<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/NCT03022578</url>
  </required_header>
  <id_info>
    <org_study_id>2016-0443</org_study_id>
    <secondary_id>NCI-2018-01286</secondary_id>
    <secondary_id>2016-0443</secondary_id>
    <secondary_id>P30CA016672</secondary_id>
    <nct_id>NCT03022578</nct_id>
  </id_info>
  <brief_title>Laser Interstitial Thermal Therapy and Lomustine in Treating Patients With Recurrent Glioblastoma or Anaplastic Astrocytoma</brief_title>
  <official_title>Phase II Study of Laser Interstitial Thermal Therapy (LITT) in Recurrent Glioblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>M.D. Anderson Cancer Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well laser interstitial thermal therapy and lomustine work in&#xD;
      treating patients with glioblastoma or anaplastic astrocytoma that has come back. Using laser&#xD;
      to heat the tumor cells may help to kill them. Drugs used in chemotherapy, such as lomustine,&#xD;
      work in different ways to stop the growth of tumor cells, either by killing the cells, by&#xD;
      stopping them from dividing, or by stopping them from spreading. Giving laser interstitial&#xD;
      thermal therapy and lomustine may work better in treating patients with glioblastoma or&#xD;
      anaplastic astrocytoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Determine the disease control rate at 6 months in patients with recurrent glioblastoma or&#xD;
      isocitrate dehydrogenase (IDH)-wildtype anaplastic astrocytoma treated with Laser&#xD;
      Interstitial Thermal Therapy (LITT) at recurrence, followed by salvage chemotherapy.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Estimate overall survival (OS) of patients with recurrent glioblastoma, or isocitrate&#xD;
      dehydrogenase (IDH)-wildtype anaplastic astrocytoma treated with LITT at tumor recurrence,&#xD;
      followed by salvage chemotherapy.&#xD;
&#xD;
      II. Estimate time to progression (TTP) of patients with recurrent glioblastoma, or isocitrate&#xD;
      dehydrogenase (IDH)-wildtype anaplastic astrocytoma that are treated with LITT at tumor&#xD;
      recurrence, followed by salvage chemotherapy.&#xD;
&#xD;
      III. Analyze volumetric data consisting of thermal damage threshold lines and overall tumor&#xD;
      volume to determine any role of 'extent of ablation' in outcomes (OS and/or TTP).&#xD;
&#xD;
      IV. Characterize the safety profile of LITT followed by treatment with lomustine chemotherapy&#xD;
      in the recurrent disease setting, using the Common Terminology Criteria for Adverse Events&#xD;
      (CTCAE) version 4.0.&#xD;
&#xD;
      V. Assess the long-term steroid requirements following LITT, compared to historical controls.&#xD;
&#xD;
      VI. Determine the radiographic evolution of LITT-treated glioblastoma over time, using&#xD;
      conventional magnetic resonance imaging (MRI) (T1 pre and post-contrast images, T2-weighted&#xD;
      images [T2WI], fluid attenuating inversion recovery [FLAIR] images) and advanced brain tumor&#xD;
      imaging (ABTI) [magnetic resonance (MR) perfusion [dynamic susceptibility contrast (DSC),&#xD;
      dynamic contrast enhancement (DCE) and arterial spin labeling (ASL)], MR-diffusion, and MR&#xD;
      spectroscopy), to include quantitative tumor metrics (volumetric extent of ablation and&#xD;
      Response Assessment in Neuro-Oncology [RANO] criteria).&#xD;
&#xD;
      VII. Analyze health care utilization as measured by length of hospital stay following LITT&#xD;
      (including inpatient rehabilitation care).&#xD;
&#xD;
      VIII. Evaluate patients' functional status (using the Karnofsky performance score [KPS] and&#xD;
      the occurrence of symptoms [using the MD Anderson Symptom Inventory-Brain Tumor Module&#xD;
      (MDASI-BT[English])] self-reporting tool), and correlate to disease progression and tolerance&#xD;
      to treatment.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. Identify correlative tumor and peripheral blood molecular markers that impact outcomes,&#xD;
      etc, and identify inflammatory/immunologic markers to assess neoantigen expression, etc, if&#xD;
      sufficient tissue is available.&#xD;
&#xD;
      II. Identify and characterize changes in tumor tissue following LITT, by analyzing and&#xD;
      comparing pre- and post-procedure tissue samples, if sufficient tissue is available.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients undergo LITT at baseline and receive lomustine orally (PO) on day 1. Treatment with&#xD;
      lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or&#xD;
      unaccepted toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Slow accrual&#xD;
  </why_stopped>
  <start_date type="Actual">November 7, 2017</start_date>
  <completion_date type="Actual">February 16, 2021</completion_date>
  <primary_completion_date type="Actual">February 16, 2021</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>Disease Control Rate at 6 Months</measure>
    <time_frame>At 6 months</time_frame>
    <description>Stable Disease per RANO occurs if the patient does not qualify for response or progression and requires stable non enhancing lesions, same/lower dose of corticosteroids, and clinical stability.&#xD;
Complete Response per RANO requires complete disappearance of all enhancing measurable and nonmeasurable disease for at least 4 weeks; no new lesions; and stable/improved nonenhancing lesions, off corticosteroids (or on physiologic replacement dose) and clinical improvement/stability. Partial Response per RANO requires ≥50% decrease of enhancing lesions compared with baseline, sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable/improved nonenhancing lesions, same/lower dose of corticosteroids not greater than the dose at time of the baseline scan and clinically improved/stable.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Progression (TTP)</measure>
    <time_frame>From date of enrollment in study to the date of first observation of progressive disease, death due to disease (event), or early discontinuation of treatment, approximately 3 years 3 months</time_frame>
    <description>Progression disease per the Response Assessment in Neuro-Oncology (RANO) is defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with the baseline scan or the best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor or to a decrease in the corticosteroid dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Long-term Steroid Requirements</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Will be summarized by frequency tables.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Data</measure>
    <time_frame>at baseline, after procedure, and with every imaging visit thereafter, up to 4 years</time_frame>
    <description>Will summarize the MDASI-BT at each time point using descriptive statistics and evaluate the change of MDASI-BT over time and its correlation with response and/or treatment tolerance using linear mixed models, where random effects will be used to account for within-subject correlations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Incidence of Toxicity (Significant Hemorrhage or Brain Herniation) Documented on Imaging</measure>
    <time_frame>approximately 3 years 3 months</time_frame>
    <description>Safety and toxicity of LITT by determination of adverse events and surgical complications within 2 weeks of the procedure, plus an additional 4 weeks (to account for potential delayed inflammatory changes and initiation of subsequent treatment). Safety for LITT procedure will be defined as the absence of severe clinical toxicity as determined by the CTCAE version 4.0, within 6 weeks of the procedure, and/or absence of acute events (ie, significant hemorrhage or brain herniation) documented on imaging. Severe toxicity will also be defined as a drop of 20 points or more in KPS and not amenable to corticosteroids, and likely attributable to the procedure, or symptomatic hemorrhage, increased brain edema resulting in herniation/impending herniation, and/or significant neurologic decline not amenable to corticosteroids. Safety and toxicity will be reassessed again throughout the duration of the study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>approximately 3 years 3 months</time_frame>
    <description>Overall Survival (OS) is the time from initial tumor diagnosis (definitive surgical resection or biopsy) to death from any cause. Will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on OS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of Hospital Stay Following LITT</measure>
    <time_frame>approximately 3 years 3 months</time_frame>
    <description>The length of hospital stay in days, weeks or months. Length of Hospital stay was summarized by using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Biomarkers in Peripheral Blood and Tumor Tissue</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Will be summarized using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables. Correlation will be assessed among continuous variables using Pearson or Spearman correlation coefficient, whichever is appropriate. Association between categorical variables will be examined by Chi-Squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test will be used to examine the difference on continuous variables between or among patient's characteristic groups.</description>
  </other_outcome>
  <other_outcome>
    <measure>Inflammatory/Immunologic Profile</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Will be summarized using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables. Correlation will be assessed among continuous variables using Pearson or Spearman correlation coefficient, whichever is appropriate. Association between categorical variables will be examined by Chi-Squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test will be used to examine the difference on continuous variables between or among patient's characteristic groups.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>IDH Family Wildtype</condition>
  <condition>Recurrent Anaplastic Astrocytoma</condition>
  <condition>Recurrent Glioblastoma</condition>
  <arm_group>
    <arm_group_label>Treatment (LITT, lomustine)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Laser Interstitial Thermal Therapy</intervention_name>
    <description>Undergo LITT</description>
    <arm_group_label>Treatment (LITT, lomustine)</arm_group_label>
    <other_name>LITT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lomustine</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (LITT, lomustine)</arm_group_label>
    <other_name>1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea</other_name>
    <other_name>1-Nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-</other_name>
    <other_name>Belustin</other_name>
    <other_name>Belustine</other_name>
    <other_name>CCNU</other_name>
    <other_name>Cecenu</other_name>
    <other_name>CeeNU</other_name>
    <other_name>Chloroethylcyclohexylnitrosourea</other_name>
    <other_name>Citostal</other_name>
    <other_name>Gleostine</other_name>
    <other_name>Lomeblastin</other_name>
    <other_name>Lomustinum</other_name>
    <other_name>Lucostin</other_name>
    <other_name>Lucostine</other_name>
    <other_name>N-(2-Chloroethyl)-N''-cyclohexyl-N-nitrosourea</other_name>
    <other_name>Prava</other_name>
    <other_name>RB-1509</other_name>
    <other_name>WR-139017</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically-proven, recurrent supratentorial grade IV&#xD;
             glioblastoma (or grade III IDH-wildtype anaplastic astrocytoma), for which a complete&#xD;
             surgical resection is unsafe due to location, shape, or size of the tumor. Diagnosis&#xD;
             of recurrence will be established by biopsy and frozen section immediately prior to&#xD;
             initiating LITT procedure. If findings on frozen section are not consistent with&#xD;
             recurrence (glioblastoma or recurrent IDH-wildtype anaplastic astrocytoma), decision&#xD;
             to proceed with LITT procedure will be at the discretion of the neurosurgeon (only&#xD;
             patients with histologically-proven recurrent tumor will be evaluable for efficacy).&#xD;
&#xD;
          -  All patients must sign an informed consent indicating that they are aware of the&#xD;
             investigational nature of this study. Patients must have signed an authorization for&#xD;
             the release of their protected health information. Patients must be registered prior&#xD;
             to treatment on study.&#xD;
&#xD;
          -  Patients must have a Karnofsky performance score (KPS) &gt; 60.&#xD;
&#xD;
          -  Patients must have received standard of care therapy with chemoradiation with&#xD;
             temozolomide followed by adjuvant chemotherapy with temozolomide. Patients may have&#xD;
             received one additional chemotherapy regimen (other than lomustine) in addition to&#xD;
             adjuvant temozolomide prior to study entry (patients at either first or second&#xD;
             recurrence are eligible).&#xD;
&#xD;
          -  In the context of this clinical trial, a lesion suitable for LITT is single,&#xD;
             enhancing, supratentorial, at least 2 cm from inner table of skull over the&#xD;
             hemispheric convexity, and &gt; 1 cm, but &lt; 4 cm in cross-sectional dimension, including&#xD;
             thalamic tumor (=&lt; 3 cm).&#xD;
&#xD;
          -  Patients must have stable cardiovascular, neurovascular and neurological status, and&#xD;
             be considered surgical candidates, as determined by any relevant pre-operative&#xD;
             assessments, at the neurosurgeon's discretion.&#xD;
&#xD;
          -  Patients must not be receiving concurrent anti-tumor treatment and must have recovered&#xD;
             from toxicity of prior treatment. Minimum interval required: 1) &gt; 6 weeks following&#xD;
             nitrosourea chemotherapy; 2) &gt; 4 weeks after recovering from any non-nitrosourea drug&#xD;
             or systemic investigational agent; 3) &gt; 2 weeks after receiving any non-cytotoxic&#xD;
             anti-tumor drug; 4) &gt; 4 weeks after receiving radiation therapy (&gt; 12 weeks following&#xD;
             upfront concurrent chemoradiation); 5) &gt; 2 weeks following Optune device use.&#xD;
&#xD;
          -  Patients must not have previously undergone an intracranial LITT procedure.&#xD;
&#xD;
          -  White blood cell (WBC) &gt; 3,000/ul (performed within 14 days (+ 3 working days) prior&#xD;
             to registration)&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt; 1,500/mm^3 (performed within 14 days (+ 3 working&#xD;
             days) prior to registration)&#xD;
&#xD;
          -  Platelet count of &gt; 100,000/mm^3 (may be reached by transfusion) (performed within 14&#xD;
             days (+ 3 working days) prior to registration)&#xD;
&#xD;
          -  Hemoglobin &gt; 10 gm/dl (may be reached by transfusion) (performed within 14 days (+ 3&#xD;
             working days) prior to registration)&#xD;
&#xD;
          -  Serum glutamic-oxaloacetic transaminase (SGOT) and bilirubin &lt; 2 times upper limit of&#xD;
             normal (ULN) (performed within 14 days (+ 3 working days) prior to registration)&#xD;
&#xD;
          -  Creatinine &lt; 1.5 mg/dL (performed within 14 days (+ 3 working days) prior to&#xD;
             registration)&#xD;
&#xD;
          -  Women of childbearing potential must have a negative B-Human chorionic gonadotropin&#xD;
             (HCG) documented within 7 days prior to registration and must agree to practice&#xD;
             adequate contraception as defined below. Non-childbearing potential (i.e.,&#xD;
             physiologically incapable of becoming pregnant), includes any female who has had:&#xD;
&#xD;
               -  A hysterectomy&#xD;
&#xD;
               -  A bilateral oophorectomy&#xD;
&#xD;
               -  A bilateral tubal ligation&#xD;
&#xD;
               -  Is post-menopausal: Subjects not using hormone replacement therapy (HRT) must&#xD;
                  have experienced total cessation of menses for &gt;= 1 year and be greater than 45&#xD;
                  years in age, OR, in questionable cases, have a follicle stimulating hormone&#xD;
                  (FSH) value &gt; 40 mIU/mL and an estradiol value &lt; 40 pg/mL (&lt; 140 pmol/L).&#xD;
&#xD;
          -  Subjects using HRT must have experienced total cessation of menses for &gt;= 1 year and&#xD;
             be greater than 45 years of age OR have had documented evidence of menopause based on&#xD;
             FSH and estradiol concentrations prior to initiation of HRT.&#xD;
&#xD;
          -  Childbearing potential includes any female who has had a negative serum pregnancy test&#xD;
             within 7 days of study registration, and agrees to use adequate contraception.&#xD;
             Acceptable contraceptive methods, when used consistently and in accordance with both&#xD;
             the product label and the instructions of the physician, are as follows:&#xD;
&#xD;
               -  Complete abstinence from sexual intercourse for 14 days before starting&#xD;
                  treatment, through the treatment, and for at least 1 month after the last dose of&#xD;
                  temozolomide&#xD;
&#xD;
               -  Oral contraceptive, either combined or progestogen alone. A second barrier method&#xD;
                  is required during the first month of treatment with oral contraceptives&#xD;
&#xD;
               -  Injectable progesterone&#xD;
&#xD;
               -  Implants of levonorgestrel&#xD;
&#xD;
               -  Estrogenic vaginal ring&#xD;
&#xD;
               -  Percutaneous contraceptive patches&#xD;
&#xD;
               -  Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure&#xD;
                  rate of less than 1% per year&#xD;
&#xD;
               -  Male partner sterilization (vasectomy with documentation of azoospermia) prior to&#xD;
                  the female subject's entry into the study, and this male is the sole partner for&#xD;
                  that subject&#xD;
&#xD;
               -  Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault&#xD;
                  caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository). Female&#xD;
                  participants who are lactating should discontinue nursing prior to the first dose&#xD;
                  of temozolomide and should refrain from nursing throughout the treatment period&#xD;
                  and for 42 days following the last dose of lomustine.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients must not have received prior treatment with bevacizumab.&#xD;
&#xD;
          -  Patients must not have had prior treatment of glioblastoma with stereotactic&#xD;
             radiosurgery, brachytherapy, or carmustine-impregnated wafers (Gliadel).&#xD;
&#xD;
          -  Patients must not have symptoms attributed to mass effect of the tumor (despite&#xD;
             corticosteroid treatment) that would be better treated with debulking surgery, or&#xD;
             wherein surgical debulking in the first 30 days following LITT procedure would be&#xD;
             anticipated for symptom management.&#xD;
&#xD;
          -  Patients unable to undergo MRI are not eligible.&#xD;
&#xD;
          -  Patients with progression of multifocal tumors or tumors involving the posterior fossa&#xD;
             (brainstem and cerebellum) will be excluded, as will patients where the anticipated&#xD;
             treatment margin will be within 5 mm of critical intracranial structures (e.g.,&#xD;
             primary branches of cerebral vessels, dural sinuses, hypophysis or cranial nerves).&#xD;
&#xD;
          -  Patients may not have undergone previous treatment with lomustine.&#xD;
&#xD;
          -  Patients must not have any significant medical illnesses that in the investigator's&#xD;
             opinion cannot be adequately controlled with appropriate therapy or would compromise&#xD;
             the patient's ability to tolerate this therapy.&#xD;
&#xD;
          -  Patients with a history of any other cancer (except non-melanoma skin cancer or&#xD;
             carcinoma in-situ of the cervix), unless in complete remission and off of all therapy&#xD;
             for that disease for a minimum of 3 years are ineligible.&#xD;
&#xD;
          -  Patients must not have active infection or serious intercurrent medical illness.&#xD;
&#xD;
          -  Patients must not be pregnant/breast feeding and must agree to practice adequate&#xD;
             contraception.&#xD;
&#xD;
          -  Patients must not have uncontrolled hypertension (systolic &gt;180 mm hg or diastolic &gt;&#xD;
             100 mg Hg), angina pectoris, cardiac dysrhythmia, or recent (within 6 weeks)&#xD;
             intracranial hemorrhage.&#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>Barbara J O'Brien</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>University of Texas MD Anderson Cancer Center Website</description>
  </link>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>January 13, 2017</study_first_submitted>
  <study_first_submitted_qc>January 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <results_first_submitted>May 25, 2022</results_first_submitted>
  <results_first_submitted_qc>July 14, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">August 10, 2022</results_first_posted>
  <disposition_first_submitted>January 5, 2022</disposition_first_submitted>
  <disposition_first_submitted_qc>July 14, 2022</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">August 10, 2022</disposition_first_posted>
  <last_update_submitted>July 14, 2022</last_update_submitted>
  <last_update_submitted_qc>July 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 10, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lomustine</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 15, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/78/NCT03022578/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>7 Participants signed consent, 3 participants inevaluable due to screen failure</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Treatment (LITT, Lomustine)</title>
          <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment (LITT, Lomustine)</title>
          <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="4"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="57" lower_limit="37" upper_limit="73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Disease Control Rate at 6 Months</title>
        <description>Stable Disease per RANO occurs if the patient does not qualify for response or progression and requires stable non enhancing lesions, same/lower dose of corticosteroids, and clinical stability.&#xD;
Complete Response per RANO requires complete disappearance of all enhancing measurable and nonmeasurable disease for at least 4 weeks; no new lesions; and stable/improved nonenhancing lesions, off corticosteroids (or on physiologic replacement dose) and clinical improvement/stability. Partial Response per RANO requires ≥50% decrease of enhancing lesions compared with baseline, sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable/improved nonenhancing lesions, same/lower dose of corticosteroids not greater than the dose at time of the baseline scan and clinically improved/stable.</description>
        <time_frame>At 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>Disease Control Rate at 6 Months</title>
          <description>Stable Disease per RANO occurs if the patient does not qualify for response or progression and requires stable non enhancing lesions, same/lower dose of corticosteroids, and clinical stability.&#xD;
Complete Response per RANO requires complete disappearance of all enhancing measurable and nonmeasurable disease for at least 4 weeks; no new lesions; and stable/improved nonenhancing lesions, off corticosteroids (or on physiologic replacement dose) and clinical improvement/stability. Partial Response per RANO requires ≥50% decrease of enhancing lesions compared with baseline, sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable/improved nonenhancing lesions, same/lower dose of corticosteroids not greater than the dose at time of the baseline scan and clinically improved/stable.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Progression Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non Evaluable</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Progression (TTP)</title>
        <description>Progression disease per the Response Assessment in Neuro-Oncology (RANO) is defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with the baseline scan or the best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor or to a decrease in the corticosteroid dose.</description>
        <time_frame>From date of enrollment in study to the date of first observation of progressive disease, death due to disease (event), or early discontinuation of treatment, approximately 3 years 3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Progression (TTP)</title>
          <description>Progression disease per the Response Assessment in Neuro-Oncology (RANO) is defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with the baseline scan or the best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor or to a decrease in the corticosteroid dose.</description>
          <units>weeks</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30" lower_limit="1" upper_limit="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Long-term Steroid Requirements</title>
        <description>Will be summarized by frequency tables.</description>
        <time_frame>Up to 4 years</time_frame>
        <population>Data were not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>Long-term Steroid Requirements</title>
          <description>Will be summarized by frequency tables.</description>
          <population>Data were not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Data</title>
        <description>Will summarize the MDASI-BT at each time point using descriptive statistics and evaluate the change of MDASI-BT over time and its correlation with response and/or treatment tolerance using linear mixed models, where random effects will be used to account for within-subject correlations.</description>
        <time_frame>at baseline, after procedure, and with every imaging visit thereafter, up to 4 years</time_frame>
        <population>Data were not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Data</title>
          <description>Will summarize the MDASI-BT at each time point using descriptive statistics and evaluate the change of MDASI-BT over time and its correlation with response and/or treatment tolerance using linear mixed models, where random effects will be used to account for within-subject correlations.</description>
          <population>Data were not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Incidence of Toxicity (Significant Hemorrhage or Brain Herniation) Documented on Imaging</title>
        <description>Safety and toxicity of LITT by determination of adverse events and surgical complications within 2 weeks of the procedure, plus an additional 4 weeks (to account for potential delayed inflammatory changes and initiation of subsequent treatment). Safety for LITT procedure will be defined as the absence of severe clinical toxicity as determined by the CTCAE version 4.0, within 6 weeks of the procedure, and/or absence of acute events (ie, significant hemorrhage or brain herniation) documented on imaging. Severe toxicity will also be defined as a drop of 20 points or more in KPS and not amenable to corticosteroids, and likely attributable to the procedure, or symptomatic hemorrhage, increased brain edema resulting in herniation/impending herniation, and/or significant neurologic decline not amenable to corticosteroids. Safety and toxicity will be reassessed again throughout the duration of the study.</description>
        <time_frame>approximately 3 years 3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Incidence of Toxicity (Significant Hemorrhage or Brain Herniation) Documented on Imaging</title>
          <description>Safety and toxicity of LITT by determination of adverse events and surgical complications within 2 weeks of the procedure, plus an additional 4 weeks (to account for potential delayed inflammatory changes and initiation of subsequent treatment). Safety for LITT procedure will be defined as the absence of severe clinical toxicity as determined by the CTCAE version 4.0, within 6 weeks of the procedure, and/or absence of acute events (ie, significant hemorrhage or brain herniation) documented on imaging. Severe toxicity will also be defined as a drop of 20 points or more in KPS and not amenable to corticosteroids, and likely attributable to the procedure, or symptomatic hemorrhage, increased brain edema resulting in herniation/impending herniation, and/or significant neurologic decline not amenable to corticosteroids. Safety and toxicity will be reassessed again throughout the duration of the study.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>Overall Survival (OS) is the time from initial tumor diagnosis (definitive surgical resection or biopsy) to death from any cause. Will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on OS.</description>
        <time_frame>approximately 3 years 3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>Overall Survival (OS) is the time from initial tumor diagnosis (definitive surgical resection or biopsy) to death from any cause. Will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on OS.</description>
          <units>weeks</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="69" lower_limit="9" upper_limit="164"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Length of Hospital Stay Following LITT</title>
        <description>The length of hospital stay in days, weeks or months. Length of Hospital stay was summarized by using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables.</description>
        <time_frame>approximately 3 years 3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>Length of Hospital Stay Following LITT</title>
          <description>The length of hospital stay in days, weeks or months. Length of Hospital stay was summarized by using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables.</description>
          <units>days</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3" lower_limit="3" upper_limit="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Biomarkers in Peripheral Blood and Tumor Tissue</title>
        <description>Will be summarized using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables. Correlation will be assessed among continuous variables using Pearson or Spearman correlation coefficient, whichever is appropriate. Association between categorical variables will be examined by Chi-Squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test will be used to examine the difference on continuous variables between or among patient's characteristic groups.</description>
        <time_frame>Up to 4 years</time_frame>
        <population>Data were not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>Biomarkers in Peripheral Blood and Tumor Tissue</title>
          <description>Will be summarized using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables. Correlation will be assessed among continuous variables using Pearson or Spearman correlation coefficient, whichever is appropriate. Association between categorical variables will be examined by Chi-Squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test will be used to examine the difference on continuous variables between or among patient's characteristic groups.</description>
          <population>Data were not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Inflammatory/Immunologic Profile</title>
        <description>Will be summarized using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables. Correlation will be assessed among continuous variables using Pearson or Spearman correlation coefficient, whichever is appropriate. Association between categorical variables will be examined by Chi-Squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test will be used to examine the difference on continuous variables between or among patient's characteristic groups.</description>
        <time_frame>Up to 4 years</time_frame>
        <population>Data were not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (LITT, Lomustine)</title>
            <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
          </group>
        </group_list>
        <measure>
          <title>Inflammatory/Immunologic Profile</title>
          <description>Will be summarized using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables. Correlation will be assessed among continuous variables using Pearson or Spearman correlation coefficient, whichever is appropriate. Association between categorical variables will be examined by Chi-Squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test will be used to examine the difference on continuous variables between or among patient's characteristic groups.</description>
          <population>Data were not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>from the start of treatment through 30 days after the last dose of treatment, approximately 3 years 3 months.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment (LITT, Lomustine)</title>
          <description>Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.&#xD;
Laser Interstitial Thermal Therapy: Undergo LITT&#xD;
Lomustine: Given PO</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle weakness right sided</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Paaresthesia (right arm numbnes)</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Dysphasia (aphasia)</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal calculi</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Facial muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Muscle weakness right-sided</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Barbara O'Brien, MD/Associate Professor, Neuro-Oncology</name_or_title>
      <organization>UT MD Anderson Cancer Center</organization>
      <phone>(713) 794-4380</phone>
      <email>bjobrien@mdanderson.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03022578
org study id: 2016-0443
secondary id: NCI-2018-01286
secondary id: 2016-0443
secondary id: P30CA016672
nct id: NCT03022578
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well laser interstitial thermal therapy and lomustine work in
      treating patients with glioblastoma or anaplastic astrocytoma that has come back. Using laser
      to heat the tumor cells may help to kill them. Drugs used in chemotherapy, such as lomustine,
      work in different ways to stop the growth of tumor cells, either by killing the cells, by
      stopping them from dividing, or by stopping them from spreading. Giving laser interstitial
      thermal therapy and lomustine may work better in treating patients with glioblastoma or
      anaplastic astrocytoma.
PRIMARY OBJECTIVES:

      I. Determine the disease control rate at 6 months in patients with recurrent glioblastoma or
      isocitrate dehydrogenase (IDH)-wildtype anaplastic astrocytoma treated with Laser
      Interstitial Thermal Therapy (LITT) at recurrence, followed by salvage chemotherapy.

      SECONDARY OBJECTIVES:

      I. Estimate overall survival (OS) of patients with recurrent glioblastoma, or isocitrate
      dehydrogenase (IDH)-wildtype anaplastic astrocytoma treated with LITT at tumor recurrence,
      followed by salvage chemotherapy.

      II. Estimate time to progression (TTP) of patients with recurrent glioblastoma, or isocitrate
      dehydrogenase (IDH)-wildtype anaplastic astrocytoma that are treated with LITT at tumor
      recurrence, followed by salvage chemotherapy.

      III. Analyze volumetric data consisting of thermal damage threshold lines and overall tumor
      volume to determine any role of 'extent of ablation' in outcomes (OS and/or TTP).

      IV. Characterize the safety profile of LITT followed by treatment with lomustine chemotherapy
      in the recurrent disease setting, using the Common Terminology Criteria for Adverse Events
      (CTCAE) version 4.0.

      V. Assess the long-term steroid requirements following LITT, compared to historical controls.

      VI. Determine the radiographic evolution of LITT-treated glioblastoma over time, using
      conventional magnetic resonance imaging (MRI) (T1 pre and post-contrast images, T2-weighted
      images [T2WI], fluid attenuating inversion recovery [FLAIR] images) and advanced brain tumor
      imaging (ABTI) [magnetic resonance (MR) perfusion [dynamic susceptibility contrast (DSC),
      dynamic contrast enhancement (DCE) and arterial spin labeling (ASL)], MR-diffusion, and MR
      spectroscopy), to include quantitative tumor metrics (volumetric extent of ablation and
      Response Assessment in Neuro-Oncology [RANO] criteria).

      VII. Analyze health care utilization as measured by length of hospital stay following LITT
      (including inpatient rehabilitation care).

      VIII. Evaluate patients' functional status (using the Karnofsky performance score [KPS] and
      the occurrence of symptoms [using the MD Anderson Symptom Inventory-Brain Tumor Module
      (MDASI-BT[English])] self-reporting tool), and correlate to disease progression and tolerance
      to treatment.

      EXPLORATORY OBJECTIVES:

      I. Identify correlative tumor and peripheral blood molecular markers that impact outcomes,
      etc, and identify inflammatory/immunologic markers to assess neoantigen expression, etc, if
      sufficient tissue is available.

      II. Identify and characterize changes in tumor tissue following LITT, by analyzing and
      comparing pre- and post-procedure tissue samples, if sufficient tissue is available.

      OUTLINE:

      Patients undergo LITT at baseline and receive lomustine orally (PO) on day 1. Treatment with
      lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or
      unaccepted toxicity.

      After completion of study treatment, patients are followed up every 3 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease Control Rate at 6 Months
time frame: At 6 months
description: Stable Disease per RANO occurs if the patient does not qualify for response or progression and requires stable non enhancing lesions, same/lower dose of corticosteroids, and clinical stability.
Complete Response per RANO requires complete disappearance of all enhancing measurable and nonmeasurable disease for at least 4 weeks; no new lesions; and stable/improved nonenhancing lesions, off corticosteroids (or on physiologic replacement dose) and clinical improvement/stability. Partial Response per RANO requires ≥50% decrease of enhancing lesions compared with baseline, sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable/improved nonenhancing lesions, same/lower dose of corticosteroids not greater than the dose at time of the baseline scan and clinically improved/stable.
measure: Time to Progression (TTP)
time frame: From date of enrollment in study to the date of first observation of progressive disease, death due to disease (event), or early discontinuation of treatment, approximately 3 years 3 months
description: Progression disease per the Response Assessment in Neuro-Oncology (RANO) is defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with the baseline scan or the best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor or to a decrease in the corticosteroid dose.
measure: Long-term Steroid Requirements
time frame: Up to 4 years
description: Will be summarized by frequency tables.
measure: MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Data
time frame: at baseline, after procedure, and with every imaging visit thereafter, up to 4 years
description: Will summarize the MDASI-BT at each time point using descriptive statistics and evaluate the change of MDASI-BT over time and its correlation with response and/or treatment tolerance using linear mixed models, where random effects will be used to account for within-subject correlations.
measure: Number of Participants With Incidence of Toxicity (Significant Hemorrhage or Brain Herniation) Documented on Imaging
time frame: approximately 3 years 3 months
description: Safety and toxicity of LITT by determination of adverse events and surgical complications within 2 weeks of the procedure, plus an additional 4 weeks (to account for potential delayed inflammatory changes and initiation of subsequent treatment). Safety for LITT procedure will be defined as the absence of severe clinical toxicity as determined by the CTCAE version 4.0, within 6 weeks of the procedure, and/or absence of acute events (ie, significant hemorrhage or brain herniation) documented on imaging. Severe toxicity will also be defined as a drop of 20 points or more in KPS and not amenable to corticosteroids, and likely attributable to the procedure, or symptomatic hemorrhage, increased brain edema resulting in herniation/impending herniation, and/or significant neurologic decline not amenable to corticosteroids. Safety and toxicity will be reassessed again throughout the duration of the study.
measure: Overall Survival (OS)
time frame: approximately 3 years 3 months
description: Overall Survival (OS) is the time from initial tumor diagnosis (definitive surgical resection or biopsy) to death from any cause. Will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on OS.
measure: Length of Hospital Stay Following LITT
time frame: approximately 3 years 3 months
description: The length of hospital stay in days, weeks or months. Length of Hospital stay was summarized by using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables.
measure: Biomarkers in Peripheral Blood and Tumor Tissue
time frame: Up to 4 years
description: Will be summarized using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables. Correlation will be assessed among continuous variables using Pearson or Spearman correlation coefficient, whichever is appropriate. Association between categorical variables will be examined by Chi-Squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test will be used to examine the difference on continuous variables between or among patient's characteristic groups.
measure: Inflammatory/Immunologic Profile
time frame: Up to 4 years
description: Will be summarized using standard descriptive statistics, such as mean, standard deviation, median, and range for continuous variables, frequency and proportion for categorical variables. Correlation will be assessed among continuous variables using Pearson or Spearman correlation coefficient, whichever is appropriate. Association between categorical variables will be examined by Chi-Squared test or Fisher's exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test will be used to examine the difference on continuous variables between or among patient's characteristic groups.
arm group label: Treatment (LITT, lomustine)
arm group type: Experimental
description: Patients undergo LITT at baseline and receive lomustine PO on day 1. Treatment with lomustine repeats every 42 days for up to 6 cycles in the absence of disease progression or unaccepted toxicity.
intervention type: Procedure
intervention name: Laser Interstitial Thermal Therapy
description: Undergo LITT
arm group label: Treatment (LITT, lomustine)
other name: LITT
intervention type: Drug
intervention name: Lomustine
description: Given PO
arm group label: Treatment (LITT, lomustine)
other name: 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea
other name: 1-Nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-
other name: Belustin
other name: Belustine
other name: CCNU
other name: Cecenu
other name: CeeNU
other name: Chloroethylcyclohexylnitrosourea
other name: Citostal
other name: Gleostine
other name: Lomeblastin
other name: Lomustinum
other name: Lucostin
other name: Lucostine
other name: N-(2-Chloroethyl)-N''-cyclohexyl-N-nitrosourea
other name: Prava
other name: RB-1509
other name: WR-139017
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Barbara J O'Brien
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
country: United States
url: http://www.mdanderson.org
description: University of Texas MD Anderson Cancer Center Website
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Astrocytoma
mesh term: Recurrence
mesh term: Lomustine
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 