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Dose-Intensive Chemotherapy in Combination With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas

Phase 1/Phase 2
18 Years
Open (Enrolling)
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

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Trial Information

Dose-Intensive Chemotherapy in Combination With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas


I. Determine the safety and feasibility of infusing autologous G-CSF (filgrastim) and
plerixafor (Mozobil) mobilized stem cells transduced with a Phoenix-GALV-pseudotype vector
expressing methylguanine methyltransferase (MGMT) (P140K).

II. Define the dose of BCNU (carmustine) that results in efficient engraftment of gene
modified cells when given with peripheral blood stem cell support.


I. Determine the engraftment of gene-modified cells after conditioning with BCNU.

II. Determine the ability to select gene-modified cells in vivo with this regimen.

III. Evaluate the molecular and clonal composition of gene-modified cells after chemotherapy
with temozolomide. IV. Observe patients for clinical anti-tumor response. V. Determine the
correlation of the level of MGMT (P140K) marking with toxicity, temozolomide dose achieved,
and response.

VI. Characterize the toxicity associated with this regimen.

OUTLINE: This is a phase I, dose-escalation study of temozolomide followed by a phase II

PHASE I: Patients undergo radiotherapy 5 days per week for 7 weeks. Patients receive
filgrastim subcutaneously (SC) on days -7 to -3 and begin stem cell collection on the 4th
day of filgrastim administration (up to 3 aphereses). Plerixafor will be used if the CD34+
cell collection from the first apheresis is low or if on day 3 of mobilization the
peripheral stem cell count is <5/mcL with G-CSF alone. The CD34+ stem cells are separated
from the patient's stem cells and they are transduced with Phoenix-RD114 pseudotype vector
(retrovirus). One day after apheresis is completed, patients receive carmustine
intravenously (IV) over 1 hour followed 2 hours later by temozolomide orally (PO). At least
twenty-four hours after completion of carmustine and temozolomide, patients undergo
reinfusion of genetically-modified stem cells.

PHASE II: Beginning approximately 4 weeks after completion of phase 1 of the study, patients
receive O6-benzylguanine IV continuously over 48 hours followed 2 hours later by
temozolomide PO. Treatment may repeat at least every 28 days for a total of 24 courses in
the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed every 1-3 months for the first 2
years, every 3-6 months for 3 years, and annually thereafter for up to 15 years.

Inclusion Criteria:

- Patients with glioblastoma multiforme or gliosarcoma

- The patient or legal guardian must be able to comprehend the informed consent form
and sign prior to patient enrollment

- Patients must be consented for MGMT promoter methylation analysis of brain tumor
tissue within twenty-eight days after surgery

- Karnofsky performance status at time of study entry must be >= 70%

- Life expectancy of >= 3 months

- Patients must agree to undergo repeat clinical neurological examinations and brain
magnetic resonance imaging (MRI) with appropriate contrast after every other cycle of

- White blood cell (WBC) > 3000/uL

- Absolute neutrophil count (ANC) > 1500/uL

- Platelets > 100,000/uL

- Hemoglobin > 10 gm/100mL

- Total and direct bilirubin < 1.5 times upper limit of laboratory normal

- Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase
(SGPT), and alkaline phosphatase =< 3 times upper limit of laboratory normal

- Blood urea nitrogen (BUN) and serum creatinine < 1.5 times upper limit of laboratory

- Left ventricular ejection fraction (LVEF) >= 40%, however, subjects with an LVEF in
the range of 40-49% should have cardiology clearance prior to intervention

- MGMT promoter methylation analysis of surgically resected tumor or tumor biopsy must
demonstrate an unmethylated or hypomethylated MGMT promoter status

Exclusion Criteria:

- Patients with cardiac insufficiency and an LVEF of < 40%; history of coronary artery
disease or arrhythmia, which has required or requires ongoing treatment

- Patients with active pulmonary infection and/or pulse oximetry < 90% and a corrected
diffusion capacity of carbon monoxide (DLCO) < 70% of predicted

- Active systemic infection

- Patients who are human immunodeficiency virus (HIV) positive

- Pregnant or lactating women; a beta-human chorionic gonadotropin (HCG) level will be
obtained from women of childbearing potential; fertile men and women should use
effective contraception

- Previous chemotherapy for any malignancy including temozolomide, dacarbazine (DTIC)
or prior nitrosourea

- Diabetes mellitus

- Bleeding disorder

- Methylated or hypermethylated MGMT promoter status within tumor tissue

- Medical or psychiatric condition which in the opinion of the protocol chairman would
compromise the patient's ability to tolerate this protocol

- Prior interstitial radiotherapy, stereotactic or gamma knife surgery or implanted

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicity (hematologic and non-hematologic) of temozolomide (Part I)

Outcome Description:

Toxicity will be assessed according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version Common Terminology Criteria for Adverse Events (CTCAE) v3.

Outcome Time Frame:

For 6 weeks after infusion of genetically modified stem cells

Safety Issue:


Principal Investigator

Hans-Peter Kiem

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

July 2006

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Glioblastoma
  • Gliosarcoma
  • Glioma



Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle, Washington  98109