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Phase I Study of Cellular Immunotherapy for Recurrent/Refractory Malignant Glioma Using Intratumoral Infusions of GRm13Z40-2, An Allogeneic CD8+ Cytolitic T-Cell Line Genetically Modified to Express the IL 13-Zetakine and HyTK and to be Resistant to Glucocorticoids, in Combination With Interleukin-2

Primary Purpose

Anaplastic Astrocytoma, Anaplastic Ependymoma, Anaplastic Meningioma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
therapeutic allogeneic lymphocytes
aldesleukin
laboratory biomarker analysis
positron emission tomography
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anaplastic Astrocytoma focused on measuring adult anaplastic astrocytoma, adult anaplastic ependymoma, adult anaplastic meningioma, adult anaplastic oligodendroglioma, adult brain stem glioma, adult ependymoblastoma, adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma, adult grade III meningioma, adult meningeal hemangiopericytoma, adult mixed glioma, adult pineal gland astrocytoma, recurrent adult brain tumor, Los Angeles

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Histological verification of grade III or IV MG at original diagnosis
  • Radiographic evidence of progression/recurrence of the measurable disease more than 12 weeks after the end of radiation therapy
  • Expression of IL13Ralpha2 by immunohistochemistry
  • Karnofsky performance status (KPS) >= 60
  • Disease recurrence/progression in the cerebral hemisphere, which is in at least one area of enhancement amenable to biopsy after protocol enrollment in the following locations:

    • Adjacent or near previous resection cavity
    • Distant from primary location; this includes tumor spread to contralateral hemisphere, corpus callosum, thalamus, basal ganglion, or subependymal locations
  • Research participant has recovered from toxicity of prior therapies; an interval of at least 12 weeks must have elapsed since the completion of radiation therapy; at least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen; and at least 4 weeks since the completion of a 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
  • History of prior treatment with Temodar if no evidence of intolerance; documentation of intolerance to Temodar is not required
  • Creatinine < 1.6
  • White blood cell (WBC) >= 2,000/dl (or absolute neutrophil count [ANC] > 1,000) Platelets >= 100,000/dl unsupported by transfusion or growth factor, international normalized ratio (INR) < 1.3
  • Bilirubin < 1.5
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) < 2 X upper limits of normal
  • Female research participants of childbearing potential must not be pregnant as evidenced by a serum beta-HCG pregnancy test obtained within 7 days of enrollment
  • Research participants having reproductive potential must agree to use effective contraception during participation on this protocol
  • In the opinion of the neurosurgeon, research participant requires on-going dexamethasone therapy

Exclusion Criteria:

  • Survival expectation less than 4 weeks
  • Pulmonary- Requirement for supplemental oxygen use that is not expected to resolve within 2 weeks, Cardiac- Uncontrolled cardiac arrhythmia, hypotension requiring pressor support, Renal- Dialysis dependent, Neurologic- refractory seizure disorder, clinically evident progressive encephalopathy
  • Tumors with the following characteristics:

    • Large tumor recurrence causing significant symptoms from brain shift or mass effect, and thus not requiring "decompressive" craniotomy
    • Tumors located primarily in the basal ganglion or thalamus
    • Tumors with significant involvement of midbrain, cerebellum, pons and medulla will be excluded due to neurological risks associated with edema exacerbation from therapy
  • 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
  • Positive human immunodeficiency virus (HIV) serology based on testing within 4 weeks of enrollment
  • Research participants being treated for severe infection or who are recovering from major surgery are ineligible until recovery is deemed complete by the investigator
  • Failure to understand the basic elements of the protocol and/or the risks/benefits of participating in this pilot study
  • History of ganciclovir and/or magnetic resonance imaging (MRI) contrast allergy or intolerance History of intolerance to IL-2

Sites / Locations

  • City of Hope

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm I

Arm Description

Patients receive intratumoral GRm13Z40-2 therapeutic allogeneic lymphocytes over 10 minutes on days 1 and 3 and intratumoral aldesleukin over 3 hours on days 2-5 (days 1-5 in week 2). Treatment repeats every week for 2 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Safety of GRm13Z40-2 CTL CNS loco-regional cellular immunotherapy
Safety of convection enhanced delivery (CED) of recombinant human Interleukin-2 (rhuIL-2) used in conjunction with GRm13Z40-2 CTL adoptive transfer
Toxicity as assessed by NCI CTCAE version 4.0

Secondary Outcome Measures

Ability of 9-(4-fluoro-3-hydroxy-methyl-butyl) guanine (18FHBG) positron emission tomography PET to image GRm13Z40-2 CTLs
Impact of concurrent dexamethasone on the tempo and magnitude of T cell allograft rejection responses by tracking the frequency of anti-GRm13Z40-2 immune responses in serially acquired peripheral blood samples
Evaluation of ganciclovir administration for ablating transferred GRm13Z40-2 in vivo should significant graft-mediated toxicities be encountered

Full Information

First Posted
March 5, 2010
Last Updated
June 3, 2015
Sponsor
City of Hope Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT01082926
Brief Title
Phase I Study of Cellular Immunotherapy for Recurrent/Refractory Malignant Glioma Using Intratumoral Infusions of GRm13Z40-2, An Allogeneic CD8+ Cytolitic T-Cell Line Genetically Modified to Express the IL 13-Zetakine and HyTK and to be Resistant to Glucocorticoids, in Combination With Interleukin-2
Official Title
Phase I Study of Cellular Immunotherapy for Recurrent/Refractory Malignant Glioma Using Intratumoral Infusions of GRm13Z40-2, An Allogeneic CD8+ Cytolitic T-Cell Line Genetically Modified to Express the IL 13-Zetakine and HyTK and to be Resistant to Glucocorticoids, in Combination With Interleukin-2
Study Type
Interventional

2. Study Status

Record Verification Date
June 2015
Overall Recruitment Status
Completed
Study Start Date
May 2010 (undefined)
Primary Completion Date
September 2013 (Actual)
Study Completion Date
September 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: Biological therapies, such as cellular adoptive immunotherapy, may stimulate the immune system in different ways and stop tumor cells from growing. Donor T cells that are treated in the laboratory may be effective treatment for malignant glioma. Aldesleukin may stimulate the white blood cells to kill tumor cells. Combining different types of biological therapies may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best way to give therapeutic donor lymphocytes together with aldesleukin in treating patients with stage III or stage IV malignant glioma.
Detailed Description
PRIMARY OBJECTIVES: I. To assess the safety of GRm13Z40-2 CTL CNS loco-regional cellular immunotherapy in research participants with recurrent or refractory/ progressive malignant glioma (WHO Grades 3 or 4). II. To assess the safety of convection enhanced delivery (CED) of recombinant human Interleukin-2 (rhuIL-2) used in conjunction with GRm13Z40-2 CTL adoptive transfer. SECONDARY OBJECTIVES: I. To investigate the ability of 9-(4-fluoro-3-hydroxy-methyl-butyl) guanine (18FHBG) positron emission tomography PET to image GRm13Z40-2 CTL's in research participants. II. To study the impact of concurrent dexamethasone administration on the tempo and magnitude of T cell allograft rejection responses in treated research participants by tracking the frequency of anti-GRm13Z40-2 immune responses in serially acquired peripheral blood samples. III. To evaluate ganciclovir administration for ablating transferred GRm13Z40-2 in vivo should significant graft-mediated toxicities be encountered. OUTLINE: Patients receive GRm13Z40-2 therapeutic allogeneic lymphocytes intratumorally (IT) over 10 minutes on days 1 and 3 and aldesleukin IT over 3 hours on days 2-5 (days 1-5 in week 2). Treatment repeats every week for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed annually for at least 15 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anaplastic Astrocytoma, Anaplastic Ependymoma, Anaplastic Meningioma, Anaplastic Oligodendroglioma, Brain Stem Glioma, Ependymoblastoma, Giant Cell Glioblastoma, Glioblastoma, Gliosarcoma, Grade III Meningioma, Meningeal Hemangiopericytoma, Mixed Glioma, Pineal Gland Astrocytoma, Brain Tumor
Keywords
adult anaplastic astrocytoma, adult anaplastic ependymoma, adult anaplastic meningioma, adult anaplastic oligodendroglioma, adult brain stem glioma, adult ependymoblastoma, adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma, adult grade III meningioma, adult meningeal hemangiopericytoma, adult mixed glioma, adult pineal gland astrocytoma, recurrent adult brain tumor, Los Angeles

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
Patients receive intratumoral GRm13Z40-2 therapeutic allogeneic lymphocytes over 10 minutes on days 1 and 3 and intratumoral aldesleukin over 3 hours on days 2-5 (days 1-5 in week 2). Treatment repeats every week for 2 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Biological
Intervention Name(s)
therapeutic allogeneic lymphocytes
Other Intervention Name(s)
ALLOLYMPH
Intervention Description
Given intratumorally
Intervention Type
Biological
Intervention Name(s)
aldesleukin
Other Intervention Name(s)
IL-2, interleukin II, Proleukin, recombinant human interleukin-2, recombinant interleukin-2, TCGF, interleukin
Intervention Description
Given intratumorally
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Optional correlative studies
Intervention Type
Procedure
Intervention Name(s)
positron emission tomography
Other Intervention Name(s)
FDG-PET, PET, PET scan, tomography, emission computed
Intervention Description
Optional correlative studies
Primary Outcome Measure Information:
Title
Safety of GRm13Z40-2 CTL CNS loco-regional cellular immunotherapy
Time Frame
Daily for first 2 weeks, weekly for month 1, every other week for month 2 , monthly for 6 months
Title
Safety of convection enhanced delivery (CED) of recombinant human Interleukin-2 (rhuIL-2) used in conjunction with GRm13Z40-2 CTL adoptive transfer
Time Frame
Weeks 1 and 2
Title
Toxicity as assessed by NCI CTCAE version 4.0
Time Frame
During treatment and up to 21 days after the last GRm13Z40-2 or CED rhuIL-2 infusion
Secondary Outcome Measure Information:
Title
Ability of 9-(4-fluoro-3-hydroxy-methyl-butyl) guanine (18FHBG) positron emission tomography PET to image GRm13Z40-2 CTLs
Time Frame
Prior to immunotherapy and 3 weeks post immunotherapy
Title
Impact of concurrent dexamethasone on the tempo and magnitude of T cell allograft rejection responses by tracking the frequency of anti-GRm13Z40-2 immune responses in serially acquired peripheral blood samples
Time Frame
Post infusion day 1, weeks 2-4 and week 8
Title
Evaluation of ganciclovir administration for ablating transferred GRm13Z40-2 in vivo should significant graft-mediated toxicities be encountered
Time Frame
When/if grade 3 or 4 toxicity occurs

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histological verification of grade III or IV MG at original diagnosis Radiographic evidence of progression/recurrence of the measurable disease more than 12 weeks after the end of radiation therapy Expression of IL13Ralpha2 by immunohistochemistry Karnofsky performance status (KPS) >= 60 Disease recurrence/progression in the cerebral hemisphere, which is in at least one area of enhancement amenable to biopsy after protocol enrollment in the following locations: Adjacent or near previous resection cavity Distant from primary location; this includes tumor spread to contralateral hemisphere, corpus callosum, thalamus, basal ganglion, or subependymal locations Research participant has recovered from toxicity of prior therapies; an interval of at least 12 weeks must have elapsed since the completion of radiation therapy; at least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen; and at least 4 weeks since the completion of a 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 History of prior treatment with Temodar if no evidence of intolerance; documentation of intolerance to Temodar is not required Creatinine < 1.6 White blood cell (WBC) >= 2,000/dl (or absolute neutrophil count [ANC] > 1,000) Platelets >= 100,000/dl unsupported by transfusion or growth factor, international normalized ratio (INR) < 1.3 Bilirubin < 1.5 Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) < 2 X upper limits of normal Female research participants of childbearing potential must not be pregnant as evidenced by a serum beta-HCG pregnancy test obtained within 7 days of enrollment Research participants having reproductive potential must agree to use effective contraception during participation on this protocol In the opinion of the neurosurgeon, research participant requires on-going dexamethasone therapy Exclusion Criteria: Survival expectation less than 4 weeks Pulmonary- Requirement for supplemental oxygen use that is not expected to resolve within 2 weeks, Cardiac- Uncontrolled cardiac arrhythmia, hypotension requiring pressor support, Renal- Dialysis dependent, Neurologic- refractory seizure disorder, clinically evident progressive encephalopathy Tumors with the following characteristics: Large tumor recurrence causing significant symptoms from brain shift or mass effect, and thus not requiring "decompressive" craniotomy Tumors located primarily in the basal ganglion or thalamus Tumors with significant involvement of midbrain, cerebellum, pons and medulla will be excluded due to neurological risks associated with edema exacerbation from therapy 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 Positive human immunodeficiency virus (HIV) serology based on testing within 4 weeks of enrollment Research participants being treated for severe infection or who are recovering from major surgery are ineligible until recovery is deemed complete by the investigator Failure to understand the basic elements of the protocol and/or the risks/benefits of participating in this pilot study History of ganciclovir and/or magnetic resonance imaging (MRI) contrast allergy or intolerance History of intolerance to IL-2
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Behnam Badie
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Phase I Study of Cellular Immunotherapy for Recurrent/Refractory Malignant Glioma Using Intratumoral Infusions of GRm13Z40-2, An Allogeneic CD8+ Cytolitic T-Cell Line Genetically Modified to Express the IL 13-Zetakine and HyTK and to be Resistant to Glucocorticoids, in Combination With Interleukin-2

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