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

This study has been terminated.
(Administratively complete.)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00086970
First received: July 8, 2004
Last updated: January 23, 2013
Last verified: January 2013
  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:


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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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
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 September 22, 2014