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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

Phase 1
5 Years
55 Years
Not Enrolling
Glioblastoma Multiforme (WHO Grade IV), Anaplastic Astrocytoma (WHO Grade III)

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Trial Information

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

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.

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).

Type of Study:


Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Outcome Measure:

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.

Outcome Time Frame:

5 years

Safety Issue:


Principal Investigator

Punam Malik, MD

Investigator Role:

Study Director

Investigator Affiliation:

Cincinnati Childrens Hospital Medical Center


United States: Food and Drug Administration

Study ID:




Start Date:

December 2005

Completion Date:

August 2012

Related Keywords:

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



Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039