Combination Chemotherapy and Radiation Therapy in Treating Younger Patients Who Are Undergoing an Autologous Stem Cell Transplant for Newly Diagnosed Gliomas

OBJECTIVES:

Primary

• Determine the safety and feasibility of a conditioning regimen comprising temozolomide, radiotherapy, and busulfan followed by an infusion of autologous stem cells genetically modified with the MGMT gene and temozolomide and O6-benzylguanine in younger patients with newly diagnosed high-grade gliomas.

Secondary

• Determine the tolerability of intrapatient dose escalation of temozolomide, in terms of transgene expression, in patients treated with this regimen.
• Determine, preliminarily, the antitumor activity of this regimen in these patients.

OUTLINE: This is a pilot study.

• Surgery: Patients undergo biopsy or surgical debulking of the tumor. Two to six weeks later, patients proceed to stem cell mobilization and apheresis.
• Autologous stem cell mobilization and apheresis: Patients receive filgrastim (G-CSF) subcutaneously or IV once daily for at least 4 days before apheresis and continuing until apheresis is complete. Patients undergo apheresis for up to 4 consecutive days until a target number of 5 X 10^6 CD34-positive peripheral blood stem cells (PBSCs) are collected. Patients with insufficient numbers of PBSCs either undergo bone marrow harvest to collect a sufficient number of cells or are removed from the study. The cells are selected for CD34-positive cells which are cryopreserved for later use. Patients then proceed to chemoradiotherapy.
• Chemoradiotherapy: Patients receive oral temozolomide once daily on days 1-42 and undergo radiotherapy once daily, 5 days a week, for 6 weeks. Four to eight weeks later, patients proceed to the low-intensity, nonmyeloablative conditioning regimen.
• Autologous PBSC or bone marrow transduction: Peripheral blood or bone marrow CD34-positive stem cells are transduced with the MGMT gene on day -4.
• Low-intensity, nonmyeloablative conditioning regimen: Patients receive busulfan IV over 2 hours on days -3 and -2. Patients then proceed to autologous PBSC or bone marrow infusion.
• Autologous PBSC or bone marrow infusion: Patients undergo autologous stem cell infusion using transduced PBSCs or bone marrow on day 0. Three to six weeks later, patients proceed to chemotherapy.
• Chemotherapy: Patients receive O6-benzylguanine IV over 1 hour followed by oral temozolomide once daily on days 1-5. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to O6-benzylguanine may receive temozolomide alone. Patients not experiencing dose-limiting toxicity and who have at least 5% transduced neutrophils by peripheral blood analysis after course 1 receive escalating doses (intrapatient) of temozolomide during courses 2-6. Some patients undergo second-look surgery after the first course of chemotherapy.

After completion of study therapy, patients are followed monthly for 3 months, every 3 months for 3 years, every 6 months for 4 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 10 patients will be accrued for this study within 1-2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed newly diagnosed high-grade glioma of 1 of the following types:

• Glioblastoma multiforme

• WHO grade IV disease
• Anaplastic astrocytoma

• WHO grade III disease
• No low-grade disease (i.e., WHO grade I-II disease)
• No WHO grade III oligodendroglioma or oligoastrocytoma
• Patients > 30 years of age who have undergone a gross total resection and have nonmeasurable disease as seen on postoperative MRI are eligible
• Measurable disease, as assessed by postoperative MRI, is required in patients ≤ 30 years of age
• No tumor arising in the spine or brainstem
• No metastatic disease in the spine

PATIENT CHARACTERISTICS:

Age

• 5 to 55

Performance status

• Karnofsky 50-100% (for patients 11-30 years of age) OR
• Lansky 50-100% (for patients 5-10 years of age)

Life expectancy

• At least 9 months

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 75,000/mm^3 (transfusion independent)

Hepatic

• Bilirubin ≤ 2.0 mg/dL
• ALT and AST ≤ 2.5 times upper limit of normal
• Albumin ≥ 2.0 g/dL
• Hepatitis B surface antigen and core antibody negative
• Hepatitis C antibody negative

Renal

• Creatinine normal OR
• Glomerular filtration rate ≥ 70 mL/min

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Neurologic deficits must be stable or decreasing
• No active infection
• HIV negative
• No other serious illness or medical condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Concurrent corticosteroids allowed provided dose is stable or decreasing

Radiotherapy

• No prior radiotherapy

Surgery

• See Disease Characteristics

Other

• No other concurrent investigational anticancer agents