Dasatinib in Treating Patients With Early Chronic Phase Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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This randomized phase II trial studies how well dasatinib works in treating patients with early chronic phase chronic myelogenous leukemia. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVE: I. To estimate the proportion of patients with previously-untreated chronic phase chronic myelogenous leukemia (CML) attaining major molecular response by 12 months of treatment with dasatinib. SECONDARY OBJECTIVES: I. To estimate the proportion of patients with Philadelphia chromosome (Ph)-positive early chronic phase CML achieving a complete cytogenetic response after dasatinib therapy. II. To evaluate the durations of hematologic, cytogenetic and molecular response to dasatinib. III. To define the time to progression and overall survival for patients with CML in early chronic phase treated with dasatinib. IV. To evaluate the toxicity profile of dasatinib in patients with CML in early chronic phase. V. To evaluate the probability of developing c-abl oncogene 1, non-receptor tyrosine kinase (ABL) mutations for patients with CML in early chronic phase treated with dasatinib. VI. To analyze differences in response rates and in prognosis within different risk groups and patient characteristics. VII. To assess correlation between trough concentration and pleural effusion. VIII. To assess the inhibition of platelet function and assess correlation between drug concentration and degree of platelet inhibition. IX. To assess the effect of dasatinib therapy in bone metabolism as determined by changes in serum alkaline phosphatase (bone specific isoenzyme), and trabecular bone volume. X. To evaluate symptom burden in patients with CML receiving dasatinib. EXPLORATORY OBJECTIVE: I. To investigate the plasma/serum levels of specific micro ribonucleic acids (miRNAs) in CML patients receiving dasatinib as initial therapy for CML in chronic phase (CP). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive dasatinib orally (PO) once daily (QD) for up to 15-18 years. ARM B: Patients receive dasatinib PO twice daily (BID) for up to 15-18 years. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Official Title
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Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) With Dasatinib (BMS-354825)

Conditions
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Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Ph-positive or Bcr-Abl positive CML in early chronic phase CML (i.e., time from diagnosis </= 12 months). Except for hydroxyurea, patients must have received no or minimal prior therapy, defined as <1 month (30 days) of prior IFN-alpha (with or without ara-C) and/or an FDA approved TKI Continued from above #1: Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has been historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis, and when present at diagnosis may not impact the prognosis at all. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study Age >/= 16 years (Age >18 years to participate in optional symptom burden assessment) ECOG performance of 0-2 5) Adequate end organ function, defined as the following: total bilirubin <1.5 x ULN, SGPT <2.5x ULN, creatinine <1.5x ULN Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital. 7) Reliable telephone access to receive calls from an interactive voice response system (IVR) (only applicable to patients who will participate in optional symptom burden assessment) Exclusion Criteria: New York Heart Association (NYHA) cardiac class 3-4 heart disease Cardiac Symptoms: Patients meeting the following criteria are not eligible unless cleared by Cardiology: Uncontrolled angina within 3 months; Diagnosed or suspected congenital long QT syndrome; Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) on both the Fridericia and Bazett's correction; Uncontrolled hypertension; History of significant bleeding disorder unrelated to cancer, including: Cont: Diagnosed congenital bleeding disorders (von Willebrand's disease) Diagnosed acquired bleeding disorder w/in 1 year (acquired anti-factor VIII antibodies);Pts currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes including: quinidine, procainamide, disopyramide amiodarone, sotalol, ibutilide, dofetilide erythromycins, clarithromycin chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders Women of pregnancy potential must practice 2 effective methods of birth control during the course of the study, in a manner such that risk of failure is minimized.Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Continued: Women must continue birth control for the duration of the trial and at least 3 months after the last dose of study drug; Pregnant or breast-feeding women are excluded; All WOCBP MUST have a negative pregnancy test prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. Patients in late chronic phase (i.e., time from diagnosis to treatment >12 months), accelerated or blast phase are excluded. The definitions of CML phases are as follows: a) Early chronic phase: time from diagnosis to therapy </= 12 months; Late chronic phase: time from diagnosis to therapy > 12 months, b) Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow, c) Accelerated phase CML: presence of any of the following features: Peripheral or marrow blasts 15% or more, Peripheral or marrow basophils 20% or more, Thrombocytopenia < 100 x 10^9/L unrelated to therapy, Documented extramedullary blastic disease outside liver or spleen

Ages Eligible for Study
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Minimum Age: 16 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (once daily dasatinib)<br>Patients receive dasatinib PO QD for up to 15-18 years. | Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm B (twice daily dasatinib)<br>Patients receive dasatinib PO BID for up to 15-18 years. | Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of major molecular response |  | 12 months | 
| Toxicity rate |  | 12 months |