Imatinib Mesylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia Who Have Received Chemotherapy

Study Overview
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Brief Summary
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RATIONALE: Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well imatinib mesylate works in treating patients with newly diagnosed acute myeloid leukemia who have received chemotherapy.

Detailed Description
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OBJECTIVES: Primary To determine whether adding imatinib mesylate as maintenance therapy improves progression-free survival in patients with c-kit positive acute myeloid leukemia (AML) compared with historical controls. Secondary To assess the feasibility of administering imatinib mesylate as maintenance therapy after the completion of induction and consolidation therapy in these patients. To evaluate potential mechanisms of relapse/resistance in c-kit positive AML by examining multidrug resistance gene expression and AF1q gene expression and to determine whether these levels correlate with c-kit expression. OUTLINE: This is a multicenter study. Patients receive oral imatinib mesylate once daily for up to 12 months. Bone marrow and peripheral blood are collected at baseline. Laboratory endpoints are evaluated by flow cytometry; mutation and gene analysis by PCR.

Official Title
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A Phase 2 Study of Imatinib Mesylate (Gleevec) as Maintenance Therapy After Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed C-kit Positive Acute Myeloid Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: imatinib mesylate
* Genetic: gene expression analysis
* Genetic: mutation analysis
* Genetic: polymerase chain reaction
* Other: flow cytometry
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Diagnostic bone marrow aspirate/ biopsy or peripheral blood confirming AML. At the time of diagnosis, patients must have c-kit (also known as CD117) positive AML (20% or more of the blasts express c-kit[CD117]). A flow scattergram (from the diagnostic AML specimen) must be available to calculate a c-kit MFI. Patients must have received standard induction chemotherapy with ADE (cytarabine, daunorubicin, and etoposide) or with 7+3 (7 days of cytarabine continuous infusion and 3 days of an anthracycline (idarubicin, daunorubicin, or mitoxantrone). Patients with persistent leukemia on a Day 10-28 marrow may have received a second course of chemotherapy. After the completion of induction therapy, patients must have attained a complete remission based on blood count recovery (neutrophil count ≥ 1,000/µL, platelet count ≥ 100,000/µL), and bone marrow aspirate and biopsy (< 5% myeloblasts). For patients < 60 years of age, patients must have received at least 2 courses of post-remission therapy with at least intermediate dose (400 mg/m2/day). *Patients with t(8;21) or inversion 16 at the time of diagnosis must have received at least 2 courses of high dose cytarabine. For patients > or = 60 years of age, patients must have received 1 course of post-remission therapy (the type of chemotherapy will not be specified). Patients must be registered on this study (maintenance Imatinib mesylate) within 60 days of the last dose of post-remission therapy. A bone marrow aspirate and/or biopsy must be done within 3 weeks of registration documenting CR. Women of childbearing potential and sexually active males must use an effective method of contraception. Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug. ECOG Performance Status 0-2. Creatinine must be ≤ 1.5 x upper limit of normal. Total bilirubin must be ≤ 2 mg/dl and AST and ALT must be ≤ 2 times the upper limit of normal. Previous treatment-related toxicities must have resolved to ≤ Grade 1 excluding alopecia. Written, voluntary informed consent. EXCLUSION CRITERIA Acute promyelocytic leukemia. Patients with an autologous or allogeneic bone marrow transplant. History of HIV. Pregnant or breast-feeding. Serious or poorly controlled medical conditions that would interfere with the protocol. At the time of study entry, any medications which could significantly interact with imatinib mesylate must be discontinued. Patients with active extramedullary disease are not eligible. Patient has received any other investigational agents within 28 days of first day of study drug dosing. Patient is < 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study) Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis). Patient previously received radiotherapy to ≥ 25 % of the bone marrow Patient had a major surgery within 2 weeks prior to study entry. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Ages Eligible for Study
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Minimum Age: 18 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: Imatinib Mesylate<br> | Drug: imatinib mesylate<br>* Patients will receive treatment with imatinib mesylate at a dose of 600 mg by mouth once a day for 12 months. The study dose can be split but the dose of 600 mg must be given within a 12 hour period.<br>* Other names: Gleevec;Genetic: gene expression analysis<br>* Multidrug resistance genes: These studies will include: MDR1, MRP1, LRP, and BCRP. Bone marrow blocks or cut slides will be sent to Duke on the diagnostic AML samples. DNA will be eluted from the samples so that the above genes can be analyzed.<br>* Other names: MRD;Genetic: mutation analysis<br>* FLT3 mutation analysis (on bone marrow aspirate or peripheral blood): These analyses will be performed by pathology at the time of diagnosis, at the participating institution. Samples will be analyzed for the FLT3 ITD and/or D835 mutation by PCR.<br>* Other names: FLT3;Genetic: polymerase chain reaction<br>* AF1q gene analysis (on bone marrow aspirate)<br>* Other names: AF1Q gene analysis;Other: flow cytometry<br>* C-kit MFI on AML samples will be calculated by using a CD45/ orthogonal light scatter gate to isolate blasts. The MFI will be calculated as the c-kit mean channel number (MCN) of the blasts/ MCN auto fluorescence.<br>* Other names: C-kit MFI, CD117;Procedure: biopsy<br>* Diagnostic bone marrow biopsy/aspirate must be done within 3 weeks of registration documenting complete remission<br>* Other names: bone marrow biopsy/aspirate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival (PFS) for Patients Less Than 60 Years of Age | PFS measured from the date of Complete Response (CR) to the date of relapse or death. Progression defined as any of the following event: progression to accelerated phase or blast crisis, death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management This outcome will be reported as median progression-free survival in months for participants less than 60 years of age. | up to 5 years from the End of Treatment | 
| Progression-free Survival for Patients 60 Years of Age and Older | Progression free survival will be measured from the date of Complete Response (CR) to the date of relapse or death. | up to 5 years from the End of Treatment | 
| Percent of Participants Less Than 60 Years of Age With PFS at 8 and 13 Months Post-treatment | Percent of participants less than 60 years of age with PFS at 8 and 13 months post-treatment | at 8 and 13 months after treatment. | 
| Percent of Participants 60 Years of Age or Older With PFS at 8 and 13 Months Post-treatment | Percent of participants 60 years of age or older with PFS at 8 and 13 months post-treatment | at 8 and 13 months after treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as Measured by NCI CTC v. 3.0 | Number of patients (%) experiencing an adverse event See adverse events section for details | 13 months from start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myelomonocytic leukemia (M4), adult acute megakaryoblastic leukemia (M7), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute myeloid leukemia in remission