Phase I/II Study of Carboplatin, Melphalan and Etoposide Phosphate in Conjunction With Osmotic Opening of the Blood-Brain Barrier and Delayed Intravenous Sodium Thiosulfate Chemoprotection, in Previously Treated Subjects With Anaplastic Oligodendroglioma or Oligoastrocytoma
- 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
- Examine the efficacy, in terms of 1-year progression-free survival (1YPFS), in patients
treated with this regimen. (phase II)
- 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
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
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of melphalan as measured by NCI CTC v3 (Phase I)
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.
Edward A. Neuwelt, MD
OHSU Knight Cancer Institute
United States: Institutional Review Board
|Knight Cancer Institute at Oregon Health and Science University||Portland, Oregon 97239-3098|
|University of Minnesota||Minneapolis, Minnesota 55455|
|Good Samaritan Hospital Cancer Treatment Center, Hatton Institute||Cincinnati, Ohio 45220|