Carboplatin, Melphalan, Etoposide Phosphate, Mannitol, and Sodium Thiosulfate in Treating Patients With Previously Treated Brain Tumors
Carboplatin, Melphalan, Etoposide Phosphate, Mannitol, and Sodium Thiosulfate in Treating Patients With Previously Treated Brain Tumors
This phase I/II trial studies the side effects and best dose of melphalan when given together
 with carboplatin, etoposide phosphate, mannitol, and sodium thiosulfate and to see how well
 they work in treating patients with previously treated brain tumors. Drugs used in
 chemotherapy, such as melphalan, carboplatin, and etoposide phosphate, work in different ways
 to stop the growth of tumor cells, either by killing the cells or by stopping them from
 dividing, or by stopping them from spreading. Osmotic blood-brain barrier disruption (BBBD)
 uses mannitol to open the blood vessels around the brain and allow cancer-killing substances
 to be carried directly to the brain. Sodium thiosulfate may help lessen or prevent hearing
 loss and toxicities in patients undergoing chemotherapy with carboplatin and BBBD. Giving
 carboplatin, melphalan, etoposide phosphate, mannitol, and sodium thiosulfate together may be
 an effective treatment for 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/mm^3

 -  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

 -  The effects of carboplatin, melphalan and etoposide phosphate on the developing human
 fetus at the recommended therapeutic dose are unknown. For this reason and because
 these agents as well as other therapeutic agents used in this trial are known to be
 teratogenic. 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