Imatinib Mesylate in Treating Patients With Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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This phase II trial is studying imatinib mesylate to see how well it works in treating patients with chronic myelogenous leukemia. Imatinib mesylate may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth

Detailed Description
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OBJECTIVES: I. Determine the response rate in patients with Philadelphia chromosome positive chronic phase chronic myelogenous leukemia treated with imatinib mesylate. II. Determine the disease-free survival of patients treated with this drug. III. Determine the pharmacokinetics of this drug in these patients. IV. Determine the toxic effects of this drug in these patients. V. Determine the rates of hematological, cytogenetic, and molecular response and time to response in patients treated with this drug. OUTLINE: This is a multicenter study. Patients are stratified according to disease (chronic myelogenous leukemia [CML] in first chronic phase after failing interferon therapy or demonstrating intolerance to interferon [closed to accrual as of 12/05/03] vs CML relapsing after stem cell transplantation or in second or subsequent chronic phase [closed to accrual as of 7/29/05] vs newly diagnosed CML in first chronic phase with no prior treatment [closed to accrual as of 7/29/05] vs newly diagnosed CML in first chronic phase with no prior treatment). Patients receive oral imatinib mesylate once daily on days 1-28. Courses repeat every 28 days for 1 year in the absence of disease progression or unacceptable toxicity. Patients who fail to achieve a complete hematologic response after 3 courses or a partial or complete cytogenic response after 6 courses are removed from the study. PROJECTED ACCRUAL: A total of 109 patients (30 for stratum I [closed to accrual as of 12/05/03] and stratum II [closed to accrual as of 7/29/05], 34 for stratum III [closed to accrual as of 7/29/05], and 45 for stratum IV) will be accrued for this study within 2 years.

Official Title
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A Phase II Study of Gleevec in Ph+ Chronic Phase Chronic Myelogenous Leukemia

Conditions
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Childhood Chronic Myelogenous Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: imatinib mesylate
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Philadelphia chromosome positive (Ph+) chronic phase chronic myelogenous leukemia (CML) Stratum I (closed to accrual as of 12/05/03): CML in first chronic phase with resistance to interferon alfa (IFN-A) therapy defined as one of the following: WBC count at least 20,000/mm^3 after at least 3 months of treatment with an IFN-A-containing regimen Rising WBC count (at least 100% increase to a level of at least 20,000/mm^3) by two samples at least two weeks apart while receiving treatment with an IFN-A-containing regimen At least 66% Ph+ cells in bone marrow after 1 year of IFN-A therapy At least 30% increase in Ph+ cells in bone marrow after IFN-A-induced cytogenetic response while continuing to receive IFN-A therapy Intolerance to interferon therapy defined as more than two grade 2 toxic effects or any grade 3 toxic effect related to interferon therapy, except grade 3 fever, that is persistent beyond the first 28-day course of therapy and unresponsive to standard supportive care interventions Stratum II (closed to accrual as of 7/29/05): CML recurring after stem cell transplantation or in second or subsequent chronic phase No molecular relapse (only evidence is detection of bcr-abl rearrangement with normal bone marrow and blood morphology and normal standard cytogenetic analysis) Stratum III (closed to accrual as of 7/29/05): Newly diagnosed CML in first chronic phase with no prior treatment except hydroxyurea Stratum IV: Newly diagnosed CML in first chronic phase with no prior treatment except hydroxyurea No accelerated or blast phase defined as one or more of the following: WBC doubling time less than 5 days Chloroma Medullary fibrosis More than 10% blasts in peripheral blood or bone marrow More than 20% promyelocytes in peripheral blood or bone marrow More than 20% basophils and eosinophils in peripheral blood Performance status - ECOG 0-2 At least 8 weeks See Disease Characteristics Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram Bilirubin no greater than 1.5 times normal ALT less than 3.0 times normal Albumin greater than 2 g/dL Creatinine no greater than 1.5 times normal Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No uncontrolled infection No CNS toxicity greater than grade 2 See Disease Characteristics No prior immunotherapy (for patients in stratum III [closed to accrual as of 7/29/05] and stratum IV only) At least 3 months since prior stem cell transplantation (SCT) (patients with allogeneic SCT must have no active graft-versus-host disease [GVHD] and have stable use of steroids) (for patients in stratum II only ) At least 1 week since prior growth factors At least 1 week since prior biologic therapy, including interferon alfa (for patients in stratum I [closed to accrual as of 12/05/03] and stratum II only) Recovered from prior immunotherapy No concurrent immunomodulating agents See Disease Characteristics No prior chemotherapy (for patients in stratum III [closed to accrual as of 7/29/05] and stratum IV only) At least 6 weeks since prior busulfan or nitrosoureas At least 7 days since prior hydroxyurea At least 7 days since prior low-dose cytarabine (less than 30 mg/m^2 every 12 to 24 hours) At least 14 days since prior moderate-dose cytarabine (100-200 mg/m^2 for 5 to 7 days) At least 28 days since prior high-dose cytarabine (1-3 g/m^2 every 12 to 24 hours for 6 to 12 doses) At least 21 days since all other cytotoxic chemotherapy Recovered from prior chemotherapy No concurrent chemotherapy No concurrent steroids other than for controlled GVHD in patients with prior allogeneic SCT No prior radiotherapy (for patients in stratum III [closed to accrual as of 7/29/05] and stratum IV only) At least 2 weeks since prior local palliative (small port) radiotherapy* At least 3 months since prior craniospinal radiotherapy or radiotherapy to 50% or more of pelvis* At least 6 weeks since prior substantial bone marrow radiotherapy* Recovered from prior radiotherapy No prior imatinib mesylate No concurrent enzyme-activating anticonvulsants No concurrent warfarin No concurrent naturopathic agents or herbal medicines No other concurrent investigational agents Concurrent low-molecular weight heparin allowed

Ages Eligible for Study
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Maximum Age: 21 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 once daily on days 1-28. Courses repeat every 28 days for 1 year in the absence of disease progression or unacceptable toxicity. Patients who fail to achieve a complete hematologic response after 3 courses or a partial or complete cytogenic response after 6 courses are removed from the study. | Drug: imatinib mesylate<br>* Given orally<br>* Other names: Glivec;Other: laboratory biomarker analysis<br>* Correlative studies<br>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 |
| --- | --- | --- |
| Response rate |  | Up to 5 years | 
| Disease-free survival |  | Up to 5 years | 
| Toxicities graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to achieve hematological cytogenetic and molecular response | Studied in a multivariate model using a Cox proportional hazards regression model. | Up to 12 months | 
| Event free survival |  | Up to 5 years |