Melphalan, Carboplatin, Mannitol, and Sodium Thiosulfate in Treating Patients With Recurrent or Progressive CNS Embryonal or Germ Cell Tumors

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of intra-arterial (IA) melphalan given with
IA carboplatin, osmotic BBBD and delayed intravenous (IV) sodium thiosulfate (STS) in
subjects with recurrent or progressive embryonal and germ cell tumors of the CNS. (Phase I)
II. To estimate the response rate in subjects with recurrent or progressive CNS embryonal and
germ cell tumors treated with IA carboplatin, IA melphalan, osmotic BBBD and delayed IV STS.
(Phase II)

SECONDARY OBJECTIVES:

I. To describe 2-year progression-free survival (PFS) and overall survival (OS) rates in
subjects with recurrent or progressive CNS embryonal and germ cell tumors treated with IA
carboplatin, IA melphalan, osmotic BBBD and delayed IV STS. (Phase II) II. To describe
neuropsychological and audiology outcomes in subjects with recurrent or progressive CNS
embryonal and germ cell tumors treated with IA carboplatin, IA melphalan, osmotic BBBD and
delayed IV STS. (Phase II) III. To describe the overall toxicity of IA carboplatin and IA
melphalan in conjunction with osmotic BBBD and delayed STS chemoprotection in subjects with
recurrent or progressive CNS embryonal or germ cell tumors. (Phase II)

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

Patients receive mannitol IA over 30 seconds, melphalan IA over 10 minutes, and carboplatin
IA over 10 minutes. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8
hours after carboplatin. Treatment repeats every 4-6 weeks for up to 12 courses in the
absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Subjects with histologically confirmed CNS embryonal tumor (primitive neuroectodermal
tumor [PNET], medulloblastoma, atypical teratoid rhabdoid tumor [ATRT],
medulloepithelioma, pineoblastoma or ependymoblastoma), or germ cell tumor, are
eligible; tumors must be relapsed or refractory to first-line therapy; diagnosis will
be made on the basis of computed tomography (CT)-assisted or stereotactic biopsy, open
biopsy, surgical resection, cerebrospinal fluid (CSF) cytology, or elevated tumor
markers

- Subjects under the age of 18 must have had prior therapy according to the best
available therapy as determined by their primary brain tumor specialist (to include
oncology, neurosurgery and/or radiation oncology) including systemic and/or cranial or
spinal radiation or chemotherapy; subjects over the age of 18 may be enrolled as part
of first-line treatment; those subjects who enroll as first-line treatment will not be
restricted from traditional treatments in the future; at least 14 days must have
elapsed since completion of cranial radiotherapy and 28 days since completion of
chemotherapy; at least 28 days must have elapsed since completion of total spine
radiotherapy

- Subjects with no previous radiotherapy treatment must have a consultation with a
radiation oncologist or providers must have a discussion in the context of
Neuro-Oncology Tumor Board within 60 days prior to start of IA/BBBD chemotherapy to
determine the need for radiotherapy prior to or after IA/BBBD

- Glomerular filtration rate (GFR) or creatinine clearance (CrCl) (24 hour urine)
greater than 30 ml/min corrected for body surface area

- Absolute granulocyte count >= 1.0 x 10^3/mm^3

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

- Creatinine < 1.5

- Total bilirubin < 2.0 mg/dl

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 x upper limits
of normal

- Subject's Karnofsky performance status (KPS) must be >= 50% (Eastern Cooperative
Oncology Group [ECOG] performance score < 3); the Lansky scale will be used for
subjects less than 16 years of age and must be >= 50%

- Subjects or their legal guardian 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 female become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately

- For the phase II portion of the study, subjects must have disease that is evaluable
for response; subjects who have had radiation to all sites of disease are not eligible
unless there is imaging evidence of active tumor, ie: increased blood volume

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 with general anesthesia

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

- Subject is pregnant or is lactating

- Subjects who have contraindications to carboplatin, melphalan, or STS