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Treatment of Newly Diagnosed Brain Tumors With Chemotherapy and Radiation Using Cells Modified for Chemoprotection and an Experimental Drug to Decrease the Tumor Cell Resistance to Chemotherapy

Primary Purpose

Glioblastoma Multiforme (WHO Grade IV), Anaplastic Astrocytoma (WHO Grade III)

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
06Benzylguanine
MGMT P140K
Meltenyi CliniMacs
Sponsored by
Children's Hospital Medical Center, Cincinnati
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Glioblastoma Multiforme (WHO Grade IV)

Eligibility Criteria

5 Years - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 3.1.1 Age > 5 years and < 55 years. NOTE: Subjects ages 5-30 are eligible to be treated at Cincinnati Children's Hospital Medical Center; subjects over age 30 will be treated at Ohio State University Comprehensive Cancer Center. 3.1.2 Anticipated life expectancy of at least nine months 3.1.3 Karnofsky score > 50 for patients > 10 years of age, and Lansky score > 50 for patients < 10 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. 3.1.4 Patients must have one of the following newly-diagnosed central nervous system tumors, confirmed by histologic verification: Glioblastoma multiforme (WHO grade IV) OR Anaplastic astrocytoma (WHO grade III) 3.1.5 Patients older than 30 years that have undergone a gross total resection and who do not have measurable disease on post operative MRI; measurable disease as assessed by post operative MRI is required on patients 30 years of age or younger. 3.1.6 Neurologic deficits and corticosteroid doses must be stable or decreasing at the time of study entry. 3.1.7 Adequate organ function as defined by: Serum creatinine < upper limit of normal, or GFR > 70 ml/min/1.73 m2 Total bilirubin < 2.0 mg/dl; SGPT (ALT) AND SGOT (AST) < 2.5x upper limit of normal; serum albumin > 2.0 g/dL Absolute neutrophil count > 1,000/µl, platelet count > 75,000/µl independent of transfusions 3.1.8 The patient and/or the patient's legally authorized guardian must give written informed consent according to local Institutional and/or University Human Experimentation Committee requirements. 3.1.9 Women or men with reproductive potential must use effective contraception throughout the study. Effective contraception methods for women would include either an oral or transdermal contraceptive, injectable contraceptive (e.g., Depo-Provera), or contraceptive implants (e.g., intrauterine device). All males on study must agree to the use of condoms during intercourse. 3.1.10 Women of reproductive potential must have a negative serum pregnancy test. Exclusion Criteria: 3.2.1 Any prior treatment with chemotherapy or radiotherapy. 3.2.2 Any tumor arising in the spine or brainstem. 3.2.3 Presence of metastatic disease in the spine. 3.2.4 WHO grade III oligodendroglioma or oligoastrocytoma. 3.2.5 Active infection at time of study entry. 3.2.6 Pregnant or lactating females are excluded, because of the known teratogenic effects of alkylating agents. 3.2.7 Known HIV-positive patients. Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy and are excluded from this study. An infectious disease screen consisting of HIV I & II Ab and NAT, HTLV I & II Ab, RPR, Hepatitis B Surface Ag, Hepatitis B Core Ab and Hepatitis C Ab will be obtained at study entry. 3.2.8 Concurrent treatment with other investigational anti-cancer agents. 3.2.9 Serious illness or medical condition which would not permit the patient to be managed according to the protocol. 3.2.10 Low-grade glioma (WHO Grade 1-2).

Sites / Locations

  • Cincinnati Children's Hospital Medical Center

Outcomes

Primary Outcome Measures

To assess the safety and feasibility of infusing autologous PBSC transduced with MSCV-MGMTP140K construct, using the fibronectin component CH-296 to assist gene transfer.

Secondary Outcome Measures

Assess the efficiency of gene transfer and durability of transgene expression in this clinical setting.
Assess the degree of chemotherapy resistance in transduced cells, and the ability to enrich the population of transduced stem cells with subsequent courses of chemotherapy.

Full Information

First Posted
January 4, 2006
Last Updated
August 28, 2012
Sponsor
Children's Hospital Medical Center, Cincinnati
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1. Study Identification

Unique Protocol Identification Number
NCT00272870
Brief Title
Treatment of Newly Diagnosed Brain Tumors With Chemotherapy and Radiation Using Cells Modified for Chemoprotection and an Experimental Drug to Decrease the Tumor Cell Resistance to Chemotherapy
Official Title
A Pilot Study of Temozolomide and 06Benzylguanine for Treatment of Newly Diagnosed High Grade Glioma, Using Autologous Peripheral Blood Stem Cells Genetically Modified for Chemoprotection
Study Type
Interventional

2. Study Status

Record Verification Date
August 2012
Overall Recruitment Status
Terminated
Why Stopped
Slow accrual; drug availability
Study Start Date
December 2005 (undefined)
Primary Completion Date
December 2008 (Actual)
Study Completion Date
August 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Medical Center, Cincinnati

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Cure rates for patients with high grade glioma remain disappointing, in part because tumor cells are often resistant to chemotherapy, and because using higher doses of chemotherapy causes damage to normal blood cells. This trial is designed to try to overcome both of these barriers. The idea is to make tumor cells more sensitive to a chemotherapy agent, Temozolomide, by using 06Benzylguanine (06BG). In addition, patients will have a portion of their blood cells modified by the insertion of a chemotherapy resistance gene which may help protect blood cells from damage by the combination of the Temozolomide and 06BG.
Detailed Description
The use of temozolomide (TEM) both during and after irradiation is a promising new approach for the treatment of patients with high-grade glioma. However, this treatment is limited by tumor cell resistance and therapy-related hematologic toxicity. To overcome TEM resistance, in this study we will add the chemotherapy sensitizing drug O6-Benzylguanine (BG). To overcome hematologic toxicity, patients will receive autologous hematopoietic stem cells transduced with a chemotherapy resistance gene designed to protect these cells from subsequent therapy with this drug combination. The potential benefit of using transduced blood stem cells is the possibility for dose escalation of TEM, since hematologic toxicity has heretofore limited higher doses. Transduction will be accomplished with a retroviral vector carrying MGMTP140K, which codes for a mutated form of the resistance protein methylguanine-DNA methyltransferase (MGMT). Successful transduction of hematopoietic cells with MGMTP140K makes them resistant to the toxic effects of both TEM + BG. Repeated doses of these drugs should therefore result in an increase in the percentage of transduced (and thus protected) blood stem cells, thus reducing the likelihood of hematologic toxicity with further therapy. Accordingly, patients who are tolerating therapy well and who have laboratory evidence of chemoprotection will receive intrapatient dose escalation of TEM + BG during courses 2-6. Eligible patients must be between 5 and 55 years of age and have newly-diagnosed high-grade glioma (anaplastic astrocytoma or glioblastoma multiforme) which cannot be completely resected. No prior therapy other than surgery is allowed, and patients must have adequate performance status and organ function as defined in the protocol.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma Multiforme (WHO Grade IV), Anaplastic Astrocytoma (WHO Grade III)

7. Study Design

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

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
06Benzylguanine
Intervention Description
120 mg/m2/day; given Day 1-5 for up to 6 courses in Block 3
Intervention Type
Genetic
Intervention Name(s)
MGMT P140K
Intervention Description
Gene manipulated cells, patients are not expected to receive greater than approximately 10 x 10e6 transduced CD34+ cells/kg
Intervention Type
Device
Intervention Name(s)
Meltenyi CliniMacs
Intervention Description
Device used for CD34+ cell separation of peripheral collection
Primary Outcome Measure Information:
Title
To assess the safety and feasibility of infusing autologous PBSC transduced with MSCV-MGMTP140K construct, using the fibronectin component CH-296 to assist gene transfer.
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Assess the efficiency of gene transfer and durability of transgene expression in this clinical setting.
Time Frame
5 years
Title
Assess the degree of chemotherapy resistance in transduced cells, and the ability to enrich the population of transduced stem cells with subsequent courses of chemotherapy.
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 3.1.1 Age > 5 years and < 55 years. NOTE: Subjects ages 5-30 are eligible to be treated at Cincinnati Children's Hospital Medical Center; subjects over age 30 will be treated at Ohio State University Comprehensive Cancer Center. 3.1.2 Anticipated life expectancy of at least nine months 3.1.3 Karnofsky score > 50 for patients > 10 years of age, and Lansky score > 50 for patients < 10 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. 3.1.4 Patients must have one of the following newly-diagnosed central nervous system tumors, confirmed by histologic verification: Glioblastoma multiforme (WHO grade IV) OR Anaplastic astrocytoma (WHO grade III) 3.1.5 Patients older than 30 years that have undergone a gross total resection and who do not have measurable disease on post operative MRI; measurable disease as assessed by post operative MRI is required on patients 30 years of age or younger. 3.1.6 Neurologic deficits and corticosteroid doses must be stable or decreasing at the time of study entry. 3.1.7 Adequate organ function as defined by: Serum creatinine < upper limit of normal, or GFR > 70 ml/min/1.73 m2 Total bilirubin < 2.0 mg/dl; SGPT (ALT) AND SGOT (AST) < 2.5x upper limit of normal; serum albumin > 2.0 g/dL Absolute neutrophil count > 1,000/µl, platelet count > 75,000/µl independent of transfusions 3.1.8 The patient and/or the patient's legally authorized guardian must give written informed consent according to local Institutional and/or University Human Experimentation Committee requirements. 3.1.9 Women or men with reproductive potential must use effective contraception throughout the study. Effective contraception methods for women would include either an oral or transdermal contraceptive, injectable contraceptive (e.g., Depo-Provera), or contraceptive implants (e.g., intrauterine device). All males on study must agree to the use of condoms during intercourse. 3.1.10 Women of reproductive potential must have a negative serum pregnancy test. Exclusion Criteria: 3.2.1 Any prior treatment with chemotherapy or radiotherapy. 3.2.2 Any tumor arising in the spine or brainstem. 3.2.3 Presence of metastatic disease in the spine. 3.2.4 WHO grade III oligodendroglioma or oligoastrocytoma. 3.2.5 Active infection at time of study entry. 3.2.6 Pregnant or lactating females are excluded, because of the known teratogenic effects of alkylating agents. 3.2.7 Known HIV-positive patients. Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy and are excluded from this study. An infectious disease screen consisting of HIV I & II Ab and NAT, HTLV I & II Ab, RPR, Hepatitis B Surface Ag, Hepatitis B Core Ab and Hepatitis C Ab will be obtained at study entry. 3.2.8 Concurrent treatment with other investigational anti-cancer agents. 3.2.9 Serious illness or medical condition which would not permit the patient to be managed according to the protocol. 3.2.10 Low-grade glioma (WHO Grade 1-2).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Punam Malik, MD
Organizational Affiliation
Cincinnati Childrens Hospital Medical Center
Official's Role
Study Director
Facility Information:
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Treatment of Newly Diagnosed Brain Tumors With Chemotherapy and Radiation Using Cells Modified for Chemoprotection and an Experimental Drug to Decrease the Tumor Cell Resistance to Chemotherapy

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