Trial Information

Standard Risk B-precursor Acute Lymphoblastic Leukemia

OBJECTIVES:

Primary

- Compare event-free survival of pediatric patients with newly diagnosed, standard-risk
(SR)-average, B-precursor acute lymphoblastic leukemia (ALL) treated with induction
therapy followed by 1 of 4 intensified phases of post-induction therapy.

- Compare event-free survival of pediatric patients with SR-low ALL treated with
consolidation and interim maintenance therapy with or without additional pegaspargase.

Secondary

- Correlate day 29 minimal residual disease (MRD) status with event-free survival and
overall survival of patients treated with these regimens.

- Correlate early marrow response with day 29 MRD status in patients treated with these
regimens.

- Determine whether outcome is improved for SR-high patients by identifying these
patients by day 29 MRD status and subsequently treating these patients with a fully
augmented Berlin Frankfurt Munster regimen.

- Correlate relative contributions of genetic factors and early treatment response with
outcome in patients treated with these regimens.

OUTLINE: This is a 2-part, partially randomized, multicenter study. Patients are stratified
according to early response to study induction therapy (rapid early response [standard risk
(SR)-low or SR-average acute lymphoblastic leukemia (ALL)] vs slow early response [SR-high
ALL]). After completion of induction therapy but before proceeding to part II therapy,
patients are assigned to 1 of 3 groups based on stratification.

Part I

- Induction therapy: All patients receive cytarabine intrathecally (IT) on day 1;
vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally twice daily on days
1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or
6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3
disease). Patients with Down syndrome (DS) receive oral leucovorin calcium at 48 and 60
hours after each dose of methotrexate IT .

Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal
residual disease (MRD) < 0.1% OR MRD ≥ 0.1% and < 1% proceed to therapy in part II. Patients
with M2 bone marrow OR M1 bone marrow AND MRD ≥ 1% proceed to extended induction therapy.
Patients with M3 bone marrow are removed from the study.

- Extended induction therapy: Patients receive dexamethasone IV or orally twice daily on
days 1-14; vincristine IV on days 1 and 8; pegaspargase IM on day 4, 5, or 6; and
daunorubicin hydrochloride IV over 15 minutes to 2 hours on day 1.

Patients with M1 bone marrow and MRD < 1% after extended induction therapy proceed to
therapy in part II. Patients with M2 or M3 bone marrow after extended induction therapy are
removed from the study.

Part II

- Group 1 (SR-low ALL): Patients are randomized to 1 of 2 treatment arms.

- Arm I:

- Standard consolidation therapy: Patients receive vincristine IV on day 1;
oral mercaptopurine on days 1-28; and methotrexate IT on days 1, 8, and 15.
Patients with Down syndrome (DS) receive oral leucovorin calcium at 48 and 60
hours after each dose of methotrexate IT.

- Standard interim maintenance therapy: Patients receive vincristine IV on days
1 and 29; dexamethasone IV or orally twice daily on days 1-5 and 29-33; oral
mercaptopurine on days 1-50; oral methotrexate on days 1, 8, 15, 22, 29, 36,
43, and 50; and methotrexate IT on day 29. Patients with DS receive oral
leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT.

- Standard delayed intensification (DI) therapy: Patients receive vincristine
IV on days 1, 8, and 15; dexamethasone IV or orally twice daily on days 1-21;
doxorubicin hydrochloride IV over 15 minutes to 2 hours on days 1, 8, and 15;
pegaspargase IM on day 4, 5, or 6; cyclophosphamide IV over 30 minutes on day
29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39; oral
thioguanine on days 29-42; and methotrexate IT on days 1 and 29. Patients
with DS receive dexamethasone IV or orally twice daily on days 1-7 and 15-21
and oral leucovorin calcium at 48 and 60 hours after each dose of
methotrexate IT.

- Arm II:

- Experimental consolidation therapy: Patients receive vincristine,
mercaptopurine, methotrexate, and leucovorin calcium as in arm I and
pegaspargase IM on days 1 and 22.

- Experimental interim maintenance therapy: Patients receive vincristine,
dexamethasone, mercaptopurine, oral methotrexate, and methotrexate IT as in
arm I and pegaspargase IM on days 15 and 36.

- Standard DI therapy: Patients receive standard DI therapy as in arm I.

- Group 2 (SR-average ALL): Patients are randomized to 1 of 4 treatment arms.

- Arm I: Patients receive standard consolidation therapy, standard interim
maintenance therapy, and standard DI therapy as in group 1, arm I.

- Arm II:

- Standard consolidation therapy: Patients receive standard consolidation
therapy as in group 1, arm I.

- Augmented interim maintenance therapy: Patients receive vincristine IV and
methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IM on days 2 and
22; and methotrexate IT on days 1 and 31. Patients with DS receive oral
leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT.

- Augmented DI therapy: Patients receive vincristine IV on days 1, 8, 15, 43,
and 50; dexamethasone IV or orally twice daily on days 1-21; doxorubicin
hydrochloride IV over 15 minutes to 2 hours on days 1, 8, and 15;
pegaspargase IM on day 4, 5, or 6 AND day 43; cyclophosphamide IV over 30
minutes on day 29; cytarabine IV or SC on days 29-32 and 36-39; oral
thioguanine on days 29-42; and methotrexate IT on days 1, 29, and 36.
Patients with DS receive dexamethasone on days 1-7 and 15-21 and oral
leucovorin calcium at 48 and 60 hours after each dose of methotrexate IT.

- Arm III:

- Intensified consolidation therapy: Patients receive cyclophosphamide IV over
30 minutes on days 1 and 29; cytarabine IV or SC on days 1-4, 8-11, 29-32,
and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days
15, 22, 43, and 50; pegaspargase IM on days 15 and 43; and methotrexate IT on
days 1, 8, 15*, and 22*. Patients with DS receive oral leucovorin calcium at
48 and 60 hours after each dose of methotrexate IT*.

NOTE: *Patients with CNS3 disease at diagnosis do not receive methotrexate on days 15 and 22
or leucovorin calcium

- Standard interim maintenance therapy: Patients receive standard interim maintenance
therapy as in group 1, arm I.

- Standard DI therapy: Patients receive standard DI therapy as in group 1, arm I.

- Arm IV:

- Intensified consolidation therapy: Patients receive intensified consolidation therapy
as in group 2, arm III.

- Augmented interim maintenance therapy: Patients receive augmented interim maintenance
therapy as in group 2, arm II.

- Augmented DI therapy: Patients receive augmented DI therapy as in group 2, arm II.

- Group 3 (SR-high ALL): Patients receive the following therapy:

- Intensified consolidation therapy: Patients receive intensified consolidation
therapy as in group 2, arm III.

- Augmented interim maintenance* therapy: Patients receive augmented interim
maintenance therapy as in group 2, arm II. Treatment repeats every 56 days
for 2 courses.

NOTE: *As of Amendment #7, all SR-High patients currently receiving AIM 1 therapy should
complete this phase of therapy and proceed to ADI 1 therapy as originally planned including
Capizzi methotrexate during AIM 1. Upon completion of ADI 1, patients should receive a
second Interim Maintenance phase with high-dose methotrexate (IM HD) rather than Capizzi
methotrexate. Patients should then proceed to ADI 2 and then Maintenance.

- Augmented DI* therapy: Patients receive augmented DI therapy as in group 2, arm II.
Treatment repeats every 56 days for 2 courses**.

NOTE: *As of Amendment #7, all SR-High patients currently receiving ADI 1 therapy should
complete this phase of therapy as originally planned. Upon completion of ADI 1, patients
should receive a second Interim Maintenance phase with IM HD. Patients should then proceed
to ADI 2 and then Maintenance.

NOTE: **Patients with CNS3 disease at diagnosis also undergo cranial radiotherapy on days
29-33 and 36-40 during course 2 only; these patients do not receive methotrexate on day 36,
thioguanine, or leucovorin calcium.

- Maintenance therapy: All patients receive vincristine IV on days 1, 29, and 57; oral
dexamethasone twice daily 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
methotrexate IT* on day 1. Courses repeat every 84 days for a total of 2 years from the
start of interim maintenance therapy for female patients and 3 years from the start of
interim maintenance therapy for male patients.

NOTE: *SR-High or CNS3 patients should receive up to a maximum of 23 intrathecal treatments
for females and 26 intrathecal treatments for males.

After the completion of study treatment, patients are followed every 1-2 months for 2 years,
every 3 months for 1 year, and then every 6-12 months for 2 years.

PROJECTED ACCRUAL: A total of 3,381 patients (1,576 for group 1,278 for group 2, and 527 for
group 3) will be accrued for this study within 4.25 years.