AALL1122, A Phase 2 Multi-Center Historically - Controlled Study of Dasatinib Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
After diagnosis of acute lymphoblastic leukemia (ALL), subjects will begin standard induction chemotherapy (Block IA). Since the diagnosis of ALL typically requires urgent treatment and it takes up to 10-14 days to determine which patients have Philadelphia chromosome positive (Ph+) ALL, frontline induction chemotherapy (Block IA) will start prior to enrollment in this trial (approximately 2 weeks) and will be based upon the investigator and #146;s institutional standard of care. Enrollment on this study will occur prior to day 15 of Induction Block IA. At day 15, dasatinib treatment shall begin and continue without planned interruption until the completion of therapy (102 weeks). The components of treatment are divided into blocks as follows: Induction IA (4-5 weeks), induction IB (28 days, 4 weeks), recovery period (2 - 4 weeks), consolidation blocks 1, 2, and 3 (21 days, 3 weeks each), recovery period (14 days, 2 weeks), reinduction block 1, including phase IIa and IIb (63 days, 9 weeks), interim maintenance (29 days, 4 weeks, overlaps 2 weeks with end of reinduction block 1), reinduction block 2 (63 days, 9 weeks), and continuation therapy (62 weeks). Chemotherapeutic agents utilized in this regimen include: cyclophosphamide, cytarabine, 6-mercaptopurine, methotrexate, leucovorin, dexamethasone, vincristine, L-asparaginase, hydrocortisone, daunorubicin, ifosfamide, etoposide, doxorubicin, and thioguanine.
Subjects who meet pre-defined criteria may receive a hematopoietic stem cell transplant (HSCT). Subjects will also have the option to receive 12 additional months of post-HSCT dasatinib. Subjects with CNS3 disease at diagnosis will receive cranial irradiation during the Interim Maintenance period.
-- Philadelphia chromosome-positive ALL
a. Documented presence of t(9;22) determined by conventional bone marrow
cytogenetics or BCR-ABL fusion via RT-PCR or FISH (local laboratory)
-- Induction chemotherapy approximately ≤ 14 days according to institutional
standard of care
-- Performance status ≥ 60% (See Appendix 8)
a. Karnofsky for patients >16 years of age and Lansky for patients younger
1-16 years of age.
-- Adequate Liver Function
a. Direct bilirubin ≤ 3 times the upper limit of normal (ULN) for age
b. ALT and AST ≤ 10 times the upper limit of normal (ULN) for age
-- Adequate Renal Function
a. Creatinine clearance or radioisotope GFR ≥ 80 ml/min/1.73m2 or serum
creatinine ≤ 1.5 times the upper limit of normal for age
-- Adequate Cardiac Function
a. QTc < 450 msec on baseline electrocardiogram as measured by the
Frederica or Bazett formula (must be performed within 14 days of study
b. LVEF ≥ 50% by gated radionuclide study/echocardiogram or shortening
fraction ≥ 27% by echocardiogram
-- Males and females, Age > 1 year (365 days) and < 18 (17 years and 364 days) years at diagnosis
-- Women of childbearing potential (WOCBP) and men must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.
-- Women must not be breastfeeding.
-- Sexually active fertile men must use effective birth control if their partners are WOCBP.