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A Phase I Study Of BG In Combination With Ifosfamide For Advanced Solid Tumors


Phase 1
18 Years
N/A
Not Enrolling
Both
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study Of BG In Combination With Ifosfamide For Advanced Solid Tumors


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change in degree of myelosuppression (thrombocytopenia and neutropenia) quantified by both duration of neutropenia and severity of neutropenia

Outcome Time Frame:

Baseline up to 1 year

Safety Issue:

Yes

Principal Investigator

Sonali Smith

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02601

NCT ID:

NCT00086970

Start Date:

June 2004

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms

Name

Location

University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470