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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 MedicineHouston, Texas  77030
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
UCSF Cancer Center and Cancer Research InstituteSan Francisco, California  94115-0128
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105