Clinical Trials /

Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma

NCT02359565

Description:

This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back, progressed, or have not responded to previous treatment. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells.

Related Conditions:
  • Glioma
  • Malignant Brain Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, or Hypermutated Brain Tumors
  • Official Title: A Safety and Preliminary Efficacy Trial of MK-3475 (Pembrolizumab; Anti-PD-1) in Children With Recurrent, Progressive or Refractory High-Grade Gliomas (HGG) and DIPGs and Hypermutated Brain Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-00130
  • SECONDARY ID: NCI-2015-00130
  • SECONDARY ID: PBTC-045
  • SECONDARY ID: PBTC-045
  • SECONDARY ID: PBTC-045
  • SECONDARY ID: UM1CA081457
  • NCT ID: NCT02359565

Conditions

  • Constitutional Mismatch Repair Deficiency Syndrome
  • Lynch Syndrome
  • Malignant Glioma
  • Recurrent Brain Neoplasm
  • Recurrent Diffuse Intrinsic Pontine Glioma
  • Refractory Brain Neoplasm
  • Refractory Diffuse Intrinsic Pontine Glioma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab)

Purpose

This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), or brain tumors with a high number of genetic mutations that have come back, progressed, or have not responded to previous treatment. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the safety and describe adverse effects associated with administration of the
      adult recommended dose of pembrolizumab (MK-3475) in children with recurrent, progressive or
      refractory non-brainstem high grade glioma (NB-HGG) and diffuse intrinsic pontine glioma
      (DIPG).

      II. To estimate the sustained objective response rate, (complete response [CR] + partial
      response [PR], sustained for at least 9 weeks) associated with pembrolizumab (MK-3475)
      treatment for pediatric patients with recurrent, progressive or refractory NB-HGG or DIPG.

      III. To establish the safety and describe adverse effects associated with administration of
      the adult recommended dose of pembrolizumab (MK-3475) in pediatric patients with progressive
      or recurrent hypermutated tumors, including those with conditional mismatch-repair deficiency
      (CMMRD) syndrome.

      IV. To estimate the sustained response rate of pediatric patients with progressive or
      recurrent hypermutated NB-HGG, including those with CMMRD syndrome, treated with
      pembrolizumab (MK-3475).

      V. To determine changes in the immunophenotypic profile of PD-1hi CD8+ T cells from serial
      peripheral blood samples obtained before and during treatment with pembrolizumab (MK-3475) in
      pediatric patients with hypermutated brain tumors, including those with CMMRD syndrome.

      SECONDARY OBJECTIVES:

      I. To assess the relationship between outcome (response and progression-free survival [PFS])
      and potential biomarkers, including PD-L1 expression, patient immunophenotype, ribonucleic
      acid (RNA) signature profile, and tumor gene expression profile.

      II. To estimate the duration of objective response, progression-free/event-free survival and
      document overall survival for patients with NB-HGG and DIPG treated with pembrolizumab
      (MK-3475).

      III. To evaluate PD-L1 expression on archival tissue obtained from patients with
      non-brainstem high-grade glioma.

      IV. To examine the ability of quantitative magnetic resonance (MR) spectroscopy and
      diffusion/weighted imaging/apparent diffusion coefficient (ADC) mapping to provide early
      assessment of tumor behavior and specifically distinguish pseudoprogression/tumor
      inflammation from tumor progression.

      V. To explore the use of serial MR permeability (dynamic contrast-enhanced [DCE]) and MR
      perfusion (dynamic susceptibility contrast [DSC]) to determine if elevated relative cerebral
      blood volume (rCBV) and transfer coefficient (ktrans) can distinguish pseudoprogression/tumor
      inflammation from tumor progression in tumors treated on this protocol.

      VI. To characterize biomarkers, patient immunophenotyping, mutational load (as determined by
      whole exome sequencing) and the tumor gene expression profile in patients with HGG receiving
      pembrolizumab (MK-3475).

      VII. To estimate the duration of objective response, PFS/event free survival and document
      overall survival of pediatric patients with progressive or recurrent hypermutated NB-HGG,
      including those with CMMRD syndrome, treated with pembrolizumab (MK-3475).

      VIII. To estimate the PFS and sustained objective response rate of pediatric patients with
      hypermutated progressive low grade gliomas including those with CMMRD, treated with
      pembrolizumab (MK-3475).

      IX. To categorize the T-cell receptor repertoire in PD-1+ cells obtained from peripheral
      blood or from tumor tissue, when available, before and after treatment with pembrolizumab
      (MK-3475) in pediatric patients treated in stratum C (hypermutated brain tumors).

      X. To define the specificity of T-cell receptors against tumor antigens identified in
      objective IX.

      XI. To characterize functional features of T-cell populations after pembrolizumab (MK-3475)
      treatment and relate these findings to epigenetic programs within these cells.

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
      every 21 days for 34 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year,
      every 6 months for 3 years, and annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 34 courses in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Tumor:
    
                   -  A diffuse intrinsic pontine glioma (DIPG) that is recurrent, progressive or
                      refractory; histologic diagnosis is not required for patients with typical
                      imaging findings of DIPG (defined as patients with a diffuse expansile mass
                      centered in and involving at least 2/3 of the pons); patients with brainstem
                      tumors who have undergone biopsy with a diagnosis of high-grade glioma or diffuse
                      infiltrating glioma are also eligible
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients with
                 DIPG who have tissue available are requested to submit similar tissue as patients with
                 NB-HGG; however, this is not required for eligibility
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): All subjects
                 must have measurable disease in 2-dimensions on MRI scan of the brain; disease should
                 be consistently measured with the two largest perpendicular dimensions
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients must
                 have received prior radiation therapy and/or chemotherapy and recovered from the acute
                 treatment related toxicities (defined as =< grade 1 if not defined in eligibility
                 criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior to entering
                 this study; there is no upper limit to the number of prior therapies that is allowed
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients must
                 have received their last dose of known myelosuppressive anticancer therapy at least
                 three (3) weeks prior to study enrollment or at least six (6) weeks if prior
                 nitrosourea
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Biologic or
                 investigational agent (anti-neoplastic): patient must have received their last dose of
                 the investigational or biologic agent >= 7 days prior to study enrollment
    
                   -  For agents that have known adverse events occurring beyond 7 days after
                      administration, this period must be extended beyond the time during which adverse
                      events are known to occur; the duration must be discussed with and approved by
                      the study chair
    
                   -  Monoclonal antibody treatment and/or agents with prolonged half-lives: at least
                      three half-lives must have elapsed prior to enrollment
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patient must
                 have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least
                 42 days prior to enrollment
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients must
                 have had their last fraction of:
    
                   -  Craniospinal irradiation >= 3 months prior to enrollment
    
                   -  Other substantial bone marrow irradiation >= 6 weeks prior to enrollment
    
                   -  Local palliative radiation therapy (XRT) (small port) >= 2 weeks
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patient must be
                 >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients must
                 be fully recovered from all acute effects of prior surgical intervention
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): All races and
                 ethnic groups are eligible for this study
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients with
                 neurological deficits should have deficits that are completely stable for a minimum of
                 1 week (7 days) prior to enrollment
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Karnofsky
                 performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =<
                 16 years of age) assessed within two weeks of enrollment must be >= 70; patients who
                 are unable to walk because of neurologic deficits, but who are up in a wheelchair,
                 will be considered ambulatory for the purpose of assessing the performance score
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Absolute
                 neutrophil count >= 1.0 x 10^9 cells/L
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Platelets >=
                 100,000/mm^3 (unsupported, defined as no platelet transfusion within 7 days)
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Hemoglobin >= 8
                 g/dl (may receive transfusions)
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Total bilirubin
                 =< 1.5 times institutional upper limit of normal (ULN)
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Alanine
                 aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
                 institutional upper limit of normal
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Albumin >= 2
                 g/dl
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Serum
                 creatinine based on age/gender as noted below; patients that do not meet the criteria
                 below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR)
                 (radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are eligible
    
                   -  1 to < 2 years: 0.6 mg/dl
    
                   -  2 to < 6 years: 0.8 mg/dl
    
                   -  6 to < 10 years: 1 mg/dl
    
                   -  10 to < 13 years: 1.2 mg/dl
    
                   -  13 to < 16 years: 1.5 mg/dl (male), 1.4 mg/dl (female)
    
                   -  >= 16 years: 1.7 mg/dl (male), 1.4 mg/dl (female)
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Pulse oximetry
                 > 93% on room air and no evidence of dyspnea at rest
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients must
                 be off all colony-forming growth factor(s) for at least 1 week prior to registration
                 (i.e. filgrastim, sargramostim, erythropoietin); 2 weeks must have elapsed for
                 long-acting formulations
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients must
                 be willing to use brief courses (at least 72 hours) of steroids as directed for
                 potential inflammatory side effects of the therapy if recommended by their treating
                 physician
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Female subjects
                 of childbearing potential must not be pregnant or breast-feeding; female patients of
                 childbearing potential must have a negative serum or urine pregnancy test within 72
                 hours prior to receiving the first dose of study medication; if the urine test is
                 positive or cannot be confirmed as negative, a serum pregnancy test will be required;
                 pregnant women are excluded from this study; breastfeeding should be discontinued if
                 the mother is to be treated with MK-3475 (pembrolizumab)
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients of
                 childbearing or child fathering potential must be willing to use 2 methods of birth
                 control or be surgically sterile or abstain from heterosexual activity while being
                 treated on this study and for 4 months after the last dose of study medication
    
              -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): The patient or
                 parent/guardian is able to understand the consent and is willing to sign a written
                 informed consent document, inclusive of assent where appropriate, according to
                 institutional guidelines
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Tumor:
    
                   -  Patients must have a histologically confirmed diagnosis of a non-brainstem
                      high-grade glioma that is recurrent, progressive or refractory; spinal primary
                      disease is eligible
    
              -  NCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients with non-brainstem high grade
                 glioma must have adequate pre-trial FFPE tumor material available for use in the
                 biology studies and genome wide sequencing; while tissue is required for PD-1, PD-L1
                 and immunophenotyping, patients will be deemed eligible for the study with a minimum
                 of 10 unstained slides for the PD-1/PD-L1 immunohistochemical analysis
    
              -  NCLUSION CRITERIA FOR NB-NGG (STRATUM B): All subjects must have measurable disease in
                 2-dimensions on MRI scan of the brain; disease should be consistently measured with
                 the two largest perpendicular dimensions
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients must have received prior radiation
                 therapy and/or chemotherapy and recovered from the acute treatment related toxicities
                 (defined as =< grade 1 if not defined in eligibility criteria) of all prior
                 chemotherapy, immunotherapy or radiotherapy prior to entering this study; there is no
                 upper limit to the number of prior therapies that is allowed
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients must have received their last dose
                 of known myelosuppressive anticancer therapy at least three (3) weeks prior to study
                 enrollment or at least six (6) weeks if prior nitrosourea
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Biologic or investigational agent
                 (anti-neoplastic): patient must have received their last dose of the investigational
                 or biologic agent >= 7 days prior to study enrollment
    
                   -  For agents that have known adverse events occurring beyond 7 days after
                      administration, this period must be extended beyond the time during which adverse
                      events are known to occur; the duration must be discussed with and approved by
                      the study chair
    
                   -  Monoclonal antibody treatment and/or agents with prolonged half-lives: at least
                      three half-lives must have elapsed prior to enrollment
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patient must have completed immunotherapy
                 (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollment
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients must have had their last fraction
                 of:
    
                   -  Craniospinal irradiation >= 3 months prior to enrollment
    
                   -  Other substantial bone marrow irradiation >= 6 weeks prior to enrollment
    
                   -  Local palliative XRT (small port) >= 2 weeks
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patient must be >= 12 weeks since
                 autologous bone marrow/stem cell transplant prior to enrollment
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients must be fully recovered from all
                 acute effects of prior surgical intervention
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): All races and ethnic groups are eligible
                 for this study
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients with neurological deficits should
                 have deficits that are completely stable for a minimum of 1 week (7 days) prior to
                 enrollment
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Karnofsky performance scale (KPS for > 16
                 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within
                 two weeks of enrollment must be >= 70; patients who are unable to walk because of
                 neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for
                 the purpose of assessing the performance score
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Absolute neutrophil count >= 1.0 x 10^9
                 cells/L
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Platelets >= 100,000/mm^3 (unsupported,
                 defined as no platelet transfusion within 7 days)
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Hemoglobin >= 8 g/dl (may receive
                 transfusions)
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Total bilirubin =< 1.5 times institutional
                 upper limit of normal (ULN)
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): ALT (SGPT) =< 3 x institutional upper limit
                 of normal
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Albumin >= 2 g/dl
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Serum creatinine based on age/gender as
                 noted below; patients that do not meet the criteria below but have a 24 hour
                 creatinine clearance or GFR (radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are
                 eligible
    
                   -  1 to < 2 years: 0.6 mg/dl
    
                   -  2 to < 6 years: 0.8 mg/dl
    
                   -  6 to < 10 years: 1 mg/dl
    
                   -  10 to < 13 years: 1.2 mg/dl
    
                   -  13 to < 16 years: 1.5 mg/dl (male), 1.4 mg/dl (female)
    
                   -  >= 16 years: 1.7 mg/dl (male), 1.4 mg/dl (female)
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Pulse oximetry > 93% on room air and no
                 evidence of dyspnea at rest
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients must be off all colony-forming
                 growth factor(s) for at least 1 week prior to registration (i.e. filgrastim;
                 sargramostim; erythropoietin); 2 weeks must have elapsed for long-acting formulations
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients must be willing to use brief
                 courses (at least 72 hours) of steroids as directed for potential inflammatory side
                 effects of the therapy if recommended by their treating physician
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Female subjects of childbearing potential
                 must not be pregnant or breast-feeding; female patients of childbearing potential must
                 have a negative serum or urine pregnancy test within 72 hours prior to receiving the
                 first dose of study medication; if the urine test is positive or cannot be confirmed
                 as negative, a serum pregnancy test will be required; pregnant women are excluded from
                 this study; breastfeeding should be discontinued if the mother is to be treated with
                 MK-3475 (pembrolizumab)
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients of childbearing or child fathering
                 potential must be willing to use 2 methods of birth control or be surgically sterile
                 or abstain from heterosexual activity while being treated on this study and for 4
                 months after the last dose of study medication
    
              -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): The patient or parent/guardian is able to
                 understand the consent and is willing to sign a written informed consent document,
                 inclusive of assent where appropriate, according to institutional guidelines
    
              -  INCLUSION CRITERIA FOR HYPERMUTATED BRAIN TUMORS (STRATUM C): Patients with brain
                 tumors and increased tumor mutation burden as determined by
    
                   -  Confirmed diagnosis of CMMRD syndrome by CLIA-certified germline gene sequencing
                      OR
    
                   -  Confirmation of high mutation burden by whole genome/exome sequencing performed
                      in a CLIA-certified laboratory and/or the use of Foundation One next generation
                      sequence panel or another CLIA approved targeted sequencing lab with publicly
                      available correlations between number of mutations found in the panel and
                      mutations per megabase and/or genome; for protocol purposes a high mutation
                      burden will be defined as at least 100 non-synonymous coding-region mutations by
                      whole exome/genome sequencing (well above two standard deviations of the number
                      of median similar mutations described in pediatric central nervous system [CNS]
                      cancers) AND/OR a high tumor mutation burden (TMB) or intermediate TMB based on
                      the reporting parameters of the panel; TMB parameters provided for the Foundation
                      One reports are high tumor mutation burden is >= 20 mutations per megabase or
                      intermediate TMB is between 6 to 19 mutations per megabase
    
                   -  Confirmed diagnosis of Lynch syndrome by CLIA-certified germline gene sequencing;
                      patients with Lynch syndrome will not be accounted for in primary objective
                      unless their tumors are determined to have the minimum number of mutations
                      described above but they will still
          
    Maximum Eligible Age:29 Years
    Minimum Eligible Age:1 Year
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
    Time Frame:Within 30 days of treatment
    Safety Issue:
    Description:All adverse events observed during the dose finding period as well as during later courses will be summarized by stratum and by dose (if applicable). Separate tables for adverse events attributable to pembrolizumab will also be provided for each of the three strata.

    Secondary Outcome Measures

    Measure:Event-free survival
    Time Frame:Up to 3 years
    Safety Issue:
    Description:Kaplan-Meier estimates of event free survival distribution for all evaluable patients within each stratum will be provided.
    Measure:Overall survival (OS)
    Time Frame:Date of diagnosis to the earliest date of death from any cause or to the date of last contact for patients who remain at risk for failure, assessed bi-annually up to 3 years and then yearly thereafter
    Safety Issue:
    Description:Kaplan-Meier estimates of OS distribution for all evaluable patients within each stratum will be provided. Log-ranks tests or Cox regression models will be used to explore associations between biomarkers and progression free survival (PFS) and OS.
    Measure:Progression-free survival (PFS)
    Time Frame:Date of initial treatment to the earliest date of disease progression or death from any cause for patients who fail and to the date of last contact for patients who remain at risk for failure, assessed bi-annually up to 3 years and then yearly thereafter
    Safety Issue:
    Description:Log-ranks tests or Cox regression models will be used to explore associations between biomarkers and PFS and OS.
    Measure:Radiologic response (Stratum C)
    Time Frame:Up to 3 years
    Safety Issue:
    Description:Will report any objective radiological responses observed in subjects who were not part of the primary cohort of progressive/recurrent high-grade gliomas (HGGs).
    Measure:Biomarker expression levels
    Time Frame:Up to 18 courses (approximately 13.5 months)
    Safety Issue:
    Description:The biomarker data generated as part of this study will be summarized via descriptive statistics and plots. The association between response and potential biomarkers will be evaluated by Fisher's exact or Chi-square test for categorical outcomes and two sample t-tests (or appropriate non-parametric counterparts) for continuous outcomes. Log-ranks tests or Cox regression models will also be used to explore associations between biomarkers and PFS and OS. These analyses will be done in a stratum specific fashion.
    Measure:Changes in quantitative imaging parameters
    Time Frame:Baseline to up to 34 courses (approximately 25.5 months)
    Safety Issue:
    Description:Observed values of the proposed quantitative imaging parameters as well as changes in these parameters across time will be described and summarized via descriptive statistics and plots. Mixed effects models will be used to explore differences in estimated slope parameters of the quantitative imaging. Pairwise changes in these imaging parameters across various time points will also be described. T-tests (or their non-parametric equivalent) will be used to compare differences in pairwise changes between patients with progression vs. pseudoprogression/tumor inflammation.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated

    April 23, 2018