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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02208362
Recruitment Status : Recruiting
First Posted : August 5, 2014
Last Update Posted : September 1, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Recurrent Glioblastoma Recurrent Malignant Glioma Recurrent WHO Grade II Glioma Recurrent WHO Grade III Glioma Refractory Glioblastoma Refractory Malignant Glioma Refractory WHO Grade II Glioma Refractory WHO Grade III Glioma Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells Biological: IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes Other: Laboratory Biomarker Analysis Procedure: Magnetic Resonance Imaging Procedure: Magnetic Resonance Spectroscopic Imaging Other: Quality-of-Life Assessment Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 92 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Cellular ImmunoTx Using Memory Enriched T Cells Lentivirally Transduced to Express an IL13Rα2-Specific, Hinge-Optimized, 41BB-Costimulatory Chimeric Receptor and a Truncated CD19 for Pts With Rec/Ref MaligGlioma
Actual Study Start Date : May 18, 2015
Estimated Primary Completion Date : January 18, 2021
Estimated Study Completion Date : January 18, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Stratum I (T lymphocytes intratumoral)

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.

Biological: IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes
Given via intratumoral, intracavitary, or intraventricular catheter
Other Name: Autologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T Cells

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Magnetic Resonance Imaging
Correlative studies
Other Names:
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

Procedure: Magnetic Resonance Spectroscopic Imaging
Correlative studies
Other Names:
  • 1H- Nuclear Magnetic Resonance Spectroscopic Imaging
  • 1H-nuclear magnetic resonance spectroscopic imaging
  • Magnetic Resonance Spectroscopy
  • MRS
  • MRS Imaging
  • MRSI
  • Proton Magnetic Resonance Spectroscopic Imaging

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Experimental: Stratum II (T lymphocytes intracavitary)
Patients receive IL13R alpha 2-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
Biological: IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes
Given via intratumoral, intracavitary, or intraventricular catheter
Other Name: Autologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T Cells

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Magnetic Resonance Imaging
Correlative studies
Other Names:
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

Procedure: Magnetic Resonance Spectroscopic Imaging
Correlative studies
Other Names:
  • 1H- Nuclear Magnetic Resonance Spectroscopic Imaging
  • 1H-nuclear magnetic resonance spectroscopic imaging
  • Magnetic Resonance Spectroscopy
  • MRS
  • MRS Imaging
  • MRSI
  • Proton Magnetic Resonance Spectroscopic Imaging

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Experimental: Stratum III (T lymphocytes intraventricular)
Patients receive IL13R alpha 2-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.
Biological: IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes
Given via intratumoral, intracavitary, or intraventricular catheter
Other Name: Autologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T Cells

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Magnetic Resonance Imaging
Correlative studies
Other Names:
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

Procedure: Magnetic Resonance Spectroscopic Imaging
Correlative studies
Other Names:
  • 1H- Nuclear Magnetic Resonance Spectroscopic Imaging
  • 1H-nuclear magnetic resonance spectroscopic imaging
  • Magnetic Resonance Spectroscopy
  • MRS
  • MRS Imaging
  • MRSI
  • Proton Magnetic Resonance Spectroscopic Imaging

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Experimental: Stratum IV (T lymphocytes intratumoral and intraventricular)
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).
Biological: IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes
Given via intratumoral, intracavitary, or intraventricular catheter
Other Name: Autologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T Cells

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Magnetic Resonance Imaging
Correlative studies
Other Names:
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

Procedure: Magnetic Resonance Spectroscopic Imaging
Correlative studies
Other Names:
  • 1H- Nuclear Magnetic Resonance Spectroscopic Imaging
  • 1H-nuclear magnetic resonance spectroscopic imaging
  • Magnetic Resonance Spectroscopy
  • MRS
  • MRS Imaging
  • MRSI
  • Proton Magnetic Resonance Spectroscopic Imaging

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Experimental: Stratum V (T lymphocytes intratumoral and intraventricular)
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).
Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
Given via intratumoral or intraventricular catheter
Other Names:
  • IL13 [EQ]BBzeta/truncated CD19[t]+ Naive and Memory T Cells
  • IL13 [EQ]BBzeta/truncated CD19[t]+ TN/MEM Cells
  • IL13Ra2-specific-hinge-optimized-4-1BB-CAR/truncated CD19-expressing Autologous TN/MEM Lymphocytes

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Magnetic Resonance Imaging
Correlative studies
Other Names:
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

Procedure: Magnetic Resonance Spectroscopic Imaging
Correlative studies
Other Names:
  • 1H- Nuclear Magnetic Resonance Spectroscopic Imaging
  • 1H-nuclear magnetic resonance spectroscopic imaging
  • Magnetic Resonance Spectroscopy
  • MRS
  • MRS Imaging
  • MRSI
  • Proton Magnetic Resonance Spectroscopic Imaging

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. Incidence of grade 3 toxicity [ Time Frame: Up to 15 years ]
    Will be graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0, the revised cytokine release syndrome grading system as well as the modified neurological grading system.

  2. Incidence of dose limiting toxicity (DLT), graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 1 week following the last course (not including optional courses 4-6) ]
    Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval) will be estimated for participants' experiencing DLTs at the recommended phase II dosing plan schedule.

  3. Incidence of toxicities, graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 as well as the modified neurological grading system [ Time Frame: Up to 15 years ]
    Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and strata.


Secondary Outcome Measures :
  1. Changes in largest length of tumor [ Time Frame: Baseline to up to 15 years ]
    Descriptive statistics will be provided for brain inflammation (largest length of tumor) pre and post treatment.

  2. Changes in cytokine levels [ Time Frame: Baseline to up to 6 weeks ]
    Statistical and graphical methods will be used to describe the cytokine levels (cyst fluid, peripheral blood) over the study period.

  3. Changes in chimeric antigen receptor (CAR) T levels [ Time Frame: Baseline to up to 6 weeks ]
    Statistical and graphical methods will be used to describe the CAR T cell levels (cyst fluid, peripheral blood) over the study period.

  4. Progression free survival (PFS) [ Time Frame: From time of surgery assessed up to 15 years ]
    Kaplan Meier methods will be used to estimate median PFS and graph the results.

  5. Disease response by the Response Assessment in Neuro-Oncology criteria [ Time Frame: Up to 15 years ]
    Estimated using 90% confidence interval.

  6. Disease response (stratum 1 and 2) [ Time Frame: Up to 15 years ]
    Estimated using 90% confidence interval.

  7. CAR T cell detection (stratum 1 and 2) [ Time Frame: Up to 15 years ]
    Will be detected peripheral blood and cerebral spinal fluid.

  8. Endogenous immune cell detection (stratum 1 and 2) [ Time Frame: Up to 15 years ]
    Will be detected peripheral blood and cerebral spinal fluid.

  9. Cytokine and post progression therapy(ies) (stratum 1 and 2) [ Time Frame: Up to 15 years ]
    Will be detected peripheral blood and cerebral spinal fluid.

  10. Overall survival (OS) [ Time Frame: From time of surgery assessed up to 15 years ]
    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.

  11. Changes in quality of life [ Time Frame: Baseline to up to 15 years ]
    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 European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and the domain scale and items scores from the QLQ-brain neoplasm20.

  12. T cell detection in tumor [ Time Frame: Up to 1 year ]
    In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.

  13. IL13Ra2 antigen expression levels [ Time Frame: Up to 1 year ]
    In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • City of Hope (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 PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION
  • Research participant must not require more than 2 mg three times daily (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 or
  • 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
  • Wash-out requirements (standard or investigational):

    • 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
  • Research participant serum total bilirubin does not exceed 2 x normal limit
  • Research participant transaminases does not exceed 2 x normal limit
  • Research participant serum creatinine =< 1.8 mg/dL
  • Research participant does not have uncontrolled seizure activity following surgery prior to starting the first T cell dose
  • Research participant 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 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 human immunodeficiency virus (HIV) within 4 weeks of screening

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02208362


Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Paige Myers-McNamara    626-256-4673 ext 89393    neurosurgerymail@coh.org   
Principal Investigator: Behnam Badie         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Food and Drug Administration (FDA)
Investigators
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Principal Investigator: Behnam Badie City of Hope Medical Center
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02208362    
Other Study ID Numbers: 13384
NCI-2014-01488 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
13384 ( Other Identifier: City of Hope Medical Center )
P30CA033572 ( U.S. NIH Grant/Contract )
R01FD005129 ( U.S. FDA Grant/Contract )
First Posted: August 5, 2014    Key Record Dates
Last Update Posted: September 1, 2020
Last Verified: May 2020
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue