Imatinib Mesylate in Treating Patients With Advanced Cancer and Liver Dysfunction

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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A Phase I Pharmacokinetic Study of STI571 in Patients With Advanced Malignancies and Varying Levels of Liver Dysfunction

Conditions
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Accelerated Phase Chronic Myelogenous Leukemia, Acute Undifferentiated Leukemia, AIDS-related Peripheral/Systemic Lymphoma, AIDS-related Primary CNS Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Blastic Phase Chronic Myelogenous Leukemia, Childhood Myelodysplastic Syndromes, Chronic Eosinophilic Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Myelomonocytic Leukemia, Chronic Neutrophilic Leukemia, Chronic Phase Chronic Myelogenous Leukemia, de Novo Myelodysplastic Syndromes, Essential Thrombocythemia, Extramedullary Plasmacytoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Gastrointestinal Stromal Tumor, Intraocular Lymphoma, Isolated Plasmacytoma of Bone, Meningeal Chronic Myelogenous Leukemia, Monoclonal Gammopathy of Undetermined Significance, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Nodal Marginal Zone B-cell Lymphoma, Polycythemia Vera, Previously Treated Myelodysplastic Syndromes, Primary Central Nervous System Non-Hodgkin Lymphoma, Primary Myelofibrosis, Primary Systemic Amyloidosis, Progressive Hairy Cell Leukemia, Initial Treatment, Prolymphocytic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Hairy Cell Leukemia, Refractory Multiple Myeloma, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage IV Adult Burkitt Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Hodgkin Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Adult T-cell Leukemia/Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Mycosis Fungoides/Sezary Syndrome, Stage IV Small Lymphocytic Lymphoma, T-cell Large Granular Lymphocyte Leukemia, Unspecified Adult Solid Tumor, Protocol Specific, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia, Untreated Hairy Cell Leukemia, Waldenström Macroglobulinemia

Intervention / Treatment
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* Drug: imatinib mesylate
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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: Chronic myelogenous leukemia or other Philadelphia chromosome-positive leukemia OR Gastrointestinal stromal tumors 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

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (imatinib mesylate)<br>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 | Drug: imatinib mesylate<br>* Given orally<br>* Other names: Glivec;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined based on the toxicities observed during the first cycle of treatment |  | 4 weeks | 
| Toxicity evaluation graded according to the NCI common toxicity criteria and relationship to the study drug | Results will be tabulated by liver dysfunction group. | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic data | Will be analyzed with ADAPT II, and results will be summarized separately for the four study groups. Additionally, results for pharmacokinetic parameters will be related to the measured level of liver dysfunction in exploratory analyses. | Day 1, 2, 3, 4, 15, 16 | 
| Responses | Will be tabulated by liver dysfunction group, and by dose if appropriate. | Up to 4 years | 
| Child-Pugh Classification | Will be correlated to the toxicities, pharmacokinetic and pharmacodynamic data seen with STI571. | Baseline |