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

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

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 O(6)-benzylguanine and carmustine in treating patients who have solid tumors.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: O6-benzylguanine; Drug: carmustine; Drug: chemosensitization/potentiation therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106-5065
      • Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44106
      • Veterans Affairs Medical Center - Cleveland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
dose escalation study of 06-benzylguanine (BG) and carmustine (BCNU)	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.

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: James KV Willson, MD, Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: January 1, 1996
• Primary Completion (Actual): July 1, 2000
• Study Completion (Actual): February 1, 2004

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: July 28, 2004
• First Posted (Estimate): July 29, 2004

Study Record Updates

• Last Update Posted (Estimate): July 8, 2010
• Last Update Submitted That Met QC Criteria: July 7, 2010
• Last Verified: July 1, 2010

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Carmustine; O(6)-benzylguanine
• Other Study ID Numbers: CWRU1994; U01CA062502 (U.S. NIH Grant/Contract); CWRU-ICC-1994; NCI-T94-0022D