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
18 Years
75 Years
Both
Brain and Central Nervous System Tumors
Trial Information
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
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.
Inclusion Criteria
INCLUSION CRITERIA:
- Signed written informed consent in accordance with institutional guidelines
- Histologically confirmed anaplastic oligodendroglioma or mixed glioma (i.e.,
oligoastrocytoma) (At least 25% of oligodendroglial element required to qualify as a
mixed tumor)
- Must have undergone prior surgical procedure, either complete resection, partial
resection, or biopsy
- Prior treatment with temozolomide required and at least 28 days since prior
temozolomide
- Radiation therapy: prior consultation OR at least 14 days since completion of
radiation
- Age 18-75 years old
- ECOG performance status (PS) 0-2 OR Karnofsky PS ≥ 50%
- WBC ≥ 2,500/mm^3
- Absolute granulocyte count > 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Creatinine < 1.5 times upper limit of normal (ULN)
- Bilirubin < 1.5 times ULN
- SGOT/SGPT < 2.5 times ULN
- Fertile patients must use effective contraception prior to and during study treatment
EXCLUSION CRITERIA:
- Radiographic signs of excessive intracranial mass effect and/or spinal cord block
- Significant risk for general anesthesia
- Uncontrolled clinically significant confounding medical condition within the past 30
days
- Pregnant, positive HCG or lactating
- Contraindications to carboplatin, melphalan, etoposide phosphate, or sodium
thiosulfate
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose (MTD) of melphalan as measured by NCI CTC v3 (Phase I)
Outcome Description:
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.
Outcome Time Frame:
Completed
Safety Issue:
Yes
Principal Investigator
Edward A. Neuwelt, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
OHSU Knight Cancer Institute
Authority:
United States: Institutional Review Board
Study ID:
OHSU-2868
NCT ID:
NCT00303849
Start Date:
September 2005
Completion Date:
December 2014
Related Keywords:
- Brain and Central Nervous System Tumors
- adult anaplastic oligodendroglioma
- adult oligoastrocytoma
- recurrent adult brain tumor
- Nervous System Neoplasms
- Oligodendroglioma
- Central Nervous System Neoplasms
Name | Location |
|---|---|
| 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 |
