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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Terminated
CT.gov ID
NCT00086970
Collaborator
(none)
32
Enrollment
1
Location
2
Arms

Study Details

Study Description

Brief Summary

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 or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

PRIMARY OBJECTIVES:

  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 OBJECTIVES:

  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.

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
32 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Study Of BG In Combination With Ifosfamide For Advanced Solid Tumors
Study Start Date :
Jun 1, 2004
Actual Primary Completion Date :
Nov 1, 2005

Arms and Interventions

Arm Intervention/Treatment
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 Names:
  • BG

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Change in degree of myelosuppression (thrombocytopenia and neutropenia) quantified by both duration of neutropenia and severity of neutropenia [Baseline up to 1 year]

    2. 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 [21 days]

      DLT is defined as any >= grade 3 non-hematologic toxicity, grade 4 thrombocytopenia, or prolonged neutropenia.

    Secondary Outcome Measures

    1. Pharmacodynamics including apoptosis and DNA damage [Up to 1 year]

    2. Pharmacokinetics of O6-benzylguanine [Up to day 3 of course 2]

      Summarized using descriptive statistics (mean, median, standard deviation, and interquartile range). Estimated via nonlinear regression.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00086970
    Other Study ID Numbers:
    • NCI-2012-02601
    • 12999B
    • U01CA069852
    • CDR0000371909
    First Posted:
    Jul 12, 2004
    Last Update Posted:
    Jan 24, 2013
    Last Verified:
    Jan 1, 2013
    Additional relevant MeSH terms:
    Neoplasms
    Ifosfamide
    O(6)-benzylguanine

    Study Results

    No Results Posted as of Jan 24, 2013