Trial Information

Treatment of Patients With Newly Diagnosed Standard Risk B-Precursor Acute Lymphoblastic Leukemia (ALL)

PRIMARY OBJECTIVES:

l. To determine if a maintenance regimen containing once weekly oral methotrexate at 40
mg/m^2/week will result in an improved disease-free survival (DFS) compared to that
containing weekly oral methotrexate at 20 mg/m^2/week in the average-risk (AR) subset of
pediatric patients with standard-risk (SR) B-precursor acute lymphoblastic leukemia (ALL).

II. To determine whether a reduced-pulses maintenance regimen with vincristine
sulfate/dexamethasone pulses delivered every 12 weeks can be used without adversely
impacting DFS as compared to pulses given every 4 weeks in the AR subset of patients with SR
B-precursor ALL.

III. To confirm that patients in the low-risk (LR) subset of SR B-precursor ALL, based on
clinical and cytogenetic features and minimal residual disease (MRD) criteria, can attain a
5-year DFS of at least 95% with either a P9904-based regimen that includes 6 courses of
intermediate dose (1 g/m^2 over 24 hours) methotrexate without alkylating agents or
anthracyclines (Arm LR-M), or an outpatient-based regimen identical to that of AR patients
with reduced vincristine sulfate/dexamethasone pulses at 12-week intervals during
maintenance (Arm LR-C).

IV. To provide standardized treatment and enhanced supportive care to children with SR Down
syndrome-ALL in order to improve outcomes and facilitate further study of this biologically
and clinically unique patient subgroup.

V. To improve understanding of the biology of localized B-LLy and DS B-LLy by obtaining
biologic data, including FISH for recurrent cytogenetic lesions on paraffin specimen, and
banking tissue for future research.

VI. To describe the 5-year EFS and overall survival (OS) of patients with Murphy Stage I and
II B-LLy receiving modified AR B-ALL therapy.

SECONDARY OBJECTIVES:

I. To assess the burden of AR-ALL therapy as measured by surveys of the child's quality of
life, missed days of school/daycare/work by children and parents, family functioning,
parental perception of the child's health vulnerability, physical functioning, and emotional
distress overall at different time points during and at the end of therapy.

II. To assess the burden of AR-ALL therapy as measured by surveys of the child's quality of
life, missed days of school/daycare/work by children and parents, family functioning,
parental perception of the child's health vulnerability, physical functioning, and emotional
distress by comparing children randomized to every 4-week vs every 12-week
dexamethasone/vincristine sulfate pulses during maintenance therapy.

III. To characterize the onset, severity, and natural history of vincristine associated
neuropathy by physical therapists (or occupational therapists) in children undergoing
therapy for AR-ALL, 1) overall at different time points during and at the end of therapy,
and by 2) comparing children randomized to every 4 week vs. every 12 week
dexamethasone/vincristine pulses during Maintenance.

IV. To characterize the onset, severity, and natural history of vincristine associated
neuropathy by physical therapists (or occupational therapists) in children undergoing
therapy for AR B-ALL, 1) overall at different time points during and at the end of therapy,
and by 2) comparing children randomized to every 4 week vs. every 12 week
dexamethasone/vincristine pulses during Maintenance.

V. To explore the correlation of minimal marrow disease (MMD) at diagnosis and outcome for
patients with B-LLy.

OUTLINE: This is a multicenter study.

All patients receive induction therapy comprising intrathecal (IT) cytarabine on day 1;
vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally or IV twice daily
(BID) on days 1-28; pegaspargase IV over 1-2 hours on day 4; and IT methotrexate* on days 8
and 29. Patients with Philadelphia chromosome-positive disease are eligible to transfer to
COG-AALL0622 by day 15 of induction therapy and patients with high-risk (HR) or very
high-risk (VHR) disease are eligible to transfer to a COG HR or VHR trial at the end of
induction therapy. Patients with standard-risk disease with Down syndrome (DS) who have bone
marrow minimal residual disease 0.01% are eligible to transfer to the DS stratum of the HR
trial. Patients with induction failure (defined as M3 [> 25% lymphoblasts] on day 29) may be
eligible for the COG VHR-acute lymphoblastic leukemia study.

NOTE: *Patients with DS also receive oral leucovorin calcium every 12 hours on days 10-11
and 31-32.

STANDARD-RISK WITH DOWN SYNDROME:

Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1; oral
mercaptopurine on days 1-28; IT methotrexate on days 1, 8, and 15; and oral leucovorin
calcium every 12 hours on days 3-4, 10-11, and 17-18. Interim maintenance I therapy (8
weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on
days 1, 11, 21, 31, and 41; IT methotrexate on day 31; and oral leucovorin calcium every 12
hours on days 36-34. Delayed-intensification therapy (8 weeks): Patients receive
dexamethasone orally or IV BID on days 1-7 and 15-21; vincristine sulfate IV and doxorubicin
hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on
day 4; cyclophosphamide IV over 30-60 minutes on day 29; oral thioguanine on days 29-42;
cytarabine IV over 1-15 minutes or subcutaneously (SC) on days 29-32 and 33-39; IT
methotrexate on days 1 and 29; and oral leucovorin calcium every 12 hours on days 3-4 and
31-32. Interim maintenance II therapy (8 weeks): Patients receive vincristine sulfate IV and
methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41; IT methotrexate on days 1
and 31; and oral leucovorin calcium every 12 hours on days 3-4 and 33-34. Maintenance
therapy: Patients receive vincristine sulfate IV on day 1; oral dexamethasone BID on days
1-5; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral
mercaptopurine on days 1-84; and IT methotrexate on day 1. Courses repeat every 12 weeks for
2 years (timed from the start of interim maintenance I therapy).

AVERAGE-RISK:

Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1; oral
mercaptopurine on days 1-28; and IT methotrexate on days 1, 8, and 15.Interim maintenance I
therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15
minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on day 31. Delayed intensification
therapy (8 weeks): Patients receive dexamethasone orally or IV BID on days 1-7 and 15-21;
vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and
15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV over 30-60 minutes on day
29; oral thioguanine on days 29-42; cytarabine IV over 15-30 minutes or SC on days 29-32 and
36-39; and IT methotrexate on days 1 and 29. Interim maintenance II therapy (8 weeks):
Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11,
21, 31, and 41 and IT methotrexate on days 1 and 31. Maintenance therapy: Patients are
randomized to 1 of 4 maintenance therapy treatment arms.

Arm A: Patients receive vincristine sulfate IV on days 1, 29, and 57; oral dexamethasone BID
on days 1-5, 29-33, and 57-61; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64,
71, and 78; oral mercaptopurine on days 1-84; and IT methotrexate on day 1.

Arm B: Patients receive vincristine sulfate IV on days 1, 29, and 57; oral dexamethasone BID
on days 1-5, 29-33, and 57-61; higher-dose oral methotrexate on days 8, 15, 22, 29, 36, 43,
50, 57, 64, 71, and 78; oral mercaptopurine on days 1-84; and IT methotrexate on day 1.

Arm C: Patients receive vincristine sulfate IV on day 1; oral dexamethasone BID on days 1-5;
oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine
on days 1-84; and IT methotrexate on day 1.

Arm D: Patients receive vincristine sulfate IV on day 1; oral dexamethasone BID on days 1-5;
higher-dose oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral
mercaptopurine on days 1-84; and IT methotrexate on day 1.

In all arms, maintenance therapy courses repeat every 12 weeks for 2 years for girls and for
3 years for boys (timed from the start of interim maintenance I therapy).

LOW-RISK: Patients are randomized to 1 of 2 treatment arms.

Arm I (LR-M): Consolidation therapy (19 weeks): Beginning one week after completion of
induction therapy, patients receive vincristine sulfate IV on days 15, 22, 78, and 85;
methotrexate IV over 24 hours and IT methotrexate on days 8, 29, 50, 71, 92, and 113;
leucovorin calcium orally or IV on days 9-10, 30-31, 51-52, 72-73, 93-94, and 114-115;
dexamethasone orally or IV BID on days 15-21 and 78-84; and oral mercaptopurine on days
1-133.Maintenance therapy: Patients receive vincristine sulfate IV on days 1 and 8; oral
dexamethasone BID on days 1-7; oral methotrexate* on days 1, 8, 15, 22, 29, 36, 43, 50, 57,
64, 71, 78, 85, 92, 99, and 106; and oral mercaptopurine on days 1-112. Courses repeat every
16 weeks. Patients also receive IT methotrexate on days 1 and 85 (courses 1 and 4), day 57
(courses 2 and 5), or day 29 (courses 3 and 6). Patients then receive course 7 comprising
vincristine sulfate IV on days 1 and 8; oral dexamethasone BID on days 1-7; oral
methotrexate on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64; and oral mercaptopurine on
days 1-70. Treatment continues for 2 and ½ years (timed from the date of diagnosis).NOTE:
*Patients do not receive oral methotrexate on the days that they receive IT methotrexate.

Arm II (LR-C): Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on
day 1; oral mercaptopurine on days 1-28; and IT methotrexate on days 1, 8, and 15. Interim
maintenance I therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV
over 2-15 minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on day 31.
Delayed-intensification therapy (8 weeks): Patients receive dexamethasone orally or IV BID
on days 1-7 and 15-21; vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15
minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV
over 30-60 minutes on day 29; oral thioguanine on days 29-42; cytarabine IV over 1-15
minutes or SC on days 29-32 and 36-39; and IT methotrexate on days 1 and 29.Interim
maintenance II therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate
IV over 2-15 minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on days 1 and 31.
Maintenance therapy: Patients receive vincristine sulfate IV on day 1; oral dexamethasone
BID on days 1-5; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78;
oral mercaptopurine on days 1-84; and IT methotrexate on day 1. Courses repeat every 12
weeks for 2 years for girls and for 3 years for boys (timed from the start of interim
maintenance I therapy).

Blood samples may be collected periodically for research studies and patients may complete
quality-of-life surveys periodically.

After completion of study treatment, patients are followed up periodically for 10 years.