Clinical trial NCT00006246: Busulfan in Treating Children and Adolescents With Refractory CNS Cancer
Official title: Phase I Study of Intrathecal Spartaject-Busulfan in Children With Neoplastic Meningitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Childhood Germ Cell Tumor
Leukemia
Lymphoma
Metastatic Cancer
Retinoblastoma
Sarcoma
Keywords: 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
Lead sponsor: Pediatric Brain Tumor Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 28
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Primary outcomes:
measure: Toxicities of IT administered busulfan in children and adolescents with refractory CNS malignancies
measure: Maximum tolerated dose of IT administered busulfan
measure: Serum and CSF pharmacokinetics of IT administered busulfan
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Cancer Center and Cancer Research Institute
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
Study officials:
affiliation: Duke University
name: Sri Gururangan, MD
role: STUDY_CHAIR
References:
citation: Gururangan S, Petros WP, Poussaint TY, Hancock ML, Phillips PC, Friedman HS, Bomgaars L, Blaney SM, Kun LE, Boyett JM. Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004). Clin Cancer Res. 2006 Mar 1;12(5):1540-6. doi: 10.1158/1078-0432.CCR-05-2094.