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

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.

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