Trial Information

A Phase II Study of Dasatinib (Sprycel®) (IND #73969, NSC #732517) as Primary Therapy Followed by Transplantation for Adults >/= 18 Years With Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia by CALGB, ECOG and SWOG

PRIMARY OBJECTIVES:

I. Estimate the disease-free survival (DFS) and overall survival (OS) profiles in newly
diagnosed patients 18 years or older who have Ph+ (BCR/ABL+) ALL receiving sequential
dasatinib followed by allogeneic or autologous HCT or chemotherapy followed by dasatinib
maintenance.

SECONDARY OBJECTIVES:

I. Compare the OS and DFS profiles for each of the three cohorts to those from similar
populations from other studies.

II. Determine the ability of dasatinib to produce or maintain a BCR/ABL-negative status, as
judged by Q-PCR following sequential dasatinib, chemotherapy, and HCT.

III. Determine the feasibility of collecting adequate peripheral blood stem cells for
autologous HCT following dasatinib therapy and assess for residual Ph+ (BCR/ABL+) cells by
Q-PCR.Study the safety and efficacy of autologous HCT following therapy with dasatinib.

IV. Study the safety and efficacy of reduced-intensity preparatory regimen followed by an
allogeneic HCT following induction therapy with dasatinib.

V. Study the safety and efficacy of dasatinib maintenance administered after allogeneic or
autologous HCT or chemotherapy.

VI. Correlate plasma and CSF levels of dasatinib when given orally during induction.

OUTLINE:

REMISSION INDUCTION THERAPY (RIT): Patients receive dasatinib orally (PO) daily continuously
and dexamethasone PO or intravenously (IV) on days 1-7.

EARLY INTENSIFICATION THERAPY: Patients with bone marrow =< 20% blasts are assigned to
cohort A and patients with bone marrow > 20% blasts are assigned to cohort B.

COHORT A: Patients receive dasatinib and dexamethasone as in RIT.

COHORT B: Patients receive dasatinib and dexamethasone as in RIT, and vincristine sulfate IV
and daunorubicin hydrochloride IV on days 1, 8, and 15. Patients who do NOT achieve a
complete response (CR) or CR with incomplete hematologic recovery based on bone marrow
continue on to second induction therapy; patients who achieve a hematologic and morphologic
CR continue on to CNS prophylaxis therapy.

SECOND INDUCTION THERAPY: Patients receive dasatinib and dexamethasone as in RIT,
cyclophosphamide IV on day 1, daunorubicin hydrochloride IV and vincristine sulfate IV on
days 1 and 8, and filgrastim subcutaneously (SC) beginning on day 9 and continuing for >= 7
days or one dose of pegfilgrastim on day 9.

CNS PROPHYLAXIS THERAPY: Patients receive dasatinib PO daily continuously during CNS
prophylaxis therapy; methotrexate intrathecally (IT), vincristine sulfate IV, and
methotrexate IV over 3 hours on days 1, 15, and 29; methotrexate PO every 6 hours for a
total of 4 doses each on days 1-2, 15-16, and 29-30; leucovorin calcium IV on days 2, 16,
and 30; and leucovorin PO calcium every 6 hours for a total of 8 doses each on days 3-4,
17-18, and 31-32.

TRANSPLANTATION OR ALTERNATIVE CHEMOTHERAPY AND MAINTENANCE THERAPY: Patients aged 50-70
years with an HLA-matched related or unrelated donor are assigned to allogeneic
transplantation, patients aged 50-70 years without an HLA-matched related or unrelated donor
are assigned to autologous transplantation, and patients aged > 70 years or who are not
transplantation candidates are assigned to alternative chemotherapy.

ALLOGENEIC TRANSPLANTATION: Patients receive fludarabine phosphate IV over 30 minutes and
alemtuzumab IV over 30 minutes on days -7 through -3 and melphalan IV over 30 minutes on day
-2. Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0.
Patients then receive filgrastim SC beginning on day 1 and continuing until count recovery
and tacrolimus IV or PO beginning on day -2 and beginning to taper on day 100 (for matched
related donors) or day 180 (for mismatched related or unrelated donors). Beginning on day
30, patients receive dasatinib PO daily as maintenance therapy. Treatment continues for >=
12 months in the absence of disease progression.

AUTOLOGOUS TRANSPLANTATION:

MOBILIZATION: Patients receive etoposide phosphate IV continuously on days 1-4, high-dose
cytarabine IV over 2 hours every 12 hours for a total of 8 doses on days 1-4, and filgrastim
SC once or twice daily beginning on day 14 and continuing until peripheral blood stem cell
collection is complete or WBC > 50,000/μL.

LEUKAPHERESIS: Patients undergo leukapheresis beginning when WBC > 10,000/μL for a target
collection of >= 5 x 10^6 CD34+ cells/kg. After completion of stem cell collection, patients
receive dasatinib PO twice daily until 3 days before transplantation.

TRANSPLANTATION: Beginning >= 4 weeks after recovery from toxicity related to previous
treatment, patients receive melphalan IV over 30 minutes on days -2 and -1. Patients undergo
autologous PBSCT on day 0. Patients then receive filgrastim SC beginning on day 0 and
continuing until count recovery.

MAINTENANCE THERAPY: Beginning on day 30, patients receive dasatinib PO once daily.
Treatment continues for >= 12 months in the absence of disease progression.

ALTERNATIVE CHEMOTHERAPY: Beginning 3-10 days after completion of CNS prophylaxis therapy,
patients receive etoposide phosphate IV continuously on days 1-4, high-dose cytarabine IV
over 2 hours every 12 hours for a total of 8 doses on days 1-4, and filgrastim SC once or
twice daily beginning on day 14 and continuing until count recovery.

MAINTENANCE THERAPY: Patients receive dasatinib PO once daily beginning on day 30. Patients
also receive vincristine sulfate IV every 4 weeks, dexamethasone for 5 days every 4 weeks,
mercaptopurine PO once daily, and methotrexate PO once weekly. Treatment continues for >= 12
months in the absence of disease progression.

NOTE: Patients with CNS leukemia or testicular disease may receive additional treatment.

After completion of study treatment, patients are followed up every month for 1 year, every
3 months for 2 years, every 6 months for 2 years, and every year for 5 years.