Combination Chemotherapy and Radiation Therapy in Treating Younger Patients Who Are Undergoing an Autologous Stem Cell Transplant for Newly Diagnosed Gliomas
Condition: Brain and Central Nervous System Tumors
MeSH terms: Nervous System Neoplasms; Central Nervous System Neoplasms
Study type: Interventional

Summary: 
      RATIONALE: Drugs used in chemotherapy, such as temozolomide, busulfan, and O6-benzylguanine,
      work in different ways to stop the growth of tumor cells, either by killing the cells or by
      stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill
      more tumor cells. O6-benzylguanine may also help temozolomide work better by making tumor
      cells more sensitive to the drug. Radiation therapy uses high-energy x-rays to kill tumor
      cells. Giving chemotherapy with a peripheral stem cell transplant or bone marrow transplant,
      using stem cells from the patient that are genetically-modified in the laboratory to protect
      them from the side effects of chemotherapy, may allow more chemotherapy to be given so that
      more tumor cells are killed. Giving combination chemotherapy and radiation therapy together
      with a peripheral stem cell transplant or bone marrow transplant may kill more tumor cells.

      PURPOSE: This clinical trial is studying how well giving combination chemotherapy together
      with radiation therapy works in treating younger patients who are undergoing an autologous
      stem cell transplant for newly diagnosed gliomas.
    

Detailed description: 
      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.
    

Intervention name(s): O6-benzylguanine; busulfan; temozolomide; adjuvant therapy; autologous bone marrow transplantation; conventional surgery; peripheral blood stem cell transplantation; radiation therapy
Intervention type(s): Drug; Drug; Drug; Procedure; Procedure; Procedure; Procedure; Radiation
Intervention MeSH terms: Temozolomide; Busulfan; O(6)-benzylguanine
Primary purpose: Treatment
Keywords: adult glioblastoma; adult anaplastic astrocytoma; childhood high-grade cerebral astrocytoma; adult giant cell glioblastoma; adult gliosarcoma