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

Purpose

This randomized phase I trial is studying the side effects and best dose of O(6)-benzylguanine when given together with ifosfamide and to see how well it works compared to ifosfamide alone in treating patients with unresectable metastatic solid tumors. Drugs used in chemotherapy, such as ifosfamide and O(6)-benzylguanine, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining ifosfamide with O(6)-benzylguanine may kill more tumor cells

Condition	Intervention	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: ifosfamide Drug: O6-benzylguanine	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase I Study Of BG In Combination With Ifosfamide For Advanced Solid Tumors

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Ifosfamide

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Change in degree of myelosuppression (thrombocytopenia and neutropenia) quantified by both duration of neutropenia and severity of neutropenia [ Time Frame: Baseline up to 1 year ] [ Designated as safety issue: Yes ]
Maximum tolerated dose (MTD) of O6-benzylguanine defined as the dose preceding that at which 3 of 6 or 4 of 12 patients experience dose-limiting toxicity [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
DLT is defined as any >= grade 3 non-hematologic toxicity, grade 4 thrombocytopenia, or prolonged neutropenia.

Secondary Outcome Measures:

Pharmacodynamics including apoptosis and DNA damage [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
Pharmacokinetics of O6-benzylguanine [ Time Frame: Up to day 3 of course 2 ] [ Designated as safety issue: No ]
Summarized using descriptive statistics (mean, median, standard deviation, and interquartile range). Estimated via nonlinear regression.

Enrollment:	32
Study Start Date:	June 2004
Primary Completion Date:	November 2005 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm I (ifosfamide) Patients receive high-dose ifosfamide IV continuously over 72 hours on days 1-3.	Drug: ifosfamide Given IV Other Names: Cyfos Holoxan IFF IFX IPP
Experimental: Arm II (O6-benzylguanine, ifosfamide) 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.	Drug: ifosfamide Given IV Other Names: Cyfos Holoxan IFF IFX IPP Drug: O6-benzylguanine Given IV Other Name: BG

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of O6-benzylguanine when administered with standard high-dose ifosfamide in patients with unresectable, metastatic solid tumors.

II. Determine whether O6-benzylguanine enhances ifosfamide-mediated myelosuppression in patients treated with this regimen.

III. Determine the relationship between O6-benzylguanine dose and intra-individual variability in the degree of myelosuppression in patients treated with this regimen.

IV. Determine the safety and toxicity of this regimen in these patients.

SECONDARY OBJECTIVES:

I. Determine the effect of O6-benzylguanine on pharmacodynamic endpoints, including apoptosis and DNA damage, in patients treated with this regimen.

II. Determine the pharmacokinetics of O6-benzylguanine and its major metabolite, 8-oxoBG, in patients treated with this regimen.

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histologically confirmed solid tumor
- Unresectable, metastatic disease
- No primary tumors
Eligible for high-dose ifosfamide-based therapy
No known brain metastases
Performance status - ECOG 0-1
Performance status - Karnofsky 70-100%
More than 12 weeks
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
AST and ALT ≤ 2.5 times upper limit of normal
Bilirubin normal
Creatinine normal
Creatinine clearance ≥ 60 mL/min
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia
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
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
More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
No other concurrent chemotherapy
No concurrent hormonal therapy
More than 4 weeks since prior radiotherapy and recovered
No concurrent therapeutic radiotherapy
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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00086970

Locations

United States, Illinois
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637-1470

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Sonali Smith

University of Chicago Comprehensive Cancer Center

More Information

No publications provided

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00086970 History of Changes
Other Study ID Numbers:	NCI-2012-02601, 12999B, U01CA069852, CDR0000371909
Study First Received:	July 8, 2004
Last Updated:	January 23, 2013
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Neoplasms
Ifosfamide
Isophosphamide mustard
O(6)-benzylguanine
Antineoplastic Agents, Alkylating
Alkylating Agents

Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on May 21, 2013