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Phase I Study of Intrathecal Spartaject-Busulfan in Children With Neoplastic Meningitis

Phase 1
3 Years
21 Years
Not Enrolling
Brain and Central Nervous System Tumors, Childhood Germ Cell Tumor, Leukemia, Lymphoma, Metastatic Cancer, Retinoblastoma, Sarcoma

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Trial Information

Phase I Study of Intrathecal Spartaject-Busulfan in Children With Neoplastic Meningitis


- 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

Inclusion Criteria


- 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



- 3 to 21

Performance status:

- Lansky 50-100% (under 10 years)

- Karnofsky 50-100% (10 to 21 years)

Life expectancy:

- Greater than 8 weeks


- Absolute neutrophil count greater than 1,000/mm^3

- Platelet count greater than 75,000/mm^3


- Bilirubin normal for age

- ALT and AST less than 5 times upper limit of normal (ULN)

- No hepatic disease


- Creatinine no greater than 1.5 times ULN OR

- Glomerular filtration rate greater than 70 mL/min

- No renal disease


- No cardiac disease


- No pulmonary disease


- No uncontrolled infection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception


Biologic therapy:

- Not specified


- 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

- 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

- Concurrent dexamethasone or prednisone with chemotherapy regimen allowed


- 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


- Not specified


- No other concurrent intrathecal or systemic therapy for leptomeningeal disease

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Primary Purpose: Treatment

Outcome Measure:

Toxicities of IT administered busulfan in children and adolescents with refractory CNS malignancies

Safety Issue:


Principal Investigator

Sri Gururangan, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Duke University


United States: Food and Drug Administration

Study ID:




Start Date:

November 2000

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Childhood Germ Cell Tumor
  • Leukemia
  • Lymphoma
  • Metastatic Cancer
  • Retinoblastoma
  • Sarcoma
  • recurrent childhood acute lymphoblastic leukemia
  • childhood infratentorial ependymoma
  • recurrent childhood rhabdomyosarcoma
  • recurrent childhood brain tumor
  • recurrent retinoblastoma
  • recurrent childhood lymphoblastic lymphoma
  • childhood central nervous system germ cell tumor
  • recurrent childhood acute myeloid leukemia
  • recurrent/refractory childhood Hodgkin lymphoma
  • leptomeningeal metastases
  • childhood high-grade cerebral astrocytoma
  • childhood oligodendroglioma
  • childhood choroid plexus tumor
  • childhood grade I meningioma
  • childhood grade II meningioma
  • childhood grade III meningioma
  • recurrent childhood large cell lymphoma
  • recurrent childhood brain stem glioma
  • recurrent childhood supratentorial primitive neuroectodermal tumor
  • recurrent childhood cerebellar astrocytoma
  • recurrent childhood cerebral astrocytoma
  • recurrent childhood medulloblastoma
  • recurrent childhood visual pathway and hypothalamic glioma
  • recurrent childhood ependymoma
  • recurrent childhood malignant germ cell tumor
  • Leukemia
  • Lymphoma
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary
  • Nervous System Neoplasms
  • Retinoblastoma
  • Central Nervous System Neoplasms
  • Neoplasms, Germ Cell and Embryonal
  • Sarcoma



Baylor College of Medicine Houston, Texas  77030
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Duke Comprehensive Cancer Center Durham, North Carolina  27710
UCSF Cancer Center and Cancer Research Institute San Francisco, California  94115-0128
Dana-Farber Cancer Institute Boston, Massachusetts  02115
Children's National Medical Center Washington, District of Columbia  20010-2970
Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105