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

Alternate Title

Ifosfamide With or Without O(6)-Benzylguanine in Treating Patients With Unresectable, Metastatic Solid Tumors

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	18 and over	NCI	UCCRC-12999B 6461, NCI-6461, NCT00086970

Objectives

Primary

1. Determine the maximum tolerated dose of O6-benzylguanine when administered with standard high-dose ifosfamide in patients with unresectable, metastatic solid tumors.
2. Determine whether O6-benzylguanine enhances ifosfamide-mediated myelosuppression in patients treated with this regimen.
3. Determine the relationship between O6-benzylguanine dose and intra-individual variability in the degree of myelosuppression in patients treated with this regimen.
4. Determine the safety and toxicity of this regimen in these patients.

Secondary

1. Determine the effect of O6-benzylguanine on pharmacodynamic endpoints, including apoptosis and DNA damage, in patients treated with this regimen.
2. Determine the pharmacokinetics of O6-benzylguanine and its major metabolite, 8-oxoBG, in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Histologically confirmed solid tumor
  • Unresectable, metastatic disease
  • No primary tumors



• Eligible for high-dose ifosfamide-based therapy



• No known brain metastases

Prior/Concurrent Therapy:

Biologic therapy

• More than 24 hours since prior colony-stimulating factors (filgrastim [G-CSF] or sargramostim [GM-CSF])
• No prior hematopoietic stem cell transplantation
• No concurrent pegfilgrastim
• No concurrent immunotherapy

Chemotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent hormonal therapy

Radiotherapy

• More than 4 weeks since prior radiotherapy and recovered
• No concurrent therapeutic radiotherapy

Surgery

• Not specified

Other

• More than 4 weeks since prior anticancer therapy
• No more than 2 prior cytotoxic regimens
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer agents or therapies
• No other concurrent investigational agents

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-1

  OR

• Karnofsky 70-100%

Life expectancy

• More than 12 weeks

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³

Hepatic

• AST and ALT ≤ 2.5 times upper limit of normal
• Bilirubin normal

Renal

• Creatinine normal

  OR

• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 4 weeks after study participation
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to O6-benzylguanine or other study agents
• No concurrent uncontrolled illness
• No active or ongoing infection
• No psychiatric illness or social situation that would preclude study compliance

Expected Enrollment

A minimum of 32 patients (at least 2 in arm I and at least 24 in arm II) will be accrued for this study within 12-15 months.

Outline

This is a randomized, open-label, multicenter, dose-escalation study of O6-benzylguanine.

• Course 1: All patients receive high-dose ifosfamide IV continuously over 72 hours on days 1-3.



• Course 2: Patients are randomized to 1 of 2 treatment arms.
  • Arm I: Patients receive high-dose ifosfamide as in course 1.
  
  
  
  • Arm II: Patients receive a bolus dose of O6-benzylguanine (BG) IV over 1 hour on day 1 followed by BG IV continuously and high-dose ifosfamide IV continuously over 72 hours on days 1-3.

    Cohorts of 6-12 patients receive escalating doses of BG (administered as a bolus and as a continuous infusion during course 2) until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 3 of 6 or 4 of 12 patients experience dose-limiting toxicity.

  
  
  



• Course 3 and all subsequent courses: All patients receive BG (at the MTD determined in course 2, arm II) and high-dose ifosfamide as in course 2, arm II.

In all courses, all patients also receive filgrastim (G-CSF) beginning on day 5 and continuing until blood counts recover.

In all courses and in both arms, treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Trial Contact Information

Trial Lead Organizations

University of Chicago Cancer Research Center

Sonali Smith, MD, Protocol chair		Ph: 773-834-2895; 888-824-0200

Registry Information
Official Title		A Phase I Study Of BG In Combination With Ifosfamide For Advanced Solid Tumors
Trial Start Date		2004-08-06
Registered in ClinicalTrials.gov		NCT00086970
Date Submitted to PDQ		2004-05-18
Information Last Verified		2005-06-02
NCI Grant/Contract Number		P30-CA14599, U01-CA69852

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