O6-benzylguanine and Carmustine in Treating Children With Refractory CNS Tumors

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00003765

Collaborator

(none)

Enrollment

Locations

Arm

0.6

Patients Per Site

Study Details

Study Description

Brief Summary

Phase I trial to study the effectiveness of O6-benzylguanine and carmustine in treating children who have refractory CNS tumors. 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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: O6-benzylguanine Drug: carmustine	Phase 1

Detailed Description

OBJECTIVES:

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

36 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Trial of 06-BG and BCNU in Children With CNS Tumors

Study Start Date :

May 1, 1999

Actual Primary Completion Date :

Mar 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I 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.	Drug: O6-benzylguanine Drug: carmustine

Arm

Intervention/Treatment

Experimental: Arm I

Drug: O6-benzylguanine

Drug: carmustine

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

PATIENT CHARACTERISTICS:

Age: 21 and under
Performance status: Karnofsky 50-100% OR Lansky 50-100%
Life expectancy: At least 8 weeks
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
Bilirubin less than 1.5 mg/dL
SGOT/SGPT no greater than 2.5 times normal
Creatinine or GFR normal for age
If required, DLCO must be 80% of normal and patient old enough to cooperate for DLCO test
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

PRIOR CONCURRENT 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
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
If receiving dexamethasone, must be on stable or decreasing dose for at least 2 weeks prior to study
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
No other concurrent anticancer or investigational agents

Contacts and Locations

Locations

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