RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of O6-benzylguanine and carmustine in treating children who have refractory CNS tumors.

Condition	Treatment or Intervention	Phase
recurrent childhood brain stem glioma childhood choroid plexus tumor recurrent childhood visual pathway glioma recurrent childhood cerebral astrocytoma childhood craniopharyngioma recurrent childhood cerebellar astrocytoma childhood central nervous system germ cell tumor recurrent childhood ependymoma recurrent childhood supratentorial primitive neuroectodermal and pineal tumors recurrent childhood medulloblastoma Childhood Oligodendroglioma	Drug: carmustine  Drug: O6-benzylguanine	Phase I

Further Study Details: 

OBJECTIVES: I. Determine the maximum tolerated dose and the dose limiting toxicity of carmustine administered after O6-benzylguanine in children with refractory primary CNS tumors. II. Determine a safe and tolerable dose of carmustine administered after O6-benzylguanine to be used in phase II studies. III. Determine the pharmacokinetics of O6-benzylguanine and its metabolite, O6-benzyl-8-oxoguanine, in these patients. IV. Seek preliminary evidence of antitumor activity of this regimen in these patients. V. Evaluate the acute and chronic toxicities, and describe cumulative toxicity, in patients treated with multiple courses of this regimen.

PROTOCOL OUTLINE: This is a dose escalation study of carmustine. Patients receive O6-benzylguanine IV over 1 hour, then, 1 hour later, carmustine IV is administered over 1 hour. Treatment is repeated every 6 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients each receive escalating doses of carmustine until the maximum tolerated dose (MTD) is reached. The MTD is defined as the dose level at which fewer than 2 of 6 patients experience dose limiting toxicity (DLT). If myelosuppression is the DLT, stratum 1 is closed and patients are accrued to stratum 2. If neutropenia is the DLT in stratum 2, patients receive filgrastim (G-CSF) subcutaneously beginning on day 2 and continuing until blood counts recover. Patients are followed every 6 months for 4 years, then annually thereafter.

PROJECTED ACCRUAL: Approximately 3-36 patients will be accrued for this study within 3 years.

Ages Eligible for Study:  up to  21 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically or cytologically proven CNS tumor that is refractory to conventional therapy or for which no effective therapy is known; Histological requirement may be waived for brainstem and optic gliomas
• Stratum 2: No bone marrow involvement

--Prior/Concurrent Therapy--

• Biologic therapy: At least 7 days since prior biologic therapy or immunotherapy and recovered; At least 6 months since prior bone marrow transplant (stratum 1 only); At least 7 days since prior growth factors; No concurrent filgrastim (G-CSF) prophylaxis; Stratum 2: No prior bone marrow transplantation
• Chemotherapy: At least 2 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) and recovered; Stratum 2: No greater than 2 prior chemotherapy regimens; No prior nitrosourea therapy
• Endocrine therapy: If receiving dexamethasone, must be on stable or decreasing dose for at least 2 weeks prior to study
• Radiotherapy: At least 2 weeks since prior local palliative radiotherapy (small port); At least 6 months since prior substantial bone marrow radiation, total body irradiation, hemipelvic radiotherapy, or total abdominal/pelvic/chest or mantle/Y ports radiotherapy Recovered from prior radiotherapy; Stratum 2: No prior central axis radiation
• Surgery: Not specified
• Other: No other concurrent anticancer or investigational agents

--Patient Characteristics--

• Age: 21 and under
• Performance status: Karnofsky 50-100% OR Lansky 50-100%
• Life expectancy: At least 8 weeks
• Hematopoietic: Absolute neutrophil count at least 1500/mm3; Platelet count at least 100,000/mm3 (stratum 2: at least 125,000/mm3); Hemoglobin at least 8 g/dL
• Hepatic: Bilirubin less than 1.5 mg/dL; SGOT/SGPT no greater than 2.5 times normal
• Renal: Creatinine or GFR normal for age
• Pulmonary: If required, DLCO must be 80% of normal and patient old enough to cooperate for DLCO test
• Other: Neurologic deficits must be stable for at least 2 weeks prior to study; Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception during and for 6 months after study

Arkansas
      University of Arkansas for Medical Sciences, Little Rock,  Arkansas,  72205,  United States
California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-0700,  United States
      Children's Hospital of Orange County, Orange,  California,  92868,  United States
      City of Hope National Medical Center, Los Angeles,  California,  91010,  United States
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States
      Stanford University Medical Center, Stanford,  California,  94305-5408,  United States
      UCSF Cancer Center and Cancer Research Institute, San Francisco,  California,  94115-0128,  United States
      University of California San Diego Cancer Center, La Jolla,  California,  92093-0658,  United States
District of Columbia
      Children's National Medical Center, Washington,  District of Columbia,  20010-2970,  United States
Florida
      University of Florida Health Science Center, Gainesville,  Florida,  32610-0296,  United States
Georgia
      Emory University Hospital - Atlanta, Atlanta,  Georgia,  30322,  United States
Illinois
      Children's Memorial Hospital, Chicago, Chicago,  Illinois,  60614,  United States
      Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago,  Illinois,  60611,  United States
Indiana
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5265,  United States
Kansas
      University of Kansas Medical Center, Kansas City,  Kansas,  66160-7357,  United States
Maryland
      Johns Hopkins Oncology Center, Baltimore,  Maryland,  21231,  United States
Massachusetts
      Boston Floating Hospital Infants and Children, Boston,  Massachusetts,  02111,  United States
      Dana-Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States
Michigan
      Children's Hospital of Michigan, Detroit,  Michigan,  48201,  United States
      University of Michigan Comprehensive Cancer Center, Ann Arbor,  Michigan,  48109-0752,  United States
Minnesota
      Mayo Clinic Cancer Center, Rochester,  Minnesota,  55905,  United States
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States
Mississippi
      University of Mississippi Medical Center, Jackson,  Mississippi,  39216-4505,  United States
Missouri
      Cardinal Glennon Children's Hospital, Saint Louis,  Missouri,  63104,  United States
      Children's Mercy Hospital, Kansas City,  Missouri,  64108,  United States
      Washington University School of Medicine, Saint Louis,  Missouri,  63110,  United States
New Jersey
      Cancer Institute of New Jersey, New Brunswick,  New Jersey,  08901,  United States
      Hackensack University Medical Center, Hackensack,  New Jersey,  07601,  United States
New York
      Columbia Presbyterian Hospital, New York,  New York,  10032,  United States
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States
      NYU School of Medicine's Kaplan Comprehensive Cancer Center, New York,  New York,  10016,  United States
      Roswell Park Cancer Institute, Buffalo,  New York,  14263-0001,  United States
      State University of New York - Upstate Medical University, Syracuse,  New York,  13210,  United States
North Carolina
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States
      Graham Children's Health Center, Asheville,  North Carolina,  28801,  United States
Ohio
      Children's Hospital Medical Center - Cincinnati, Cincinnati,  Ohio,  45229-3039,  United States
      Children's Hospital of Columbus, Columbus,  Ohio,  43205-2696,  United States
Oklahoma
      University of Oklahoma Health Sciences Center, Oklahoma City,  Oklahoma,  73190,  United States
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States
South Carolina
      Medical University of South Carolina, Charleston,  South Carolina,  29425-0721,  United States
Tennessee
      Vanderbilt Cancer Center, Nashville,  Tennessee,  37232-6838,  United States
Texas
      Cook Children's Medical Center - Fort Worth, Fort Worth,  Texas,  76104,  United States
      Simmons Cancer Center - Dallas, Dallas,  Texas,  75235-9154,  United States
      Texas Children's Cancer Center, Houston,  Texas,  77030-2399,  United States
      University of Texas - MD Anderson Cancer Center, Houston,  Texas,  77030-4009,  United States
      University of Texas Health Science Center at San Antonio, San Antonio,  Texas,  78284-7811,  United States
Utah
      Primary Children's Medical Center, Salt Lake City,  Utah,  84113,  United States
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States
Wisconsin
      Midwest Children's Cancer Center, Milwaukee,  Wisconsin,  53226,  United States
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792,  United States
Australia, Victoria
      Royal Children's Hospital, Parkville,  Victoria,  3052,  Australia
Australia, Western Australia
      Princess Margaret Hospital for Children, Perth,  Western Australia,  6001,  Australia
Canada, Ontario
      Hospital for Sick Children, Toronto,  Ontario,  M5G 1X8,  Canada
Canada, Quebec
      Hopital Sainte Justine, Montreal,  Quebec,  H3T 1C5,  Canada
      Montreal Children's Hospital, Montreal,  Quebec,  H3H 1P3,  Canada

Study chairs or principal investigators

Denise Adams,  Study Chair,  Pediatric Oncology Group   

Study ID Numbers:  CDR0000066891; POG-9870
Record last reviewed:  April 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00003765
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08