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

Glioblastoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01082926
• Other study ID #: 07082
• Secondary ID: NCI-2010-00303
• Status: Completed
• Phase: Phase 1
• First received: March 5, 2010
• Last updated: June 3, 2015
• Start date: May 2010
• Est. completion date: September 2013

Study information

• Verified date: June 2015
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anaplastic Astrocytoma
• Anaplastic Ependymoma
• Anaplastic Meningioma
• Anaplastic Oligodendroglioma
• Astrocytoma
• Brain Neoplasms
• Brain Stem Glioma
• Brain Tumor
• Ependymoblastoma
• Ependymoma
• Giant Cell Glioblastoma
• Glioblastoma
• Glioma
• Gliosarcoma
• Grade III Meningioma
• Hemangiopericytoma
• Meningeal Hemangiopericytoma
• Meningioma
• Mixed Glioma
• Oligodendroglioma
• Pineal Gland Astrocytoma
• Solitary Fibrous Tumors

Intervention

Biological:
• therapeutic allogeneic lymphocytes
Given intratumorally
• aldesleukin
Given intratumorally

Other:
• laboratory biomarker analysis
Optional correlative studies

Procedure:
• positron emission tomography
Optional correlative studies

Locations

Country	Name	City	State
United States	City of Hope	Duarte	California

Sponsors (1)

Lead Sponsor	Collaborator
City of Hope Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety of GRm13Z40-2 CTL CNS loco-regional cellular immunotherapy		Daily for first 2 weeks, weekly for month 1, every other week for month 2 , monthly for 6 months	Yes
Primary	Safety of convection enhanced delivery (CED) of recombinant human Interleukin-2 (rhuIL-2) used in conjunction with GRm13Z40-2 CTL adoptive transfer		Weeks 1 and 2	Yes
Primary	Toxicity as assessed by NCI CTCAE version 4.0		During treatment and up to 21 days after the last GRm13Z40-2 or CED rhuIL-2 infusion	Yes
Secondary	Ability of 9-(4-fluoro-3-hydroxy-methyl-butyl) guanine (18FHBG) positron emission tomography PET to image GRm13Z40-2 CTLs		Prior to immunotherapy and 3 weeks post immunotherapy	No
Secondary	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		Post infusion day 1, weeks 2-4 and week 8	No
Secondary	Evaluation of ganciclovir administration for ablating transferred GRm13Z40-2 in vivo should significant graft-mediated toxicities be encountered		When/if grade 3 or 4 toxicity occurs	No