Combination Chemotherapy and Dasatinib in Treating Participants With Philadelphia Positive or BCR-ABL Positive Acute Lymphoblastic Leukemia.
Combination Chemotherapy and Dasatinib in Treating Participants With Philadelphia Positive or BCR-ABL Positive Acute Lymphoblastic Leukemia.
This phase II trial studies how well combination chemotherapy and dasatinib works in treating
 participants with Philadelphia-positive or B-cell receptor-ABL positive acute lymphoblastic
 leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, doxorubicin,
 dexamethasone, methotrexate, and cytarabine, work in different ways to stop the growth of
 tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them
 from spreading. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes
 needed for cell growth. Giving chemotherapy in combination with dasatinib may work better in
 treating participants with Philadelphia-positive or BCR-ABL positive acute lymphoblastic
 leukemia.
PRIMARY OBJECTIVES:

 I. To evaluate the clinical efficacy (event-free survival) of an intensive short-term
 chemotherapy regimen (Hyper- cyclophosphamide, vincristine, doxorubicin, dexamethasone [CVAD]
 program) given in combination with the tyrosine kinase inhibitor dasatinib for Philadelphia
 (Ph)-positive and/or B-cell receptor BCR-ABL-positive acute lymphoblastic leukemia (ALL).

 II. To evaluate other clinical efficacy (overall response rate and survival) and safety of an
 intensive short-term chemotherapy regimen (Hyper-CVAD program) given in combination with the
 tyrosine kinase inhibitor dasatinib for Philadelphia (Ph)-positive and/or BCR-ABL-positive
 acute lymphoblastic leukemia (ALL).

 OUTLINE:

 HYPER-CVAD THERAPY: Participants receive cyclophosphamide intravenously (IV) twice daily
 (BID) over 3 hours on days 1-3, vincristine IV over 30 minutes on days 4 and 11, and
 doxorubicin IV over 24-48 hours on day 4. Participants also receive dexamethasone orally (PO)
 or IV over 30 minutes on days 1-4 and 11-14, and dasatinib PO once daily (QD) on days 1-14 of
 course 1 and on days 1-21 for subsequent courses. Courses repeat every 21 days for up to 4
 odd courses (1, 3, 5, and 7) in the absence of disease progression or unacceptable toxicity.

 METHOTREXATE PLUS CYTARABINE: Participants receive methotrexate IV over 24 hours on day 1,
 dasatinib PO on days 1-21, and cytarabine IV BID over 2 hours on days 2 and 3. Courses repeat
 every 21 days for up to 4 even courses (2, 4, 6, and 8) in the absence of disease progression
 or unacceptable toxicity.

 MAINTENANCE THERAPY: Participants receive vincristine IV over 30 minutes on day 1, prednisone
 PO on days 1-5, and dasatinib PO BID. Courses repeat every 28 days for up to 2 years in the
 absence of disease progression or unacceptable toxicity. During courses 6 and 13,
 participants may receive an additional course of hyper-CVAD therapy.

 After completion of study treatment, participants are followed for up to 12 months.
Inclusion Criteria:

 -  Diagnosis of one of the following: Previously untreated Ph-positive acute
 lymphoblastic leukemia (ALL) (either t(9;22) and/or BCR-ABL positive) (includes
 patients initiated on first course of hyper-CVAD before cytogenetics known). These
 groups will be analyzed separately. After 1-2 courses of chemotherapy with or without
 imatinib mesylate (Gleevec). If they achieved complete response (CR), they are
 assessable only for event-free and overall survival, or if they failed to achieve CR,
 they are assessable for CR, event-free, and overall survival. Patients with relapsed
 Ph-positive ALL or lymphoid blast phase of chronic myelogenous leukemia (CML)

 -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

 -  Adequate liver function (bilirubin less than or equal to 3.0 mg/dl, unless considered
 due to tumor), and renal function (creatinine less than or equal to 3.0 mg/dl, unless
 considered due to tumor)

 -  Adequate cardiac function as assessed clinically

 -  Signed informed consent

 Exclusion Criteria:

 -  Active serious infection not controlled by oral or intravenous antibiotics

 -  Treatment with any investigational antileukemic agents or chemotherapy agents in the
 last 7 days before study entry, unless full recovery from side effects has occurred or
 patient has rapidly progressive disease judged to be life-threatening by the
 investigator

 -  Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
 squamous cell carcinoma) that in the investigator's opinion will shorten survival to
 less than 1 year

 -  Active grade III-V cardiac failure as defined by the New York Heart Association
 criteria. Uncontrolled angina, or myocardial infarction (MI) within 6 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 corrected QT (QTc) interval on
 pre-entry electrocardiogram (> 470 msec). Patients currently taking drugs that are
 generally accepted to have a risk of causing Torsades de Pointes (unless these can be
 changed to acceptable alternatives)

 -  Prior history of treatment with dasatinib

 -  Pregnant and lactating women will not be eligible; women of childbearing potential
 should have a negative pregnancy test prior to entering on the study and be willing to
 practice methods of contraception. Women do not have childbearing potential if they
 have had a hysterectomy or are postmenopausal without menses for 12 months. In
 addition, men enrolled on this study should understand the risks to any sexual partner
 of childbearing potential and should practice an effective method of birth control

 -  History of significant bleeding disorder unrelated to cancer, including:

 -  Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

 -  Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
 VIII antibodies)

 -  Patients with documented significant pleural or pericardial effusions unless they are
 thought to be secondary to their leukemia