Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

O(6)-benzylguanine and Carmustine in Treating Patients With Solid Tumors

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	Over 18	NCI	CWRU-ICC-1994 NCI-T94-0022D, T94-0022, NCT00002604

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.

Entry 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

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

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

Expected Enrollment

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

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.  

Trial Contact Information

Trial Lead Organizations

Case Comprehensive Cancer Center

Smitha Krishnamurthi, MD, Protocol chair		Ph: 216-844-1160

Registry Information
Official Title		PHASE I TRIAL OF O6-BENZYLGUANINE AND BCNU: A BIOCHEMICAL MODULATION TRIAL BASED UPON DEPLETION OF O6-ALKYLGUANINE DNA ALKYLTRANSFERASE DIRECTED DNA REPAIR
Trial Start Date		1996-01-01
Registered in ClinicalTrials.gov		NCT00002604
Date Submitted to PDQ		1996-01-01
Information Last Verified		2004-07-30
NCI Grant/Contract Number		CA62502