A Phase I Pharmacokinetic Study of STI571 in Patients With Advanced Malignancies and Varying Levels of Liver Dysfunction
A Phase I Pharmacokinetic Study of STI571 in Patients With Advanced Malignancies and Varying Levels of Liver Dysfunction
Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Phase I trial to study the effectiveness of imatinib mesylate in treating patients who have advanced cancer and liver dysfunction
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose and dose-limiting toxicity of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction.
II. Determine the effects of hepatic dysfunction on the pharmacodynamics and pharmacokinetics of this drug in these patients.
III. Determine the non-dose-limiting toxic effects of this drug in these patients.
IV. Determine the response rate of these patients treated with this drug. V. Correlate the Childs-Pugh classification of hepatic dysfunction with observed toxic effects, pharmacodynamics, and pharmacokinetics of this drug in these patients.
OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to liver dysfunction (normal vs mild vs moderate vs severe).
Patients receive oral imatinib mesylate daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients within each stratum (except normal stratum) receive escalating doses of imatinib mesylate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study within 1 year.
Inclusion Criteria:
Histologically or cytologically confirmed surgically incurable solid tumor orhematologic malignancy for which no standard or palliative therapy exists oris no longer effective
All tumor types are eligible, including:
Patients with gliomas that require corticosteroids or anticonvulsants must beon a stable dose and seizure-free for 1 month
No unstable or untreated (non-irradiated) brain metastases
Performance status - ECOG 0-2
Performance status - Karnofsky 60-100%
More than 3 months
WBC at least 3,000/mm^3
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
No active hemolysis
See Surgery
No evidence of biliary sepsis
Creatinine normal
Creatinine clearance at least 60 mL/min
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia
Able to swallow pills
No other uncontrolled concurrent illness that would preclude study participation
No ongoing or active infection
No uncontrolled diarrhea
No psychiatric illness or social situation that would preclude study compliance
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier contraception during and for 6 months after study completion
At least 24 hours since prior colony-stimulating factors
No concurrent colony-stimulating factors
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
See Disease Characteristics
See Disease Characteristics
At least 4 weeks since prior radiotherapy and recovered
See Disease Characteristics
At least 10 days since prior placement of shunt for treatment of biliary obstruction
At least 14 days since prior major surgery
No prior solid organ transplantation
No other concurrent investigational agents
No concurrent therapeutic doses of warfarin for anticoagulation
No other concurrent investigational or commercial agents or therapies for treatment of this disease
No concurrent combination antiretroviral therapy for HIV-positive patients
No concurrent acetaminophen of more than 4,000 mg/day