Combination Chemotherapy With BBBD Followed By Sodium Thiosulfate in Treating Patients With Anaplastic Oligodendroglioma or Oligoastrocytoma

• Maximum tolerated dose (MTD) of melphalan as measured by NCI CTC v3 (Phase I) [ Time Frame: Completed ] [ Designated as safety issue: Yes ]

  MTD = 1 dose level below dose level that produces grade 4 toxicity attributable to the chemotherapy regimen that occurs during cycle one of chemotherapy, in 33% of subjects.

  The Melphalan MTD when given with this combination chemotherapy has been determined to be 4mg/m2/day x 2 days.

  
  
• Progression-free survival as measured by radiographic response at one year progression free survival (1YPFS) (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  

• Incidence of neutropenia as measured by complete blood cell count lab values done weekly during study treatment [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Evaluate incidence of severe neutropenia (febrile neutropenia or sepsis) of carboplatin, melphalan, and etoposide phosphate in conjunction with BBBD
  
  
• Overall toxicity of chemotherapy as measured by NCI CTC v3 during study treatment [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  
• Estimate differences in tumor response, 1YPFS, and survival in patients with and without allelic loss as measured by lab assays before study treatment [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Evaluation of allelic loss by lab assays testing for chromosomes 1p and 19q and p53 immunocytochemistry
  
  
• Quality of life (QOL) as measured by EORTC QOL [ Time Frame: Up to 3 years plus follow up ] [ Designated as safety issue: No ]
  Every 3 months during treatment and within 30 days of final treatment. After final treatment, QOL assessment annually.
  
  
• Estimate differences in 1YPFS between subjects with anaplastic oligodendroglioma and oligoastrocytoma [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  
• Describe role of biopsy vs extent of surgery on 1YPFS and survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Role of biopsy versus extent of surgery (sub-maximal versus maximal safe resection)on 1YPFS and survival
  
  
• Role of prior radiation on tumor response, 1YPFS, and survival. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Describe role of prior radiation on tumor response, 1YPFS, and survival.
  
  

OBJECTIVES:

Primary

• Evaluate toxicity and estimate the maximum tolerated dose (MTD) of melphalan administered in conjunction with carboplatin and etoposide phosphate in combination with blood-brain barrier disruption (BBBD) with mannitol and delayed sodium thiosulfate, in patients with anaplastic oligodendroglioma or oligoastrocytoma. (phase I)
• Examine the efficacy, in terms of 1-year progression-free survival (1YPFS), in patients treated with this regimen. (phase II)

Secondary

• Evaluate the incidence of severe neutropenia (specifically febrile neutropenia or sepsis) in patients treated with this regimen.
• Evaluate the overall toxicity of this regimen.
• Compare tumor response, 1YPFS, and survival in patients with vs without allelic loss of chromosomes 1p and 19q and p53 immunocytochemistry.
• Assess quality of life, cognitive function, and performance status in these patients.
• Estimate differences in 1YPFS between patients with anaplastic oligodendroglioma and patients with oligoastrocytoma.
• Describe the role of biopsy versus extent of surgery (sub-maximal versus maximal safe resection) on 1YPFS and survival.
• Describe the role of prior radiotherapy on tumor response, 1YPFS, and survival.

OUTLINE: This is a multi-center, phase I dose-escalation study of melphalan followed by a phase II study.

• Phase I: Patients receive etoposide phosphate IV over 10 minutes, mannitol intra-arterially (IA), carboplatin IA over 10 minutes, and melphalan IA over 10 minutes on days 1 and 2 and sodium thiosulfate IV over 15 minutes beginning 4 and 8 hours after completion of chemotherapy on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 4 and continuing until blood counts recover OR a small dose of pegfilgrastim SC on day 2. Treatment repeats every 4 weeks for up to 12 monthly courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive etoposide phosphate, mannitol, carboplatin, melphalan at the MTD, sodium thiosulfate, and G-CSF or pegfilgrastim as in phase I. Treatment repeats every 4 weeks for up to 12 monthly courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for one year; every 6 months for the next two years; then annually.

PROJECTED ACCRUAL: Up to 60 patients will be accrued for this study.