Trial Information

A Children's Oncology Group Pilot Study for the Treatment of Very High Risk Acute Lymphoblastic Leukemia in Children and Adolescents (Imatinib (STI571, GLEEVEC) NSC#716051/IND#61135)

PRIMARY OBJECTIVES:

I. Determine the feasibility of treatment with intensified chemotherapy, in terms of
toxicity and patient accrual, in children with very high-risk acute lymphoblastic leukemia.

II. Determine the feasibility and efficacy of following intensified chemotherapy with
allogeneic hematopoietic stem cell transplantation in patients with HLA-matched related
donors.

III. Determine the toxicity of imatinib mesylate in combination with intensified
chemotherapy in Philadelphia chromosome-positive patients.

IV. Determine the event-free survival of patients treated with this regimen. V. Determine
whether minimal residual disease (MDR) after induction therapy and prior to intensification
therapy can predict relapse in these patients.

VI. Determine whether MDR after intensification is prognostically significant. VII.
Determine whether gene expression patterns predict disease recurrence or response to
imatinib mesylate.

OUTLINE: This is a multicenter study. This is also a dose-escalation study of imatinib
mesylate in Philadelphia chromosome-positive (Ph+) patients. Patients are stratified
according to Philadelphia chromosome (Ph) status (Ph-positive vs Ph-negative or
indeterminate), hypodiploidy (yes vs no), MLL translocation (11q23) AND slow early response
to prior induction therapy (yes vs no), and failed prior induction therapy (yes vs no).

Cohorts of 8-12 Ph+ patients receive escalating doses of imatinib mesylate, according to the
guidelines for each treatment block of this study, until the maximum tolerated dose (MTD)
for each treatment combination is determined. The MTD is defined as the dose preceding that
at which 2 of 6 patients experience dose-limiting toxicity. An additional 35 patients are
treated at the MTD.

CONSOLIDATION BLOCK 1: Patients receive etoposide IV over 1 hour followed by ifosfamide IV
over 1.5 hours on days 1-5. Patients also receive methotrexate intrathecally on day 1 and
filgrastim (G-CSF) subcutaneously (SC) on days 6-15 or until blood counts recover. Patients
with CNS 2/3 at diagnosis also receive intrathecal triple therapy comprising methotrexate,
hydrocortisone, and cytarabine (ITT) on days 8 and 15. Ph+ patients in cohorts 3, 4, and 5
receive oral imatinib mesylate on days 1-21. Within 4 days of starting consolidation
therapy, patients with biopsy-proven testicular leukemia undergo radiotherapy daily for 12
days.

CONSOLIDATION BLOCK 2: Patients receive high-dose methotrexate IV over 24 hours and ITT on
day 1 followed by high-dose cytarabine IV over 3 hours, every 12 hours on days 2 and 3.
Patients also receive leucovorin calcium IV or orally every 6 hours for 3 doses beginning on
day 2, and G-CSF SC on days 4-13 or until blood counts recover. Ph+ patients in cohorts 2,
3, 4, and 5 receive oral imatinib mesylate as in consolidation block 1. Patients undergoing
allogeneic hematopoietic stem cell transplantation (HSCT) proceed to preparative
chemotherapy. All other patients proceed to reinduction block 1.

REINDUCTION BLOCK 1: Patients receive vincristine IV on days 1, 8, and 15; daunorubicin IV
on days 1 and 2; cyclophosphamide IV over 30 minutes, every 12 hours on days 3 and 4;
pegaspargase intramuscularly (IM) on day 4; and ITT on days 1 and 15. Patients also receive
oral dexamethasone twice daily on days 1-7 and 15-21 and G-CSF SC on days 5-14 or until
blood counts recover. Ph+ patients in cohorts 2, 4, and 5 receive imatinib mesylate as in
consolidation block 1.

INTENSIFICATION BLOCK 1: Patients receive high-dose methotrexate IV over 24 hours on days 1
and 15 and ITT on days 1 and 22. Patients also receive leucovorin calcium IV or orally every
6 hours for 3 doses beginning on days 2 and 16. Patients receive etoposide IV over 2 hours
followed by cyclophosphamide IV over 30 minutes on days 22-24; G-CSF SC on days 27-36 or
until blood counts recover; high-dose cytarabine IV over 3 hours, every 12 hours on days 43
and 44; and asparaginase IM on day 44. Ph+ patients in cohorts 1 and 4 receive oral imatinib
mesylate on days 43-63, and patients in cohort 5 receive oral imatinib mesylate on days
1-56.

REINDUCTION BLOCK 2: Patients receive vincristine, daunorubicin, cyclophosphamide,
pegaspargase, dexamethasone, and G-CSF as in reinduction block 1. Patients also receive ITT
on days 1 and 15. Ph+ patients receive imatinib mesylate as in reinduction block 1.

INTENSIFICATION BLOCK 2: Patients receive methotrexate, leucovorin calcium, etoposide,
cyclophosphamide, filgrastim, cytarabine, and asparaginase as in intensification block 1.
Ph+ patients receive imatinib mesylate as in intensification block 1.

MAINTENANCE 1: Patients receive high-dose methotrexate IV and leucovorin calcium as in
consolidation block 2. Patients also receive ITT and vincristine IV on days 1 and 29; oral
dexamethasone twice daily on days 1-5 and 29-33; oral methotrexate on days 8, 15, and 22;
oral mercaptopurine on days 8-28; etoposide IV over 2 hours followed by cyclophosphamide IV
over 30 minutes on days 29-33; and G-CSF SC on days 34-43. Ph+ patients in cohorts 1-4
receive oral imatinib mesylate on days 29-49 and patients in cohort 5 receive oral imatinib
mesylate on days 1-56. Treatment repeats every 8 weeks for 4 courses in the absence of
disease progression or unacceptable toxicity.

MAINTENANCE 2: Patients receive vincristine and dexamethasone as in maintenance 1. Beginning
on day 1, patients undergo cranial radiotherapy once daily, 5 days a week, for approximately
2 weeks. Patients also receive oral methotrexate on days 8, 15, 22, 29, 36, 43, and 50 and
oral mercaptopurine on days 11-56. Ph+ patients in cohorts 1-4 receive oral imatinib
mesylate on days 1-21 and 29-49, and patients in cohort 5 receive oral imatinib mesylate on
days 1-56.

MAINTENANCE 3: Patients receive vincristine and dexamethasone as in maintenance 2. Patients
also receive oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, and 50; and oral
mercaptopurine on days 1-56. Ph+ patients receive imatinib mesylate as in maintenance 2.
Treatment repeats every 8 weeks for 7 courses (12 courses total in maintenance 1, 2, and 3)
in the absence of disease progression or unacceptable toxicity.

Patients may undergo allogeneic HSCT after consolidation block 2 if there is an available
HLA-DR matched or HLA-A or -B matched or 1 antigen mismatched relative donor.

Patients with CNS leukemia undergo cranial radiotherapy 3 times daily on days -10 to -8. All
patients undergo radiotherapy twice daily on days -7 to -5 and receive etoposide IV on day
-4 and cyclophosphamide IV on days -3 and -2. Patients undergo allogeneic bone marrow,
peripheral blood stem cell, or umbilical cord blood transplantation on day 0. Patients
receive cyclosporine IV beginning on day -1 and continuing every 12 hours, switching to oral
administration when possible, until day 60 and tapering thereafter. Patients also receive
methotrexate on days 1, 3, and 6. Beginning 16-24 weeks after transplantation, Ph+ patients
receive oral imatinib mesylate once daily for 24 weeks.

Patients are followed every 4-8 weeks for 1 year, every 3 months for 1 year, every 6 months
for 1 year, and then annually thereafter. Patients undergoing HSCT are followed weekly for
the first year.