Imatinib Mesylate or Dasatinib in Treating Patients With Previously Untreated Chronic Phase Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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This randomized phase IIB trial studies imatinib mesylate at two different doses and dasatinib to see how well they work in treating patients with previously untreated chronic phase chronic myelogenous leukemia. Imatinib mesylate or 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 OBJECTIVES: I. To compare the molecular response rates, as measured by the decrease in breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) transcripts after 12 months of treatment, in patients with previously untreated chronic myelogenous leukemia (CML) in chronic phase who are treated with either dasatinib 100 mg/day or imatinib (STI571, Gleevec) (imatinib mesylate) 400 mg/day. II. To test whether increasing the dose of imatinib (STI571, Gleevec®) from 400 mg/day to 800 mg/day increases the rate of molecular response, as measured by the decrease in BCR-ABL transcripts after 12 months of treatment, in patients with previously untreated CML in chronic phase. III. To estimate rates of cytogenetic and hematologic responses to imatinib 400 mg/day, imatinib 800 mg/day, and dasatinib 100 mg/day. IV. To evaluate in a preliminary manner the prognostic effects of derivative (der)(9) and der(22) chromosomal deletions for response in CML patients treated with imatinib and dasatinib. V. To investigate in a preliminary manner changes in gene expression at relapse or progression compared to pre-treatment. VI. To estimate the frequency and severity of toxicities of the three treatment regimens. VII. To evaluate, in a preliminary manner, the overall survival and relapse-free survival of patients treated with these regimens. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive imatinib mesylate orally (PO) once daily (QD). Treatment repeats every 4 weeks for up to 5 years in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive imatinib mesylate PO twice daily (BID). Treatment repeats every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity. ARM III: Patients receive dasatinib PO BID. Treatment repeats every 4 weeks for up to 5 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 15 years.

Official Title
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A Phase IIb Study of Molecular Responses to Imatinib, at Standard or Increased Doses, or Dasatinib (BMS-354825) (NSC-732517) for Previously Untreated Patients With Chronic Myelogenous Leukemia (CML) in Chronic Phase

Conditions
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Chronic Myeloid Leukemia, BCR-ABL1 Positive

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Imatinib Mesylate
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have CML in chronic phase based on bone marrow aspiration and biopsy and peripheral blood counts obtained within 28 days before registration Patients must be registered on this study within 180 days after the date of first being diagnosed with CML, based on a cytogenetic or molecular analysis of peripheral blood or bone marrow, demonstrating the presence of the Philadelphia chromosome or variants of the (9;22) translocation or testing positive for Bcr-Abl by real time-polymerase chain reaction (RT-PCR); patients may have secondary chromosomal abnormalities in addition to the Philadelphia chromosome and remain eligible Patients must have Zubrod performance status 0-2 Patients must not have received prior treatment for CML with the exception of hydroxyurea and/or anagrelide Patients must not have received any prior chemotherapy regimen for peripheral blood stem cell mobilization; (prior collection of unmobilized peripheral blood stem cells is permitted) Serum bilirubin =< 2.0 x the institutional upper limit of the normal (IULN) Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) or serum glutamate pyruvate transaminase (SGPT)/alanine transaminase (ALT) =< 2.0 x the IULN Patients (Southwestern Oncology Group [SWOG] institutions only) must be registered on SWOG-9007, Cytogenetic Studies in Leukemia Patients; collection of the pretreatment bone marrow specimen must be completed within 28 days prior to registration; the pretreatment bone marrow specimen must be submitted to an approved Southwest Oncology Group Cytogenetics Laboratory for cytogenetic analysis as described, and an aliquot of the bone marrow (or peripheral blood if the marrow aspiration is a dry tap) must be submitted for fluorescent in situ hybridization (FISH) analysis; note that protocol SWOG-9007 also requires submission of bone marrow specimens at the time of progression to the accelerated or blastic phase of CML or the loss of complete hematologic response and every six months while the patient is on this study Patients (SWOG institutions only) must be registered on S9910, Leukemia Centralized Reference Laboratories and Tissue Repositories, Ancillary; specimens of peripheral blood and bone marrow must be submitted to the Southwest Oncology Group Lymphoid Leukemia and CML Centralized Laboratory in Seattle, Washington; collection of pretreatment blood and marrow specimens must be completed within 28 days prior to registration; note that this study also requires submission of peripheral blood and bone marrow specimens at various times after entry into the study Patients must not have undergone major surgery within 28 days before registration, and must have fully recovered from any other prior major surgery Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, cervical carcinoma in situ, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for five years Patients must have an electrocardiogram (ECG) within 42 days prior to registration, and must not have any of the following cardiac symptoms prior to entry on study: Uncontrolled angina, congestive heart failure or myocardial infarction (MI) within 6 months of study entry 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 corrected QT (QTc) interval on pre-entry electrocardiogram (> 450 msec) Uncontrolled hypertension Patients must not have a history of significant bleeding disorder unrelated to cancer, including: Congenital bleeding disorders (e.g., von Willebrand's disease) Acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines At the time of patient registration, the treating institution's name and identification (ID) number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (QD imatinib mesylate)<br>Patients receive imatinib mesylate PO QD. Treatment repeats every 4 weeks for up to 5 years in the absence of disease progression or unacceptable toxicity. | Drug: Imatinib Mesylate<br>* Given PO<br>* Other names: STI571;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm II (BID imatinib mesylate)<br>Patients receive imatinib mesylate PO BID. Treatment repeats every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity. | Drug: Imatinib Mesylate<br>* Given PO<br>* Other names: STI571;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm III (dasatinib)<br>Patients receive dasatinib PO BID. Treatment repeats every 4 weeks for up to 5 years in the absence of disease progression or unacceptable toxicity. | Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular Response Rate at 12 Months | Median value of baseline bcr-abl/bcr ratio from pretreatment was used as the baseline value for assessing each patient's molecular response. Molecular response criteria were: 1) not failed treatment on or before 12-month evaluation; 2) met criteria for hemalotogic response; 3) bcr-abl/bcr ration at 12-months must be 10,000 times smaller than the pretreatment ratio. | pretreatment and after 12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Response | Hematologic response assesses whether patients' blood counts return to normal | 1 month after starting treatment | 
| 2-year Overall Survival (OS) | Overall survival was measured from the date of registration to study until death from any cause with observations censored at the date of last contact for patients last known to be alive. | Every three months for the first year, every six months in years 2 and 3, and annually for years 4 and 5 | 
| Two Year Relapse-free Survival | Relapse-free survival is measured from the date of documented (possibly unconfirmed) hematologic complete remission until loss of hematologic complete remission or death from any cause. Observations are censored at the date of last contact for patients last known to be alive with report of loss of hematologic complete remission. | every 3 months for the first year, every six months for years 2 and 3, annually for years 4 and 5 | 
| Toxicity | Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event | Patients were assessed for adverse events monthly every 4 weeks for the first year, every 6 months for years 2 and 3, and annually for years 4 and 5. |