Busulfan in Treating Children and Adolescents With Refractory CNS Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase I trial to study the safety of delivering intrathecal busulfan in children and adolescents who have refractory CNS cancer and to estimate the maximum tolerated dose of this treatment regimen.

OBJECTIVES:

* Determine the qualitative and quantitative toxicities of intrathecally administered busulfan in children and adolescents with refractory CNS malignancies.
* Determine the maximum tolerated dose of this treatment regimen in these patients.
* Determine the cerebrospinal fluid and serum pharmacokinetics of this treatment regimen in these patients.
* Determine the efficacy of this treatment regimen in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive intrathecal busulfan twice a week, at least 3 days apart, for 2 weeks. Patients with complete or partial response or stable disease may continue therapy once a week for 2 weeks, once a week every other week for 2 treatments, and then once a month thereafter in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of busulfan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose limiting toxicities.

Patients are followed every 3 months for the first year, every 6 months for 4 years, and then annually for 5 years.

PROJECTED ACCRUAL: Approximately 18-24 patients will be accrued for this study over 18-38 months.

Eligibility Criteria:
DISEASE CHARACTERISTICS:

* Histologically confirmed CNS malignancy, including any of the following:

  * Primary malignant brain tumor refractory to standard therapy and metastatic to the cerebrospinal fluid (CSF) or leptomeningeal subarachnoid space
  * Recurrent or persistent leptomeningeal leukemia, lymphoma, or germ cell tumor refractory to conventional therapy

    * In second or greater relapse
    * CSF white blood count greater than 5 cells/mm3 with blasts on cytospin OR
    * Evidence of leptomeningeal tumor by MRI
* No concurrent bone marrow disease
* No obstruction or compartmentalization of CSF flow on CSF flow study

PATIENT CHARACTERISTICS:

Age:

* 3 to 21

Performance status:

* Lansky 50-100% (under 10 years)
* Karnofsky 50-100% (10 to 21 years)

Life expectancy:

* Greater than 8 weeks

Hematopoietic:

* Absolute neutrophil count greater than 1,000/mm\^3
* Platelet count greater than 75,000/mm\^3

Hepatic:

* Bilirubin normal for age
* ALT and AST less than 5 times upper limit of normal (ULN)
* No hepatic disease

Renal:

* Creatinine no greater than 1.5 times ULN OR
* Glomerular filtration rate greater than 70 mL/min
* No renal disease

Cardiovascular:

* No cardiac disease

Pulmonary:

* No pulmonary disease

Other:

* No uncontrolled infection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Not specified

Chemotherapy:

* At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas)
* At least 1 week since prior intrathecal chemotherapy (2 weeks for cytarabine) and recovered
* Evidence of subsequent disease progression
* Concurrent systemic chemotherapy allowed for recurrent disease after first course of treatment except for the following:

  * Chemotherapy targeted at leptomeningeal disease
  * Other phase I agent
  * Any agent that significantly penetrates the CSF (e.g., high dose methotrexate greater than 1 g/m2, thiotepa, high dose cytarabine, fluorouracil, IV mercaptopurine, nitrosoureas, or topotecan)
  * Any agent that causes serious unpredictable CNS side effects

Endocrine therapy:

* Prior dexamethasone allowed with decreasing or stable dose at least one week before study
* Concurrent dexamethasone or prednisone with chemotherapy regimen allowed

Radiotherapy:

* At least 1 week since prior focal irradiation to the brain or spine
* At least 8 weeks since prior craniospinal irradiation
* No concurrent cranial or craniospinal irradiation

Surgery:

* Not specified

Other:

* No other concurrent intrathecal or systemic therapy for leptomeningeal disease