Carboplatin, Melphalan, Etoposide Phosphate, Mannitol, and Sodium Thiosulfate in Treating Patients With Previously Treated Brain Tumors

PRIMARY OBJECTIVES:

I. To evaluate toxicity and estimate the maximum tolerated dose (MTD) of melphalan
(intra-arterially [i.a.]) administered in conjunction with carboplatin (i.a.) and etoposide
phosphate (intravenously [i.v.]) undergoing BBBD, in subjects with anaplastic
oligodendroglioma or oligoastrocytoma. (Phase I) II. To examine the efficacy (one year
progression free survival [1YPFS]) of carboplatin (i.a.), melphalan (i.a.) and etoposide
phosphate (i.v.) in conjunction with BBBD, in subjects with anaplastic oligodendroglioma or
oligoastrocytoma. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the incidence of severe neutropenia (specifically febrile neutropenia or
sepsis) of carboplatin (i.a.), melphalan (i.a.) and etoposide phosphate (i.v.) in conjunction
with BBBD, in subjects with anaplastic oligodendroglioma or oligoastrocytoma.

II. To evaluate the overall toxicity of carboplatin (i.a.), melphalan (i.a.), and etoposide
phosphate (i.v.) in conjunction with BBBD.

III. To estimate the differences in tumor response, 1YPFS and survival, in subjects with
allelic loss of chromosomes 1p and 19q, and tumor protein p53 (p53) immunocytochemistry,
versus subjects without allelic loss.

IV. To assess quality of life, cognitive function, and performance status of subjects
undergoing treatment with carboplatin, melphalan and etoposide phosphate in conjunction with
BBBD.

V. To estimate differences in 1YPFS between subjects with anaplastic oligodendroglioma and
patients with oligoastrocytoma.

VI. To describe the role of biopsy versus extent of surgery (sub-maximal versus maximal safe
resection) on 1YPFS and survival.

VII. To describe the role of prior radiation on tumor response, 1YPFS and survival.

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

Patients receive etoposide phosphate IV over 10 minutes, mannitol IA over 30 seconds,
melphalan IA over 10 minutes, and carboplatin IA over 10 minutes on days 1 and 2. Patients
then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin.
Courses repeat every 4 to 6 weeks for up to 12 months.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

- Subjects with pathologic evidence of an anaplastic oligodendroglioma or mixed glioma
(i.e. oligoastrocytoma) are eligible; histopathologic diagnosis will be made using
World Health Organization classification criteria; to qualify as a mixed tumor there
must be a minimum of 25% oligodendroglial element

- Surgical procedure may have been complete resection, partial resection, or biopsy

- Subjects must have had prior treatment with temozolomide; at least 28 days must have
elapsed since completion of temozolomide or other chemotherapy

- If subject has not undergone radiation therapy, then subject must have undergone prior
consultation with a radiation oncologist (who is not an investigator on this study);
if the subject has undergone radiation therapy, then at least 14 days must have
elapsed since completion of radiation

- Subjects performance status must be (Karnofsky performance status [KPS] greater than
or equal to 50; Eastern Cooperative Oncology Group [ECOG] less than or equal to 2)

- White blood cell count >= 2.5 x 10^3/mm^3

- Absolute granulocyte count > 1.5 x 10^3/mm3

- Platelets >= 100 x 10^3/mm^3

- Serum creatinine < 1.5 x upper limit of normal

- Bilirubin < 1.5 x upper limit of normal

- Subjects baseline serum glutamic oxaloacetic transaminase (SGOT)/serum glutamate
pyruvate transaminase (SGPT) must be < 2.5 x institutional upper limit of normal

- Subjects must sign a written informed consent in accordance with institutional
guidelines

- Sexually active women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
treatment and for the duration of study treatment; should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately

Exclusion Criteria:

- Subjects with radiographic signs of excessive intracranial mass effect with associated
rapid neurologic deterioration, and/or spinal cord block

- Subjects at significant risk for general anesthesia

- Subjects with uncontrolled (over the last 30 days) clinically significant confounding
medical conditions

- Subject is pregnant, has a positive serum human chorionic gonadotropin (hCG) or is
lactating

- Subjects who have contraindications to carboplatin, melphalan, etoposide phosphate, or
sodium thiosulfate