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Phase I Trial of O6 Benzylguanine and BCNU; A Biochemical Modulation Trial Based Upon Depletion of O6 Alkylguanine DNA Alkyltransferase Directed DNA Repair


Phase 1
18 Years
N/A
Not Enrolling
Both
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Trial of O6 Benzylguanine and BCNU; A Biochemical Modulation Trial Based Upon Depletion of O6 Alkylguanine DNA Alkyltransferase Directed DNA Repair


OBJECTIVES: I. Determine the biochemical modulation dose l of O6-benzylguanine (BG), defined
as the dose at which baseline O6-alkylguanine DNA alkyltransferase (AGT) activity in
circulating peripheral blood mononuclear cells (PBMC) decreases by greater than 90% in
patients with advanced solid tumors at 2 hours after BG infusion. II. Determine the
biochemical modulation dose t/18 (BMDt/18) of BG, defined as the dose at which AGT activity
in human metastatic tumor tissue decreases to undetectable levels at 18 hours after BG
infusion. III. Determine the maximum tolerated dose of carmustine (BCNU) when administered
with BG at the BMDt/18 in these patients. IV. Determine the toxicities of BG and BCNU in
these patients. V. Determine the pharmacokinetic parameters of BG administered at the
BMDt/18, and determine any effects of BCNU on BG pharmacokinetics. VI. Assess any antitumor
response in patients with metastatic solid tumors treated with this regimen. VII. Determine
the effect of lower, more frequent bolus doses or a continuous infusion of BG on the
depletion of AGT activity in PBMC and tumor tissue in these patients. VIII. Determine the
pharmacokinetics of BG in lower, more frequent bolus doses or continuous infusion.

OUTLINE: This is a dose escalation study of 06-benzylguanine (BG) and carmustine (BCNU).
Patients receive BG IV over 1 hour during week 1, and then BG IV over 1 hour followed 1 hour
later by BCNU IV over 1 hour during week 3. Courses repeat every 6 weeks in the absence of
disease progression or unacceptable toxicity. Cohorts of 1-3 patients receive escalating
doses of BG until the biochemical modulation dose l (BMDl) is determined. The BMDl is
defined as the dose at which baseline O6-alkylguanine DNA alkyltransferase (AGT) activity in
circulating peripheral blood mononuclear cells decreases by greater than 90% at 2 hours
after BG infusion. Cohorts of 3 patients receive escalating doses of BG beginning at the
BMDl until the biochemical modulation dose t/2 (BMDt/2) is determined. The BMDt/2 is defined
as the dose at which AGT activity in human metastatic tumor tissue decreases by greater than
90% at 2 hours after BG infusion. Cohorts of 3 patients receive escalating doses of BG
beginning at the BMDt/2 until the biochemical modulation dose t/18 (BMDt/18) is determined.
The BMDt/18 is defined as the dose at which AGT activity in human metastatic tumor tissue
decreases to undetectable levels at 18 hours after BG infusion. Patients then receive BG IV
over 1 hour followed 1 hour later by BCNU IV over 1 hour during week 1. Courses repeat every
6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6
patients receive escalating doses of BCNU combined with BG at the BMDt/18 until the maximum
tolerated dose (MTD) of BCNU is determined. The MTD of BCNU is defined as the dose preceding
that at which 2 or more of 6 patients experience dose limiting toxicity. A cohort of 3
patients receives BG IV over 2 minutes and another cohort of 3 patients receives BG IV over
24 hours. An additional cohort of 6 patients receives BG IV over 24 hours and BCNU IV over 1
hour beginning 2 hours into BG infusion during week 3.

PROJECTED ACCRUAL: A total of 51 patients will be accrued for this study over 36 months.

Inclusion Criteria


DISEASE CHARACTERISTICS: Histologically confirmed solid tumor for which no standard
treatment exists (including surgery, radiotherapy, or systemic agents) No primary CNS
malignancy No CNS metastases Only disease that can be sequentially biopsied is eligible
for determination of the biochemical modulating dose that decreases AGT in tumor tissue

PATIENT CHARACTERISTICS: Age: Over 18 Performance status: ECOG 0-2 Hematopoietic: WBC
greater than 4,000/mm3 Absolute neutrophil count greater than 2,000/mm3 Platelet count
greater than 100,000/mm3 Hepatic: Bilirubin less than 1.5 mg/dL AST less than 3 times
normal Prothrombin time less than upper limit of normal Renal: Creatinine no greater than
1.5 mg/dL OR Creatinine clearance at least 60 mL/min Calcium normal Electrolytes normal
Other: Diabetes controlled by diet or insulin allowed Not pregnant Fertile patients must
use effective contraception during and for 2 months after study

PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: At least 4 weeks
since chemotherapy (6 weeks since mitomycin) and recovered No prior nitrosoureas Endocrine
therapy: Not specified Radiotherapy: See Disease Characteristics Surgery: Not specified

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

dose escalation study of 06-benzylguanine (BG) and carmustine (BCNU)

Outcome Time Frame:

Courses (each course is 3 weeks) repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 1-3 patients receive escalating doses of BG until the biochemical modulation dose l (BMDl) is determined.

Safety Issue:

Yes

Principal Investigator

James KV Willson, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Authority:

United States: Federal Government

Study ID:

CWRU1994

NCT ID:

NCT00002604

Start Date:

January 1996

Completion Date:

February 2004

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • Neoplasms

Name

Location

Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065
Veterans Affairs Medical Center - ClevelandCleveland, Ohio  44106