Clinical Trials /

Genetically Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma

NCT02208362

Description:

This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma that has come back (recurrent) or has not responded to therapy (refractory). A T cell is a type of immune cell that can recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and a modified gene is placed into them in the laboratory and this may help them recognize and kill glioma cells. Genetically modified T-cells may also help the body build an immune response against the tumor cells. Funding Source - FDA OOPD

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Genetically Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma
  • Official Title: Phase I Study of Cellular Immunotherapy Using Memory Enriched T Cells Lentivirally Transduced to Express an IL13Rα2-Specific, Hinge-Optimized, 41BB-Costimulatory Chimeric Receptor and a Truncated CD19 for Patients With Recurrent/Refractory Malignant Glioma

Clinical Trial IDs

  • ORG STUDY ID: 13384
  • SECONDARY ID: NCI-2014-01488
  • SECONDARY ID: 13384
  • SECONDARY ID: R01FD005129
  • NCT ID: NCT02208362

Conditions

  • Malignant Glioma
  • Refractory Brain Neoplasm
  • Recurrent Brain Neoplasm
  • Glioblastoma

Interventions

DrugSynonymsArms
IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing Autologous T lymphocytesautologous IL13(EQ)BBzeta/CD19t+ Tcm-enriched T cellsStratum I (T lymphocytes intratumoral)
IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing Autologous T lymphocytesautologous IL13(EQ)BBzeta/CD19t+ Tcm-enriched T cellsStratum IV (T lymphocytes intratumoral and intraventricular)
Vaccine TherapyStratum V (T lymphocytes intratumoral and intraventricular)

Purpose

This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma that has come back (recurrent) or has not responded to therapy (refractory). A T cell is a type of immune cell that can recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and a modified gene is placed into them in the laboratory and this may help them recognize and kill glioma cells. Genetically modified T-cells may also help the body build an immune response against the tumor cells. Funding Source - FDA OOPD

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded
      autologous memory-enriched T cells that are genetically modified using a self-inactivating
      (SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13R alpha
      2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as
      a truncated human cluster of differentiation 19 (CD19) for participants with
      recurrent/refractory malignant glioma in one of the following ways: stratum 1 (intratumoral
      delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ central memory T cells [Tcm]) (IL13R alpha
      2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes),
      stratum 2 (intracavitary delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm, stratum 3
      (intraventricular delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm), stratum 4 (dual
      delivery [both intratumoral and intraventricular] of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm),
      or stratum 5 (dual delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ naive and memory T cells
      [Tn/mem]).II. To determine maximum tolerated dose schedule (MTD) and a recommended phase II
      dosing plan (RP2D) for each stratum based on dose limiting toxicities (DLTs) and the full
      toxicity profile.

      SECONDARY OBJECTIVES:

      I. To assess the timing and extent of brain inflammation, as assessed by magnetic resonance
      imaging (MRI)/magnetic resonance spectroscopy (MRS), following T cell administration.

      II. To describe cytokine levels (cyst fluid, peripheral blood) over the study period.

      III. In research participants who receive the full schedule of three CAR+ T cell doses:
      estimate the six month progression free survival rate, disease response rates, and median
      overall survival.

      IV. In research participants who receive intraventricular infusions after progressing
      following intratumoral/intracranial infusions (stratum 1 or 2): estimate disease response.

      V. In research participants who receive at least one dose of CAR+ T cells estimate the mean
      change from baseline in quality of life using the European Organization for Research and
      Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and EORTC QLQ brain
      neoplasm (BN)-20 survey scale, domain and item scores during and post treatment.

      VI. To evaluate CAR T cell persistence in the tumor micro-environment and the location of the
      CAR T cells with respect to the injection. (For research participants who undergo a second
      resection or autopsy).

      VII. To evaluate IL13R alpha 2 antigen expression levels pre and post CAR T cell therapy.
      (For research participants who undergo a second resection or autopsy) OUTLINE: This is a
      dose-escalation study. Patients are assigned to 1 of 5 strata.

      STRATUM I (Intratumoral delivery) CLOSED TO ACCRUAL 03/02/2018: Patients receive IL13R alpha
      2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes
      via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
      later, patients may receive additional T cell infusions as long as patients remain eligible
      and there is product available. Patients who progress on intracavitary or intratumoral
      administration may move to intraventricular catheter for the optional infusions.

      STRATUM II (Intracavitary delivery): Patients receive IL13R alpha 2-specific,
      hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via
      intracavitary catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later,
      patients may receive additional T cell infusions as long as patients continue to remain
      eligible and there is product available. Patients who progress on intracavitary or
      intratumoral administration may move to intraventricular catheter for the optional infusions.

      STRATUM III (Intraventricular delivery): Patients receive IL13R alpha 2-specific,
      hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via
      intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
      later, patients may receive additional T cell infusions as long as patients continue to
      remain eligible and there is product available.

      STRATUM IV (Dual delivery): Patients receive IL13R alpha 2-specific, hinge-optimized,
      41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and
      intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
      later, patients may receive additional T cell infusions as long as patients continue to
      remain eligible and there is product available. Based on clinical response after the first 3
      infusions, the study principal investigator may decide to continue with the optional
      infusions at either one or both sites (instead of requiring injections at both sites).

      STRATUM V (Dual delivery): Patients receive IL13 [EQ]BBzeta/truncated CD19[t]+ Tn/mem via
      intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks.
      Beginning as early as 1 week later, patients may receive additional T cell infusions as long
      as patients continue to remain eligible and there is product available. Based on clinical
      response after the first 3 infusions, the study principal investigator may decide to continue
      with the optional infusions at either one or both sites (instead of requiring injections at
      both sites).

      After completion of study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10 and 12
      months and then yearly for 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Stratum I (T lymphocytes intratumoral)ExperimentalCLOSED TO ACCRUAL 03/02/2018 Patients receive IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.
  • IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing Autologous T lymphocytes
Stratum II (T lymphocytes intracavitary)ExperimentalPatients receive IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intracavitary catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.
  • IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing Autologous T lymphocytes
Stratum III (T lymphocytes intraventricular)ExperimentalPatients receive IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intraventricular catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available.
  • IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing Autologous T lymphocytes
Stratum IV (T lymphocytes intratumoral and intraventricular)ExperimentalPatients receive IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).
  • IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing Autologous T lymphocytes
Stratum V (T lymphocytes intratumoral and intraventricular)ExperimentalPatients receive IL13 [EQ]BBzeta/truncated CD19[t]+ Tn/mem via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).
  • Vaccine Therapy

Eligibility Criteria

        Inclusion Criteria:

        SCREENING INCLUSION CRITERIA

          -  Participant has a prior histologically-confirmed diagnosis of a grade III or IV
             glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now
             has radiographic progression consistent with a grade III or IV malignant glioma (MG)
             after completing standard therapy

          -  Radiographic evidence of progression/recurrence of the measurable disease more than 12
             weeks after the end of the initial radiation therapy

          -  Karnofsky performance status (KPS) >= 60%

          -  Life expectancy > 4 weeks

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control or abstinence) prior to study entry and
             for six months following duration of study participation; should a woman become
             pregnant or suspect that she is pregnant while participating on the trial, she should
             inform her treating physician immediately

          -  COH Clinical Pathology confirms IL13R alpha 2+ tumor expression by
             immunohistochemistry (>= 20%, 1+)

          -  All research participants must have the ability to understand and the willingness to
             sign a written informed consent

        ELIGIBILITY TO PROCEED WITH PBMC COLLECTION:

          -  Research participant must not require more than 2 mg TID of Dexamethasone on the day
             of PBMC collection

          -  Research participant must have appropriate venous access

          -  At least 2 weeks must have elapsed since the research participant received his/her
             last dose of prior chemotherapy or radiation

        ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT:

          -  Creatinine < 1.6 mg/dL

          -  White blood cell (WBC) > 2,000/dl

          -  Absolute neutrophil count (ANC) > 1,000

          -  Platelets >= 100,000/dl

          -  International normalized ratio (INR) < 1.3

          -  Bilirubin < 1.5 mg/dL

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper
             limits of normal

          -  An interval of at least 12 weeks must have elapsed since the completion of initial
             radiation therapy

          -  At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen

          -  At least 23 days since the completion of Temodar and/or 4 weeks for any other
             non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most recent
             treatment was with a targeted agent only, and s/he has recovered from any toxicity of
             this targeted agent, then a waiting period of only 2 weeks is needed from the last
             dose and the start of study treatment, with the exception of bevacizumab where a wash
             out period of at least 4 weeks is required before starting study treatment

        ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH CAR T CELL INFUSION:

          -  Research participant has a released cryopreserved T cell product

          -  Research participant does not require supplemental oxygen to keep saturation greater
             than 95% and/or does not have presence of any radiographic abnormalities on chest
             x-ray that are progressive

          -  Research participant does not require pressor support and/or does not have symptomatic
             cardiac arrhythmias

          -  Research participant does not have a fever exceeding 38.5° Celsius (C); there is an
             absence of positive blood cultures for bacteria, fungus, or virus within 48-hours
             prior to T cell infusion and/or there aren't any indications of meningitis

          -  Serum total bilirubin does not exceed 2 x normal limit

          -  Transaminases does not exceed 2 x normal limit

          -  Serum creatinine =< 1.8 mg/dL

          -  Research participant does not have uncontrolled seizure activity following surgery
             prior to starting the first T cell dose

          -  Platelet count must be >= 100,000; however, if platelet level is between
             75,000-99,000, then T-cell infusion may proceed after platelet transfusion is given
             and the post transfusion platelet count is >= 100,000

          -  Research participants must not require more than 2 mg thrice daily (TID) of
             dexamethasone during T cell therapy

        Exclusion Criteria:

        SCREENING EXCLUSION CRITERIA

          -  Research participant requires supplemental oxygen to keep saturation greater than 95%
             and the situation is not expected to resolve within 2 weeks

          -  Research participant requires pressor support and/or has symptomatic cardiac
             arrhythmias

          -  Research participant requires dialysis

          -  Research participant has uncontrolled seizure activity and/or clinically evident
             progressive encephalopathy

          -  Failure of research participant to understand the basic elements of the protocol
             and/or the risks/benefits of participating in this phase I study; a legal guardian may
             substitute for the research participant

          -  Research participants with any non-malignant intercurrent illness which is either
             poorly controlled with currently available treatment, or which is of such severity
             that the investigators deem it unwise to enter the research participant on protocol
             shall be ineligible

          -  Research participants with any other active malignancies

          -  Research participants being treated for severe infection or who are recovering from
             major surgery are ineligible until recovery is deemed complete by the investigator

          -  Research participants with any uncontrolled illness including ongoing or active
             infection; research participants with known active hepatitis B or C infection;
             research participants with any signs or symptoms of active infection, positive blood
             cultures or radiological evidence of infections

          -  Research participants who have confirmed HIV positivity within 4 weeks of screening

          -  Subjects, who in the opinion of the investigator, may not be able to comply with the
             safety monitoring requirements of the study
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of grade 3 toxicity, graded using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0, the revised cytokine release syndrome grading system as well as the modified neurological grading system
Time Frame:Up to 15 years
Safety Issue:
Description:Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval) will be estimated for participants' experiencing DLTs at the RP2D schedule.

Secondary Outcome Measures

Measure:Changes in largest length of tumor
Time Frame:Baseline to up to 15 years
Safety Issue:
Description:Descriptive statistics will be provided for brain inflammation (largest length of tumor) pre and post treatment.
Measure:Changes in cytokine levels
Time Frame:Baseline to up to 6 weeks
Safety Issue:
Description:Statistical and graphical methods will be used to describe the cytokine levels (cyst fluid, peripheral blood) over the study period.
Measure:Changes in CAR T cell levels
Time Frame:Baseline to up to 6 weeks
Safety Issue:
Description:Statistical and graphical methods will be used to describe the CAR T cell levels (cyst fluid, peripheral blood) over the study period.
Measure:Progression free survival
Time Frame:At 6 months
Safety Issue:
Description:Kaplan Meier methods will be used to estimate median PFS and graph the results.
Measure:Disease response by the Response Assessment in Neuro-Oncology criteria
Time Frame:Up to 15 years
Safety Issue:
Description:Estimated using 90% confidence interval.
Measure:Overall survival (OS)
Time Frame:Up to 15 years
Safety Issue:
Description:Kaplan Meier methods will be used to estimate median overall survival and graph the results. OS will also be examined for all patients, as well as, separately for those that received initial treatment only and those that received intraventricular infusion following progression
Measure:Changes in quality of life
Time Frame:Baseline to up to 15 years
Safety Issue:
Description:Estimate the mean and standard error for change from baseline during treatment and post treatment in the quality of life functioning scale, symptom scale and item scores from the EORTC QLQ-C30 and the domain scale and items scores from the QLQ-BN20.
Measure:T cell detection in tumor
Time Frame:Up to 1 year
Safety Issue:
Description:In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.
Measure:IL13Ra2 antigen expression levels
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Disease response from intraventricular infusion following progression after intracranial infusion (stratum 1 and 2)
Time Frame:Up to 15 years
Safety Issue:
Description:Estimated using 90% confidence

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Trial Keywords

  • chimeric antigen receptor
  • glioblastoma

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