HSPPC-96&#xD;
                is generated, subjects will be included in the main cohort and will be randomized&#xD;
                on a 1:1 basis to receive:&#xD;
&#xD;
                  -  RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab + Placebo&#xD;
&#xD;
      OR&#xD;
&#xD;
      --- RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab+HSPPC-96&#xD;
&#xD;
      -Subjects whose tumor does not meet the criteria (unmethylated MGMT promoter and IDH wildtype&#xD;
      by pathology) and for whom &lt; 80 % of tumor is removed or &lt; 7g of tumor is resected are not&#xD;
      eligible for further intervention. Approximately 8 potentially eligible patients are screened&#xD;
      per month, and it is anticipated that at least 1-2 per month will be accrued per site.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 21, 2017</start_date>
  <completion_date type="Actual">December 20, 2022</completion_date>
  <primary_completion_date type="Actual">December 20, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To determine whether the one-year overall survival (OS) is improved in newly diagnosed MGMT unmethylated GBM patients treated with RT + TMZ + Pembrolizumab followed by Pembrolizumab + TMZ +/- HSPPC-96 x 6 cycles (1 cycle is 9 weeks) months.</measure>
    <time_frame>one year</time_frame>
    <description>One-year overall survival</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Glioblastoma</condition>
  <arm_group>
    <arm_group_label>1/Radiation Therapy</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Standard radiation therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2/RT+TMZ + Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard treatment with experimental treatment (pembro) added</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3/RT+TMZ+Pembrolizumab+HSPPC96 Vaccine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard treatment with experimental treatment (pembro+ vaccine) added</description>
  </arm_group>
  <arm_group>
    <arm_group_label>4/RT+TMZ+Pembrolizumab+ Placebo Vaccine</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Standard treatment with experimental treatment and placebo added</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Pembrolizumab at 200mg will be administered on day 1 as a 30 minute IV infusion (prior to RT) every 3 weeks during RT on days 1, 22 and 43. At one year, if patients are doing well they may continue pembolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.</description>
    <arm_group_label>2/RT+TMZ + Pembrolizumab</arm_group_label>
    <arm_group_label>3/RT+TMZ+Pembrolizumab+HSPPC96 Vaccine</arm_group_label>
    <arm_group_label>4/RT+TMZ+Pembrolizumab+ Placebo Vaccine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>HSPPC-96</intervention_name>
    <description>One week post RT, patients will receive weekly x 4 a dose of HSPPC-96 0.4mL intradermal vaccine or placebo. HSPPC-96 vaccine or placebo will then be given 21 days after the day 5 dose of TMZ. HSPPC-96 vaccine or placebo vaccine will be given for 6 cycles or until supply runs out. Patients who receive placebo will be matched for number of vaccine injections that were generated by their tumor tissue. At one year, if patients are doing well they may continue pembrolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.</description>
    <arm_group_label>3/RT+TMZ+Pembrolizumab+HSPPC96 Vaccine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Temozolomide</intervention_name>
    <description>TMZ will be administered on day 1 of radiation therapy (before RT treatment) and continue throughout RT at the dose of 75 mg/m2. Post RT: The starting TMZ dose will be 150 mg/m2/day for cycle 1, days 1-5, with a single dose escalation to 200 mg/m2/day (days 29-33) and for all subsequent treatment if no treatment-related adverse events greater than Grade 2 are noted. TMZ will be given for 6 cycles.</description>
    <arm_group_label>1/Radiation Therapy</arm_group_label>
    <arm_group_label>2/RT+TMZ + Pembrolizumab</arm_group_label>
    <arm_group_label>3/RT+TMZ+Pembrolizumab+HSPPC96 Vaccine</arm_group_label>
    <arm_group_label>4/RT+TMZ+Pembrolizumab+ Placebo Vaccine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>One week post RT, patients will receive weekly x 4 a dose of HSPPC-96 0.4mL intradermal vaccine or placebo. HSPPC-96 vaccine or placebo will then be given 21 days after the day 5 dose of TMZ. HSPPC-96 vaccine or placebo vaccine will be given for 6 cycles or until supply runs out. Patients who receive placebo will be matched for number of vaccine injections that were generated by their tumor tissue. At one year, if patients are doing well they may continue pembrolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.</description>
    <arm_group_label>4/RT+TMZ+Pembrolizumab+ Placebo Vaccine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        Pre Surgery (Step 1) Inclusion:&#xD;
&#xD;
          -  MRI findings consistent with a suspected GBM or a histologically confirmed newly&#xD;
             diagnosed GBM that has not been treated and would benefit from further surgical&#xD;
             resection. As vaccine needs to be generated from the patient s tumor, patients will&#xD;
             need to be identified prior to definitive surgery.&#xD;
&#xD;
          -  Preliminary assessment by the neurosurgeons that &gt;80% of the tumor can be resected&#xD;
             with an expectation that &gt;7gm of tissue would be resected&#xD;
&#xD;
          -  Age greater than or equal to 18 years on day of signing informed consent.&#xD;
&#xD;
          -  Karnofsky performance status greater than or equal to 70%.&#xD;
&#xD;
          -  Tumor must be supratentorial only.&#xD;
&#xD;
          -  Stereotactic biopsy will not be allowed unless there is plans for second surgery to&#xD;
             remove greater than or equal to 80 % of the tumor.&#xD;
&#xD;
          -  No prior treatment with radiation or chemotherapy for their GBM.&#xD;
&#xD;
          -  No prior treatment with carmustine wafers.&#xD;
&#xD;
        Post-Surgery (Step 2) Inclusion:&#xD;
&#xD;
          -  Pathology must be a GBM, MGMT promoter region determined to be unmethylated and IDH&#xD;
             wild type greater than or equal to 80 % resection of contrast enhanced tumor on post&#xD;
             operative MRI and greater than 7 grams of tumor resected are required otherwise&#xD;
             patient is ineligible.&#xD;
&#xD;
          -  Treatment must be initiated greater than or equal to 14 days and &lt; 6 weeks from&#xD;
             surgery.&#xD;
&#xD;
          -  Craniotomy site must be adequately healed and free of drainage or cellulitis, and the&#xD;
             underlying cranioplasty must appear intact at the time of radiation. Radiation must&#xD;
             start within 6 weeks of surgery.&#xD;
&#xD;
          -  Dexamethasone dose should be less than or equal to 4 mg/day or steroid equivalent&#xD;
             prior to starting treatment. If higher doses are needed, consult with Study Chair.&#xD;
&#xD;
          -  Female subjects of childbearing potential should have a negative urine or serum&#xD;
             pregnancy within 7 days prior to receiving the first dose of study medication. If the&#xD;
             urine test is positive or cannot be confirmed as negative, a negative serum pregnancy&#xD;
             test will be required.&#xD;
&#xD;
          -  Patients must have adequate organ and bone marrow function within 14 days prior to&#xD;
             step 2 registration, as defined below:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt; 1.5 (SqrRoot) 10(9)/L; platelet count &gt; 100&#xD;
                  (SqrRoot) 10(9)/L; and hemoglobin (Hb) &gt;9.0 g/dL within 7 days prior to step 2&#xD;
                  registration. Note: The use of transfusion or other intervention to achieve Hb&#xD;
                  greater than or equal to 9.0 g/dL is acceptable.&#xD;
&#xD;
               -  Total bilirubin &lt; 1.5 (SqrRoot) ULN (except in patients diagnosed with Gilbert s&#xD;
                  disease)&#xD;
&#xD;
               -  AST (SGOT), ALT (SGPT), and alkaline phosphatase (ALP) &lt; 2.5 (SqrRoot) ULN&#xD;
&#xD;
               -  Serum creatinine &lt; 1.5 (SqrRoot) ULN&#xD;
&#xD;
               -  International normalized ratio (INR), prothrombin time (PT), or activated partial&#xD;
                  thromboplastin time (APTT) as follows: In the absence of therapeutic intent to&#xD;
                  anticoagulate the patient: INR &lt; 1.5 or PT &lt; 1.5(SqrRoot) ULN or aPTT &lt;&#xD;
                  1.5(SqrRoot) ULN. In the presence of therapeutic intent to anticoagulate the&#xD;
                  patient: INR or PT and aPTT within therapeutic limits (according to the medical&#xD;
                  standard in the institution) and the patient has been on a stable dose of&#xD;
                  anticoagulants for at least 2 weeks before registration.&#xD;
&#xD;
          -  Females of child-bearing potential (FOCBP) and males must agree to use two adequate&#xD;
             contraception methods (give examples, e.g. hormonal or barrier method of birth&#xD;
             control; abstinence) prior to study entry, for the duration of study participation,&#xD;
             and for 120 days following completion of therapy. Should a female patient become&#xD;
             pregnant or suspect she is pregnant while participating in this study, she should&#xD;
             inform her treating physician immediately. Male patients who father a child should&#xD;
             notify the treating physician.&#xD;
&#xD;
        NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal&#xD;
        ligation, or remaining celibate by choice) who meets the following criteria:&#xD;
&#xD;
          1. Has not undergone a hysterectomy or bilateral oophorectomy&#xD;
&#xD;
          2. Has had menses at any time in the preceding 12 consecutive months (and therefore has&#xD;
             not been naturally postmenopausal for &gt; 12 months)&#xD;
&#xD;
               -  Patients must have the ability to understand and the willingness to sign a&#xD;
                  written informed consent prior to registration on study.&#xD;
&#xD;
               -  Diagnosis must be made by surgical excision.&#xD;
&#xD;
               -  Patients should not be on antibiotics for any infection but post operative&#xD;
                  antibiotics are allowed if used prophylactically but should be completed prior to&#xD;
                  starting RT.&#xD;
&#xD;
             EXCLUSION CRITERIA:&#xD;
&#xD;
             Pre-Surgery (Step 1) Exclusion:&#xD;
&#xD;
               -  Known history of immunodeficiency (HIV). This medical entity can be exacerbated&#xD;
                  by PD-1 blockade.&#xD;
&#xD;
               -  History of another malignancy in the previous 3 years, with a disease-free&#xD;
                  interval of &lt; 3 years. Exceptions include basal cell carcinoma of the skin,&#xD;
                  squamous cell carcinoma of the skin, or in situ cervical cancer that has&#xD;
                  undergone potentially curative therapy. Patients who have undergone a bone marrow&#xD;
                  or stem-cell transplant for any malignancy are excluded.&#xD;
&#xD;
               -  Has an active autoimmune disease requiring systemic treatment within the past 3&#xD;
                  months or a documented history of clinically severe autoimmune disease, or a&#xD;
                  syndrome that requires chronic systemic steroids or immunosuppressive agents&#xD;
                  except as noted above. Subjects with vitiligo or resolved childhood asthma/atopy&#xD;
                  would be an exception to this rule. Subjects that require intermittent use of&#xD;
                  bronchodilators or local steroid injections will not be excluded from the study.&#xD;
                  Subjects with hypothyroidism stable on hormone replacement or Sjorgen s syndrome&#xD;
                  will not be excluded from the study.&#xD;
&#xD;
               -  Has a history of interstitial lung disease, non-infectious pneumonitis or&#xD;
                  pneumonitis.&#xD;
&#xD;
               -  Has a history or current evidence of any condition, therapy, or laboratory&#xD;
                  abnormality that might confound the results of the trial, interfere with the&#xD;
                  subject s participation for the full duration of the trial, or is not in the best&#xD;
                  interest of the subject to participate, in the opinion of the treating&#xD;
                  investigator. Examples include:&#xD;
&#xD;
                    -  Hypertension (defined as 160/95) that is not controlled on medication&#xD;
&#xD;
                    -  Ongoing or active infection requiring systemic treatment&#xD;
&#xD;
                    -  Symptomatic congestive heart failure&#xD;
&#xD;
                    -  Unstable angina pectoris&#xD;
&#xD;
                    -  Cardiac arrhythmia&#xD;
&#xD;
                    -  Psychiatric illness/social situations or substance abuse disorders that&#xD;
                       would limit compliance with study requirements&#xD;
&#xD;
                    -  Any other illness or condition that the treating investigator feels would&#xD;
                       interfere with study compliance or would compromise the patient s safety or&#xD;
                       study endpoints.&#xD;
&#xD;
               -  Is pregnant or breastfeeding or expecting to conceive or father children within&#xD;
                  the projected duration of the trial, starting with the pre-screening or screening&#xD;
                  visit through 120 days after the last dose of trial treatment.&#xD;
&#xD;
               -  The effects of pembrolizumab and HSPPC-96 on the developing human fetus are&#xD;
                  unknown. For this reason and because checkpoint inhibitors and immunotherapeutic&#xD;
                  vaccines as well as other therapeutic agents used in this trial are known to be&#xD;
                  teratogenic, women of child-bearing potential and men must agree to use adequate&#xD;
                  contraception (hormonal or barrier method of birth control; abstinence) prior to&#xD;
                  study entry, and for the duration of study participation. Should a woman become&#xD;
                  pregnant or suspect she is pregnant while she or her partner is participating in&#xD;
                  this study, she should inform her treating physician immediately.&#xD;
&#xD;
               -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-&#xD;
                  CD137, or anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody&#xD;
                  (including ipilimumab or any other antibody or drug specifically targeting T-cell&#xD;
                  co-stimulation or checkpoint pathways).&#xD;
&#xD;
               -  On treatment for Hepatitis B or Hepatitis C or history of TB.&#xD;
&#xD;
               -  Patients who have a history of allergic reactions attributed to compounds of&#xD;
                  similar chemical or biologic composition to Pembrolizumab are not eligible. Known&#xD;
                  hypersensitivity to any excipients of Pembrolizumab.&#xD;
&#xD;
             Post-Surgery (Step 2) Exclusion:&#xD;
&#xD;
               -  Patients are ineligible if the tumor is not a GBM, MGMT promoter region&#xD;
                  determined to be unmethylated and IDH wild type, or if &lt; 80 % resection of&#xD;
                  contrast enhanced tumor on post-operative MRI or &lt; 7 grams of tumor is resected.&#xD;
&#xD;
               -  Patients who are receiving any other investigational agents.&#xD;
&#xD;
               -  Known history of immunodeficiency (HIV). This medical entity can be exacerbated&#xD;
                  by PD-1 blockade.&#xD;
&#xD;
               -  Any form of immunosuppressive therapy within 7 days prior to the first dose of&#xD;
                  trial treatment excluding steroids. Attempts should be made to have patient on&#xD;
                  lowest possible dose of steroids. These medical entities can be exacerbated by&#xD;
                  PD-1 blockade.&#xD;
&#xD;
               -  History of another malignancy in the previous 3 years, with a disease-free&#xD;
                  interval of &lt; 3 years. Exceptions include basal cell carcinoma of the skin,&#xD;
                  squamous cell carcinoma of the skin, or in situ cervical cancer that has&#xD;
                  undergone potentially curative therapy. Patients who have undergone a bone marrow&#xD;
                  or stem-cell transplant for any malignancy are excluded.&#xD;
&#xD;
               -  Has an active autoimmune disease requiring systemic treatment within the past 3&#xD;
                  months or a documented history of clinically severe autoimmune disease, or a&#xD;
                  syndrome that requires chronic systemic steroids or immunosuppressive agents&#xD;
                  except as noted above. Subjects with vitiligo or resolved childhood asthma/atopy&#xD;
                  would be an exception to this rule. Subjects that require intermittent use of&#xD;
                  bronchodilators or local steroid injections will not be excluded from the study.&#xD;
                  Subjects with hypothyroidism stable on hormone replacement or Sjorgen s syndrome&#xD;
                  will not be excluded from the study.&#xD;
&#xD;
               -  Has a history of interstitial lung disease, non-infectious pneumonitis or&#xD;
                  pneumonitis.&#xD;
&#xD;
               -  Has an active infection requiring systemic antibiotics within 10 days of surgery.&#xD;
&#xD;
               -  Has a history or current evidence of any condition, therapy, or laboratory&#xD;
                  abnormality that might confound the results of the trial, interfere with the&#xD;
                  subject s participation for the full duration of the trial, or is not in the best&#xD;
                  interest of the subject to participate, in the opinion of the treating&#xD;
                  investigator. Examples include:&#xD;
&#xD;
                    -  Hypertension (defined as 160/95) that is not controlled on medication&#xD;
&#xD;
                    -  Ongoing or active infection requiring systemic treatment&#xD;
&#xD;
                    -  Symptomatic congestive heart failure&#xD;
&#xD;
                    -  Unstable angina pectoris&#xD;
&#xD;
                    -  Cardiac arrhythmia&#xD;
&#xD;
                    -  Psychiatric illness/social situations or substance abuse disorders that&#xD;
                       would limit compliance with study requirements&#xD;
&#xD;
                    -  Any other illness or condition that the treating investigator feels would&#xD;
                       interfere with study compliance or would compromise the patient s safety or&#xD;
                       study endpoints.&#xD;
&#xD;
               -  Is pregnant or breastfeeding or expecting to conceive or father children within&#xD;
                  the projected duration of the trial, starting with the pre-screening or screening&#xD;
                  visit through 120 days after the last dose of trial treatment.&#xD;
&#xD;
               -  The effects of pembrolizumab and HSPPC-96 on the developing human fetus are&#xD;
                  unknown. For this reason and because checkpoint inhibitors and immunotherapeutic&#xD;
                  vaccines as well as other therapeutic agents used in this trial are known to be&#xD;
                  teratogenic, women of child-bearing potential and men must agree to use adequate&#xD;
                  contraception (hormonal or barrier method of birth control; abstinence) prior to&#xD;
                  study entry, and for the duration of study participation. Should a woman become&#xD;
                  pregnant or suspect she is pregnant while she or her partner is participating in&#xD;
                  this study, she should inform her treating physician immediately.&#xD;
&#xD;
               -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137,&#xD;
                  or anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including&#xD;
                  ipilimumab or any other antibody or drug specifically targeting T-cell&#xD;
                  co-stimulation or checkpoint pathways).&#xD;
&#xD;
               -  On treatment for Hepatitis B or Hepatitis C or history of TB.&#xD;
&#xD;
               -  Has received a live vaccine within 30 days prior to the first dose of trial&#xD;
                  treatment&#xD;
&#xD;
               -  Patients who have a history of allergic reactions attributed to compounds of&#xD;
                  similar chemical or biologic composition to Pembrolizumab are not eligible. Known&#xD;
                  hypersensitivity to any excipients of Pembrolizumab.&#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 R Gilbert, 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-0034.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>December 22, 2022</verification_date>
  <study_first_submitted>January 11, 2017</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <last_update_submitted>December 23, 2022</last_update_submitted>
  <last_update_submitted_qc>December 23, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Malignant Gliomas</keyword>
  <keyword>Immunotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Temozolomide</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. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.@@@@@@All collected IPD will be shared with collaborators under the terms of collaborative agreements.</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. @@@@@@All collected IPD will be available after primary analysis have been published.</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/NCT03018288
org study id: 170034
secondary id: 17-C-0034
nct id: NCT03018288
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      GBM refers to a specific kind of brain cancer called glioblastoma. The standard treatment for
      GBM is radiation plus temozolomide, an oral chemotherapy drug. Pembrolizumab is an immune
      therapy that is now used to treat other cancers. The addition of pembrolizumab to the
      standard treatment of radiation and temozolomide has been shown to be well tolerated.
      Researchers want to see if adding a vaccine made from the person s own tumor will improve the
      effect of the pembrolizumab. The vaccine which is developed from fresh tumor taken at the
      time of surgery is called HSPPC-96.

      Objectives:

      To see if the adding pembrolizumab and HSPPC-96 improves the standard treatment for
      glioblastoma multiforme.

      Eligibility:

      Adults at least 18 years old with glioblastoma.

      Design:

      Participants will be screened with typical cancer tests:

      Brain scan

      Medical history

      Blood and urine tests

      Questions about quality of life and symptoms

      These tests will be repeated throughout the study.

      Participants will have surgery to remove their tumor. A tissue sample from the tumor will be
      sent to a lab. A vaccine will be made from it.

      Some participants will get pembrolizumab and vaccine. Some will get pembrolizumab and
      placebo. Participants will not know which they get.

      Participants will get radiation for 6 weeks.

      Participants will take temozolomide by mouth before each treatment.

      Participants will get pembrolizumab by IV for 30 minutes 3 times over the radiation cycle.

      Participants will keep taking the 2 drugs every few weeks for about a year. Some may take
      pembrolizumab for an additional year.

      Most participants will get the vaccine or placebo after radiation. They will get it 5 times
      over 6 weeks. Some participants will continue to get the vaccine every few weeks for 1 or 2
      years.

      Participants will repeat the screening tests when they stop study treatment. They will also
      have follow-up phone calls.
Background:

        -  Malignant gliomas are unfortunately, in most cases, a uniformly fatal tumor. Despite
           aggressive surgery, radiation treatment (RT) and chemotherapy at initial diagnosis these
           tumors almost always recur.

        -  Many clinical trials in glioblastoma (GBM) have evaluated the addition of agent(s) to
           standard therapy which consists of concurrent radiation with temozolomide chemotherapy
           after maximal surgical resection in patients with newly diagnosed disease and salvage
           chemotherapy with either rechallenge with temozolomide or an alternative alkylating
           agent such as CCNU or cisplatin. To date, none of the combination strategies have
           demonstrated clinical benefit. Furthermore, in subjects with an unmethylated MGMT
           (O6-methylguanine-DNA methyltransferase) promoter temozolomide has only modest benefit
           and salvage therapies have not demonstrated a significant impact in this subject group
           underscoring the need for more research.

        -  Immunotherapy offers the promise of improving outcomes for patients with GBM by evoking
           specific immune responses that may produce a more sustained and less toxic effect than
           conventional therapy. Heat-shock proteins (HSPs), which function as intracellular
           chaperones, can be used to deliver a variety of tumor antigens to antigen presenting
           cells for immune stimulation.

        -  Heat Shock Protein-Peptide Complex-96 (HSPPC-96) consists of the heat shock protein
           glycoprotein-96 (HSP gp-96) and a wide array of chaperoned proteins, including
           autologous antigenic peptides (aka vaccine ). Heat shock proteins (HSP) are molecules
           that respond to cellular stress and counteract abnormal protein folding. They are known
           to modulate immune responses, especially the HSP gp-96. In a stressful environment, such
           as a tumor, HSPs are upregulated and highly expressed on tumor cells. This protects the
           tumor and leads to resistance to therapy. HSP expression is associated with cellular
           proliferation, apoptosis evasion, tissue invasion, metastasis, and angiogenesis.

        -  Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of
           the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its
           ligands, PD-L1 and PD-L2. Additionally, pembrolizumab is thought to also have activity
           in the peripherally circulating T-effector cells by reversing lymphocyte exhaustion. It
           is currently FDA approved for use in patients with unresectable or metastatic melanoma
           and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF
           inhibitor and NSCLC with elevated PD-L1 in the tumor. recurrent or metastatic HNSCC with
           disease progression on or after platinum-containing chemotherapy. It is also FDA
           approved for use with advanced (metastatic) non-small cell lung cancer (NSCLC) whose
           disease has progressed after other treatments and with tumors that express a protein
           called PD-L1 and for the treatment of patients with recurrent or metastatic head and
           neck squamous cell carcinoma (HNSCC) with disease progression on or after
           platinum-containing chemotherapy

        -  This study will be the first to evaluate this combination of vaccine (HSPPC-96) and PD-1
           inhibition (pembrolizumab) in newly diagnosed GBM patients whose tumors are MGMT
           promoter unmethylated and are isocytrate dehydrogenase (IDH) wildtype; and will provide
           important data on immune-modulatory effect of this combination. This may be of
           particular value in patients with high peripheral PD-L1 expression, but also the value
           of PD-1 added to standard GBM therapy. As vaccine needs to be generated from the patient
           s tumor, patients will need to be identified prior to surgery.

      Eligibility:

        -  MRI findings consistent with a suspected GBM or histologically confirmed newly diagnosed
           GBM that has not been treated and would benefit from further surgical resection.

        -  Tumor must be supratentorial.

        -  GBM diagnosis must be made by surgical excision (stereotactic biopsy will not be allowed
           unless there is plan for second surgery to remove greater than or equal to 80% of the
           tumor) and patients tumors must not have MGMT promoter methylation and must be IDH
           wildtype.

        -  No prior treatment with radiation or chemotherapy for their GBM.

        -  Age greater than or equal to 18 years on day of signing informed consent

      Objective:

      - The primary endpoint is to determine whether the one year overall survival (OS) rate is
      improved in newly diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and
      are IDH wildtype treated with RT + TMZ + Pembrolizumab followed by TMZ + Pembrolizumab +
      HSPPC-96 vaccine or Placebo vaccine x 6 cycles (1 cycle is 9 weeks).

      Design:

        -  This will be a randomized, double blind phase II trial of surgery, RT + TMZ +
           Pembrolizumab followed by TMZ + Pembrolizumab +/- HSPPC-96 in newly diagnosed GBM
           patients whose tumors have an unmethylated MGMT promotor and are IDH wildtype.

        -  Subjects will be assigned to intervention based on ability to generate vaccine as
           follows:

             -  If >= 80 % of tumor removed, >=7 g of tumor is resected but HSPPC-96 cannot be
                generated, subjects will be treated on the ancillary arm of RT+TMZ +Pembrolizumab
                followed by TMZ+ Pembrolizumab.

             -  If>= 80% of contrasting enhanced tumor removed (based on T1 Post contrast MRI using
                cross sectional measurement), >= 7 g of tumor is resected and sufficient HSPPC-96
                is generated, subjects will be included in the main cohort and will be randomized
                on a 1:1 basis to receive:

                  -  RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab + Placebo

      OR

      --- RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab+HSPPC-96

      -Subjects whose tumor does not meet the criteria (unmethylated MGMT promoter and IDH wildtype
      by pathology) and for whom < 80 % of tumor is removed or < 7g of tumor is resected are not
      eligible for further intervention. Approximately 8 potentially eligible patients are screened
      per month, and it is anticipated that at least 1-2 per month will be accrued per site.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: To determine whether the one-year overall survival (OS) is improved in newly diagnosed MGMT unmethylated GBM patients treated with RT + TMZ + Pembrolizumab followed by Pembrolizumab + TMZ +/- HSPPC-96 x 6 cycles (1 cycle is 9 weeks) months.
time frame: one year
description: One-year overall survival
arm group label: 1/Radiation Therapy
arm group type: Other
description: Standard radiation therapy
arm group label: 2/RT+TMZ + Pembrolizumab
arm group type: Experimental
description: Standard treatment with experimental treatment (pembro) added
arm group label: 3/RT+TMZ+Pembrolizumab+HSPPC96 Vaccine
arm group type: Experimental
description: Standard treatment with experimental treatment (pembro+ vaccine) added
arm group label: 4/RT+TMZ+Pembrolizumab+ Placebo Vaccine
arm group type: Placebo Comparator
description: Standard treatment with experimental treatment and placebo added
intervention type: Drug
intervention name: Pembrolizumab
description: Pembrolizumab at 200mg will be administered on day 1 as a 30 minute IV infusion (prior to RT) every 3 weeks during RT on days 1, 22 and 43. At one year, if patients are doing well they may continue pembolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.
arm group label: 2/RT+TMZ + Pembrolizumab
arm group label: 3/RT+TMZ+Pembrolizumab+HSPPC96 Vaccine
arm group label: 4/RT+TMZ+Pembrolizumab+ Placebo Vaccine
intervention type: Biological
intervention name: HSPPC-96
description: One week post RT, patients will receive weekly x 4 a dose of HSPPC-96 0.4mL intradermal vaccine or placebo. HSPPC-96 vaccine or placebo will then be given 21 days after the day 5 dose of TMZ. HSPPC-96 vaccine or placebo vaccine will be given for 6 cycles or until supply runs out. Patients who receive placebo will be matched for number of vaccine injections that were generated by their tumor tissue. At one year, if patients are doing well they may continue pembrolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.
arm group label: 3/RT+TMZ+Pembrolizumab+HSPPC96 Vaccine
intervention type: Drug
intervention name: Temozolomide
description: TMZ will be administered on day 1 of radiation therapy (before RT treatment) and continue throughout RT at the dose of 75 mg/m2. Post RT: The starting TMZ dose will be 150 mg/m2/day for cycle 1, days 1-5, with a single dose escalation to 200 mg/m2/day (days 29-33) and for all subsequent treatment if no treatment-related adverse events greater than Grade 2 are noted. TMZ will be given for 6 cycles.
arm group label: 1/Radiation Therapy
arm group label: 2/RT+TMZ + Pembrolizumab
arm group label: 3/RT+TMZ+Pembrolizumab+HSPPC96 Vaccine
arm group label: 4/RT+TMZ+Pembrolizumab+ Placebo Vaccine
intervention type: Other
intervention name: Placebo
description: One week post RT, patients will receive weekly x 4 a dose of HSPPC-96 0.4mL intradermal vaccine or placebo. HSPPC-96 vaccine or placebo will then be given 21 days after the day 5 dose of TMZ. HSPPC-96 vaccine or placebo vaccine will be given for 6 cycles or until supply runs out. Patients who receive placebo will be matched for number of vaccine injections that were generated by their tumor tissue. At one year, if patients are doing well they may continue pembrolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.
arm group label: 4/RT+TMZ+Pembrolizumab+ Placebo Vaccine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark R Gilbert, 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-0034.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Pembrolizumab
mesh term: Temozolomide
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.@@@@@@All collected IPD will be shared with collaborators under the terms of collaborative agreements.
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. @@@@@@All collected IPD will be available after primary analysis have been published.
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.