<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/NCT03277638</url>
  </required_header>
  <id_info>
    <org_study_id>CASE3316</org_study_id>
    <secondary_id>NCI-2017-02417</secondary_id>
    <nct_id>NCT03277638</nct_id>
  </id_info>
  <brief_title>Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)</brief_title>
  <official_title>Phase I/II Study of Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Case Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Case Comprehensive Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to test the side effects and efficacy of using Laser&#xD;
      Interstitial Thermotherapy (LITT) combined with Pembrolizumab. LITT is a minimally invasive&#xD;
      surgical technique that uses a laser to heat brain tumors.&#xD;
&#xD;
      Pembrolizumab is an investigational (experimental) drug that works by helping participants'&#xD;
      immune system work correctly to detect and fight cancer cells. Pembrolizumab is experimental&#xD;
      because it is not approved by the Food and Drug Administration (FDA), for this use, though it&#xD;
      is approved to treat other cancers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objectives:&#xD;
&#xD;
        1. Phase I: To determine the optimal timing for combining LITT and pembrolizumab in&#xD;
           patients with rGBM:&#xD;
&#xD;
           • To determine the feasibility, safety, tolerability and side effect profiles for&#xD;
           combining LITT and pembrolizumab at various time points pre-LITT vs. post-LITT (Phase&#xD;
           I).&#xD;
&#xD;
        2. Phase II: To estimate the response to pembrolizumab combined with LITT in patients with&#xD;
           rGBM;&#xD;
&#xD;
           • To estimate the response rate after treatment with LITT combined with pembrolizumab in&#xD;
           patients with rGBM (Phase II).&#xD;
&#xD;
        3. To collect and record the side effect profiles for combining LITT and pembrolizumab&#xD;
           (Phase I and Phase II).&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
        1. To determine the effect of pembrolizumab on systemic immune microenvironment in patients&#xD;
           with rGBM.&#xD;
&#xD;
        2. To determine the effect of pembrolizumab on the intra-tumoral immunosuppressive&#xD;
           microenvironment within rGBM.&#xD;
&#xD;
        3. Secondary for Phase II, to estimate progression free survival (PFS) and overall survival&#xD;
           (OS) after treatment with LITT combined with pembrolizumab in patients with rGBM (Phase&#xD;
           II).&#xD;
&#xD;
        4. Measure radiological response using both conventional RANO criterion, a modified RANO&#xD;
           (RANOi) designed specifically for immunotherapy response assessment, as well as MRI&#xD;
           fingerprinting (MRF), recently demonstrated by the PI and collaborators to accurately&#xD;
           and precisely distinguish recurrent GBM from radiation injury.&#xD;
&#xD;
        5. Correlate clinical and radiological response to known biomarkers of GBM such as&#xD;
           Isocitrate Dehydrogenase 1 (IDH-1) mutations, Isocitrate Dehydrogenase 2 (IDH-2)&#xD;
           mutations, Methyl-Guanine Methyl Transferase (MGMT) promoter methylation, Phosphatase&#xD;
           and tensin homologue (PTEN) loss and KI-67.&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
      The Phase I component will involve up to two of a possible 3 cohorts of 3-4 patients each for&#xD;
      a total of 6-8 evaluable patients. Each patient will undergo a stereotactic biopsy. If GBM or&#xD;
      Gliosarcoma is confirmed by frozen section, patients will undergo LITT then treatment with&#xD;
      200 mg pembrolizumab IV. Cohort I will receive pembrolizumab on post operative day 14 and&#xD;
      every 3 weeks thereafter. In the event that one patient suffers non-hematologic toxicity of&#xD;
      grade 3 or more, or if hematologic toxicity is grade 4 or higher, the investigators will&#xD;
      delay the 2nd dose of pembrolizumab by 3 weeks and a 4th patient will be accrued. If there&#xD;
      are two patients in the initial cohort with non-hematologic toxicities grade 3, or if&#xD;
      hematological toxicity in two patients is grade 4 or higher, the second cohort will delay&#xD;
      initiation of pembrolizumab until post operative day 35 after LITT. Conversely, if there are&#xD;
      no non-hematologic adverse events (AEs) of grade 3 or higher, the investigators will proceed&#xD;
      to cohort IB using the same dose of pembrolizumab given 7 days prior to surgery, then every 3&#xD;
      weeks. Similarly, feasibility and safety will be addressed as above in deciding whether or&#xD;
      not to proceed to the next cohort.&#xD;
&#xD;
      The Phase II component of the study will consist of additional patients receiving&#xD;
      pembrolizumab at the earliest tolerated time post LITT:&#xD;
&#xD;
        -  14 days post-op&#xD;
&#xD;
        -  -7 days pre-op;&#xD;
&#xD;
        -  35 days post-opto achieve a total of 23 evaluable patients at the earliest tolerated&#xD;
           dose.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 29, 2017</start_date>
  <completion_date type="Anticipated">December 15, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 15, 2023</primary_completion_date>
  <phase>Phase 1/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>
    <intervention_model_description>Three parallel groups given Pembrolizumab injections at different timepoints</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Because this is an open-label, safety and tolerability study in which all enrolled subjects will receive Pembrolizumab in Combination with LITT, this study is unblinded.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Phase I endpoint: Optimal timing of LITT with pembrolizumab</measure>
    <time_frame>Up to 24 months after beginning Pembrolizumab</time_frame>
    <description>Optimal timing of LITT with pembrolizumab</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II endpoint: Tumor Response</measure>
    <time_frame>Up to 24 months after beginning Pembrolizumab</time_frame>
    <description>Response rates for the Phase II component will be calculated and compared to historical controls using chi-square tests or Fishers exact tests.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>Up to 24 months after beginning Pembrolizumab</time_frame>
    <description>PFS, defined as time from diagnosis to documented progression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 24 months after beginning Pembrolizumab</time_frame>
    <description>OS, defined as time from diagnosis to death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients who achieve progression free survival at 6 months (PFS6)</measure>
    <time_frame>Up to 6 months after diagnosis</time_frame>
    <description>PFS6, Proportion of patients who do not progress at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients who achieve progression free survival at 12 months (PFS12)</measure>
    <time_frame>Up to 12 months after diagnosis</time_frame>
    <description>PFS12, Proportion of patients who do not progress at 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients who achieve progression free survival at 24 months (PFS24)</measure>
    <time_frame>Up to 24 months after diagnosis</time_frame>
    <description>PFS24, Proportion of patients who do not progress at 24 months</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">34</enrollment>
  <condition>Glioblastoma, Adult</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab injections 7 days before surgery</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will have intravenous pembrolizumab 7 days before surgery with Laser Interstitial Thermotherapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pembrolizumab injections 14 days after surgery</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will have intravenous pembrolizumab 14 days after surgery with Laser Interstitial Thermotherapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pembrolizumab injections 35 days after surgery</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will have intravenous pembrolizumab 35 days after surgery with Laser Interstitial Thermotherapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab at 7 days prior</intervention_name>
    <description>Pembrolizumab injections 7 days before surgery</description>
    <arm_group_label>Pembrolizumab injections 7 days before surgery</arm_group_label>
    <other_name>Pembrolizumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab at 14 days post</intervention_name>
    <description>Pembrolizumab injections 14 days after surgery</description>
    <arm_group_label>Pembrolizumab injections 14 days after surgery</arm_group_label>
    <other_name>Pembrolizumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab at 35 days post</intervention_name>
    <description>Pembrolizumab injections 35 days after surgery</description>
    <arm_group_label>Pembrolizumab injections 35 days after surgery</arm_group_label>
    <other_name>Pembrolizumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Laser Interstitial Thermotherapy</intervention_name>
    <description>surgical procedure to heat hard to reach tumors with a laser beam</description>
    <arm_group_label>Pembrolizumab injections 14 days after surgery</arm_group_label>
    <arm_group_label>Pembrolizumab injections 35 days after surgery</arm_group_label>
    <arm_group_label>Pembrolizumab injections 7 days before surgery</arm_group_label>
    <other_name>LITT</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histopathologically proven diagnosis of glioblastoma or gliosarcoma prior to&#xD;
             registration by pathology report;&#xD;
&#xD;
          -  The tumor must be confined to the supratentorial compartment&#xD;
&#xD;
          -  The Formaldehyde Fixed-Paraffin Embedded tumor tissue block must be available to be&#xD;
             sent for retrospective central pathology review after registration).&#xD;
&#xD;
          -  History/physical examination within 7 days prior to registration&#xD;
&#xD;
          -  Karnofsky performance status ≥ 60 within 7 days prior to registration&#xD;
&#xD;
          -  Adequate Organ Function Laboratory Values&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥1,500/mcL&#xD;
&#xD;
               -  Platelets ≥100,000/mcL&#xD;
&#xD;
               -  Hemoglobin ≥9.0 g/gL or ≥5.6 mmol/L, without recent transfusion&#xD;
&#xD;
               -  Creatine ≤1.7 x upper limit of normal (ULN) or Measure or Calculated creatinine&#xD;
                  clearance ≥ 60.0mL/min for subject with creatinine levels &gt; 1.5 X institutional&#xD;
                  ULN (GFR can also be used in place of creatinine or CrCl)&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x ULN or Direct bilirubin ≤ ULN for subjects with total&#xD;
                  bilirubin levels &gt; 1.5 x ULN&#xD;
&#xD;
               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for subjects with liver&#xD;
                  metastases&#xD;
&#xD;
               -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN unless&#xD;
                  subject is receiving anticoagulant therapy as long as PT or PTT is within&#xD;
                  therapeutic range of intended use of anticoagulants&#xD;
&#xD;
               -  Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless subject is&#xD;
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range&#xD;
                  of intended use of anticoagulants&#xD;
&#xD;
          -  Adequate hematologic function based on complete blood count (CBC)/differential within&#xD;
             7 days prior to registration defined as follows:&#xD;
&#xD;
               -  Absolute neutrophil count ≥ 1,500 cells/mm3;&#xD;
&#xD;
               -  Platelet count ≥ 100,000 cells/mm3&#xD;
&#xD;
               -  Hgb &gt; 9 g/dL (can be achieved with transfusion)&#xD;
&#xD;
          -  Adequate renal function within 7 days prior to registration defined as follows:&#xD;
&#xD;
               -  Blood Urea Nitrogen (BUN) ≤ 30 mg/dl and&#xD;
&#xD;
               -  Serum creatinine ≤ 1.7 mg/dl&#xD;
&#xD;
          -  Adequate hepatic function within 7 days prior to registration defined as follows:&#xD;
&#xD;
               -  Total bilirubin (except patients with Gilbert's Syndrome, who are eligible for&#xD;
                  the study but exempt from the total bilirubin eligibility criterion) ≤ 2.0 mg/dl&#xD;
                  and&#xD;
&#xD;
               -  Alanine Aminotransferase (ALT) and Aspartate Amino Transferase (AST) ≤ 2.5 x ULN&#xD;
&#xD;
          -  The patient must have completed chemoradiation with Radiotherapy and Temozolomide of&#xD;
             the primary tumor according to standards of care&#xD;
&#xD;
          -  The treating physician expects that the patient will not require more than physiologic&#xD;
             replacement dose of steroids defined as 4 mg of dexamethasone per day or its&#xD;
             equivalent.&#xD;
&#xD;
          -  Patients must have received no more than 3 prior therapies for Recurrent High Grade&#xD;
             Glioma&#xD;
&#xD;
          -  Subjects must have the ability to understand and the willingness to sign a written&#xD;
             informed consent document.&#xD;
&#xD;
          -  Female subject of childbearing potential should have a negative urine or serum&#xD;
             pregnancy test within 72 hours prior to receiving the first dose of study medication.&#xD;
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy&#xD;
             test will be required.&#xD;
&#xD;
          -  Female subjects of childbearing potential should be willing to use 2 methods of birth&#xD;
             control or be surgically sterile, or abstain from heterosexual activity for the course&#xD;
             of the study through 120 days after the last dose of study medication. Subjects of&#xD;
             childbearing potential are those who have not been surgically sterilized or have not&#xD;
             been free from menses for &gt; 1 year.&#xD;
&#xD;
          -  Male subjects should agree to use an adequate method of contraception starting with&#xD;
             the first dose of study therapy through 120 days after the last dose of study therapy.&#xD;
&#xD;
          -  Tumor diameter in the plane perpendicular to LITT trajectory must be ≤ 6.0 cm in&#xD;
             diameter&#xD;
&#xD;
          -  It must be the surgeon's expectation that ≥ 90 of the tumor can be treated with LITT&#xD;
             to the yellow thermal damage threshold (TdT) line (ie, 43 degrees for 2 min)&#xD;
&#xD;
          -  Tumor must be Unifocal &amp; Unilateral-Two enhancing nodules within the same FLAIR&#xD;
             hyperintense region are still eligible; 1-2 secondary enhancing or non-enhancing&#xD;
             lesions may be present as long as they have been radiologically stable for greater&#xD;
             than or equal to 3 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or&#xD;
             intracavitary or convectional enhanced delivery of therapy in the past&#xD;
&#xD;
          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free&#xD;
             for a minimum of 3 years&#xD;
&#xD;
          -  Severe, active co-morbidity defined as follows:&#xD;
&#xD;
               -  Unstable angina within the last 6 months prior to registration&#xD;
&#xD;
               -  Transmural myocardial infarction within the last 6 months prior to registration&#xD;
&#xD;
               -  Evidence of recent myocardial infarction or ischemia by the findings of S-T&#xD;
                  elevations of ≥ 2 mm using the analysis of an EKG performed within 7 days prior&#xD;
                  to registration&#xD;
&#xD;
               -  New York Heart Association grade II or greater congestive heart failure requiring&#xD;
                  hospitalization within 12 months prior to registration&#xD;
&#xD;
               -  History of stroke, cerebral vascular accident (CVA) or transient ischemic attack&#xD;
                  within 6 months prior to registration&#xD;
&#xD;
               -  Serious and inadequately controlled cardiac arrhythmia&#xD;
&#xD;
               -  Significant vascular disease (e.g., aortic aneurysm, history of aortic&#xD;
                  dissection) or clinically significant peripheral vascular disease&#xD;
&#xD;
               -  Evidence of bleeding diathesis or coagulopathy&#xD;
&#xD;
               -  Serious or non-healing wound, ulcer, or bone fracture or history of abdominal&#xD;
                  fistula, gastrointestinal perforation, intra-abdominal abscess major surgical&#xD;
                  procedure, open biopsy, or significant traumatic injury within 28 days prior to&#xD;
                  registration, with the exception of the craniotomy for tumor resection.&#xD;
&#xD;
               -  Known history of Tuberculosis&#xD;
&#xD;
               -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time&#xD;
                  of registration&#xD;
&#xD;
               -  Chronic obstructive pulmonary disease exacerbation or other respiratory illness&#xD;
                  requiring hospitalization or precluding study therapy at the time of registration&#xD;
&#xD;
               -  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects&#xD;
&#xD;
               -  Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease&#xD;
                  Control and Prevention (CDC) definition; note, however, that HIV testing is not&#xD;
                  required for entry into this protocol. The need to exclude patients with AIDS&#xD;
                  from this protocol is necessary because the treatments involved in this protocol&#xD;
                  may be significantly immunosuppressive and worsen the patient's HIV symptoms.&#xD;
&#xD;
               -  Active connective tissue disorders, such as lupus or scleroderma, which in the&#xD;
                  opinion of the treating physician may put the patient at high risk for&#xD;
                  immunologic toxicity.&#xD;
&#xD;
               -  History of (non-infectious) pneumonitis that required steroids, evidence of&#xD;
                  interstitial lung disease or active, non-infectious pneumonitis&#xD;
&#xD;
               -  Patients with active autoimmune disease or history of autoimmune disease that&#xD;
                  might recur, which may affect vital organ function or require immune suppressive&#xD;
                  treatment including systemic corticosteroids, should be excluded. These include&#xD;
                  but are not limited to patients with a history of immune related neurologic&#xD;
                  disease, multiple sclerosis, autoimmune (demyelinating) neuropathy,&#xD;
                  Guillain-Barre syndrome or Chronic Inflammatory Demyelinating Polyneuropathy,&#xD;
                  myasthenia gravis; systemic autoimmune disease such as Systemic Lupus&#xD;
                  Erythematosus, connective tissue diseases, scleroderma, inflammatory bowel&#xD;
                  disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a&#xD;
                  history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or&#xD;
                  phospholipid syndrome should be excluded because of the risk of recurrence or&#xD;
                  exacerbation of disease.&#xD;
&#xD;
               -  Of note, patients with vitiligo, endocrine deficiencies including thyroiditis&#xD;
                  managed with replacement hormones including physiologic corticosteroids are&#xD;
                  eligible. Patients with rheumatoid arthritis and other arthropathies, Sjögren's&#xD;
                  syndrome and psoriasis controlled with topical medication and patients with&#xD;
                  positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies&#xD;
                  should be evaluated for the presence of target organ involvement and potential&#xD;
                  need for systemic treatment but should otherwise be eligible.&#xD;
&#xD;
               -  Any other major medical illnesses or psychiatric impairments that in the&#xD;
                  investigator's opinion will prevent administration or completion of protocol&#xD;
                  therapy.&#xD;
&#xD;
               -  Has a known additional malignancy that is progressing or requires active&#xD;
                  treatment. Exceptions include basal cell carcinoma of the skin or squamous cell&#xD;
                  carcinoma of the skin that has undergone potentially curative therapy or in situ&#xD;
                  cervical cancer.&#xD;
&#xD;
               -  Has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
                  meningitis. Subjects with previously treated brain metastases may participate&#xD;
                  provided they are stable (without evidence of progression by imaging for at least&#xD;
                  four weeks prior to the first dose of trial treatment and any neurologic symptoms&#xD;
                  have returned to baseline), have no evidence of new or enlarging brain&#xD;
                  metastases, and are not using steroids for at least 7 days prior to trial&#xD;
                  treatment. This exception does not include carcinomatous meningitis which is&#xD;
                  excluded regardless of clinical stability.&#xD;
&#xD;
               -  Has 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). Replacement therapy (eg, 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;
               -  Has known history of, or any evidence of active, non-infectious pneumonitis.&#xD;
&#xD;
               -  Has an active infection requiring systemic therapy?&#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.&#xD;
&#xD;
               -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
                  cooperation with the requirements of the trial&#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;
               -  Has received prior therapy with an anti-Programmed Death 1 (PD-1), anti-&#xD;
                  Programmed Death-ligand 1 (PD-L1), or anti- Programmed Death-ligand 1 (PD-L2)&#xD;
                  agent.&#xD;
&#xD;
               -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV ½ antibodies).&#xD;
&#xD;
               -  Has known active Hepatitis B (e.g., HbsAg reactive) or Hepatitis C (eg, HCV RNA&#xD;
                  [qualitative] is detected).&#xD;
&#xD;
               -  Has received a live attenuated vaccine within 30 days of planned start of study&#xD;
                  therapy.&#xD;
&#xD;
                    -  Note: Seasonal influenza vaccines for injection are generally inactivated&#xD;
                       flu vaccines and are allowed; however Intranasal influenza vaccines (e.g.,&#xD;
                       Flu-Mist®) are live attenuated vaccines, and are not allowed.&#xD;
&#xD;
          -  Patient must have &lt; 1.0 cm midline shift pre-operative&#xD;
&#xD;
          -  History of severe hypersensitivity reaction to any monoclonal antibody including&#xD;
             pembrolizumab.&#xD;
&#xD;
          -  Patients who cannot safely undergo MRI due to non-MRI compatible pacemaker, or other&#xD;
             reason.&#xD;
&#xD;
          -  Patients who have tumors for which the Gd-enhancing mass appears to be covered ≤ 90%&#xD;
             using 2 catheters and assuming a 3.0 cm diameter based on pre-operative planning are&#xD;
             unlikely to have adequate LITT and thus ineligible for the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tiffany Hodges, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Tiffany Hodges, MD</last_name>
    <phone>1-800-641-2422</phone>
    <email>CTUReferral@UHhospitals.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tiffany Hodges, MD</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Tiffany Hodges, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>September 7, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 11, 2017</study_first_posted>
  <last_update_submitted>August 24, 2023</last_update_submitted>
  <last_update_submitted_qc>August 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>recurrent glioblastoma</keyword>
  <keyword>brain cancer</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>
  </intervention_browse>
  <!-- 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/NCT03277638
org study id: CASE3316
secondary id: NCI-2017-02417
nct id: NCT03277638
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The purpose of this study is to test the side effects and efficacy of using Laser
      Interstitial Thermotherapy (LITT) combined with Pembrolizumab. LITT is a minimally invasive
      surgical technique that uses a laser to heat brain tumors.

      Pembrolizumab is an investigational (experimental) drug that works by helping participants'
      immune system work correctly to detect and fight cancer cells. Pembrolizumab is experimental
      because it is not approved by the Food and Drug Administration (FDA), for this use, though it
      is approved to treat other cancers.
Primary Objectives:

        1. Phase I: To determine the optimal timing for combining LITT and pembrolizumab in
           patients with rGBM:

           • To determine the feasibility, safety, tolerability and side effect profiles for
           combining LITT and pembrolizumab at various time points pre-LITT vs. post-LITT (Phase
           I).

        2. Phase II: To estimate the response to pembrolizumab combined with LITT in patients with
           rGBM;

           • To estimate the response rate after treatment with LITT combined with pembrolizumab in
           patients with rGBM (Phase II).

        3. To collect and record the side effect profiles for combining LITT and pembrolizumab
           (Phase I and Phase II).

      Secondary Objectives:

        1. To determine the effect of pembrolizumab on systemic immune microenvironment in patients
           with rGBM.

        2. To determine the effect of pembrolizumab on the intra-tumoral immunosuppressive
           microenvironment within rGBM.

        3. Secondary for Phase II, to estimate progression free survival (PFS) and overall survival
           (OS) after treatment with LITT combined with pembrolizumab in patients with rGBM (Phase
           II).

        4. Measure radiological response using both conventional RANO criterion, a modified RANO
           (RANOi) designed specifically for immunotherapy response assessment, as well as MRI
           fingerprinting (MRF), recently demonstrated by the PI and collaborators to accurately
           and precisely distinguish recurrent GBM from radiation injury.

        5. Correlate clinical and radiological response to known biomarkers of GBM such as
           Isocitrate Dehydrogenase 1 (IDH-1) mutations, Isocitrate Dehydrogenase 2 (IDH-2)
           mutations, Methyl-Guanine Methyl Transferase (MGMT) promoter methylation, Phosphatase
           and tensin homologue (PTEN) loss and KI-67.

      Study Design:

      The Phase I component will involve up to two of a possible 3 cohorts of 3-4 patients each for
      a total of 6-8 evaluable patients. Each patient will undergo a stereotactic biopsy. If GBM or
      Gliosarcoma is confirmed by frozen section, patients will undergo LITT then treatment with
      200 mg pembrolizumab IV. Cohort I will receive pembrolizumab on post operative day 14 and
      every 3 weeks thereafter. In the event that one patient suffers non-hematologic toxicity of
      grade 3 or more, or if hematologic toxicity is grade 4 or higher, the investigators will
      delay the 2nd dose of pembrolizumab by 3 weeks and a 4th patient will be accrued. If there
      are two patients in the initial cohort with non-hematologic toxicities grade 3, or if
      hematological toxicity in two patients is grade 4 or higher, the second cohort will delay
      initiation of pembrolizumab until post operative day 35 after LITT. Conversely, if there are
      no non-hematologic adverse events (AEs) of grade 3 or higher, the investigators will proceed
      to cohort IB using the same dose of pembrolizumab given 7 days prior to surgery, then every 3
      weeks. Similarly, feasibility and safety will be addressed as above in deciding whether or
      not to proceed to the next cohort.

      The Phase II component of the study will consist of additional patients receiving
      pembrolizumab at the earliest tolerated time post LITT:

        -  14 days post-op

        -  -7 days pre-op;

        -  35 days post-opto achieve a total of 23 evaluable patients at the earliest tolerated
           dose.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Three parallel groups given Pembrolizumab injections at different timepoints
primary purpose: Treatment
masking: None (Open Label)
masking description: Because this is an open-label, safety and tolerability study in which all enrolled subjects will receive Pembrolizumab in Combination with LITT, this study is unblinded.
measure: Phase I endpoint: Optimal timing of LITT with pembrolizumab
time frame: Up to 24 months after beginning Pembrolizumab
description: Optimal timing of LITT with pembrolizumab
measure: Phase II endpoint: Tumor Response
time frame: Up to 24 months after beginning Pembrolizumab
description: Response rates for the Phase II component will be calculated and compared to historical controls using chi-square tests or Fishers exact tests.
measure: Progression free survival (PFS)
time frame: Up to 24 months after beginning Pembrolizumab
description: PFS, defined as time from diagnosis to documented progression
measure: Overall survival (OS)
time frame: Up to 24 months after beginning Pembrolizumab
description: OS, defined as time from diagnosis to death
measure: The proportion of patients who achieve progression free survival at 6 months (PFS6)
time frame: Up to 6 months after diagnosis
description: PFS6, Proportion of patients who do not progress at 6 months
measure: The proportion of patients who achieve progression free survival at 12 months (PFS12)
time frame: Up to 12 months after diagnosis
description: PFS12, Proportion of patients who do not progress at 12 months
measure: The proportion of patients who achieve progression free survival at 24 months (PFS24)
time frame: Up to 24 months after diagnosis
description: PFS24, Proportion of patients who do not progress at 24 months
arm group label: Pembrolizumab injections 7 days before surgery
arm group type: Experimental
description: Patients will have intravenous pembrolizumab 7 days before surgery with Laser Interstitial Thermotherapy
arm group label: Pembrolizumab injections 14 days after surgery
arm group type: Experimental
description: Patients will have intravenous pembrolizumab 14 days after surgery with Laser Interstitial Thermotherapy
arm group label: Pembrolizumab injections 35 days after surgery
arm group type: Experimental
description: Patients will have intravenous pembrolizumab 35 days after surgery with Laser Interstitial Thermotherapy
intervention type: Drug
intervention name: Pembrolizumab at 7 days prior
description: Pembrolizumab injections 7 days before surgery
arm group label: Pembrolizumab injections 7 days before surgery
other name: Pembrolizumab
intervention type: Drug
intervention name: Pembrolizumab at 14 days post
description: Pembrolizumab injections 14 days after surgery
arm group label: Pembrolizumab injections 14 days after surgery
other name: Pembrolizumab
intervention type: Drug
intervention name: Pembrolizumab at 35 days post
description: Pembrolizumab injections 35 days after surgery
arm group label: Pembrolizumab injections 35 days after surgery
other name: Pembrolizumab
intervention type: Procedure
intervention name: Laser Interstitial Thermotherapy
description: surgical procedure to heat hard to reach tumors with a laser beam
arm group label: Pembrolizumab injections 14 days after surgery
arm group label: Pembrolizumab injections 35 days after surgery
arm group label: Pembrolizumab injections 7 days before surgery
other name: LITT
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Tiffany Hodges, MD
role: Principal Investigator
affiliation: University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
last name: Tiffany Hodges, MD
phone: 1-800-641-2422
email: CTUReferral@UHhospitals.org
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Pembrolizumab