Trial Information

INTENSIVE TREATMENT FOR INTERMEDIATE-RISK RELAPSE OF CHILDHOOD B-PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): A RANDOMIZED TRIAL OF VINCRISTINE STRATEGIES

PRIMARY OBJECTIVES:

I. Determine the efficacy of an intensive chemotherapy regimen (based on POG-9412) for
pediatric patients with intermediate-risk relapsed B-precursor acute lymphoblastic leukemia.

SECONDARY OBJECTIVES:

I. Compare the 3-year event-free survival and frequency and severity of adverse effects in
patients treated with high-dose (closed to accrual as of 9/2010) vs low-dose vincristine.

II. To determine levels of minimal residual disease (MRD) present at the end of the first &
third blocks of Induction and determine if higher MRD levels at these times identify
patients at higher risk of relapse who might be candidates for alternative therapies in
future trials.

III. To determine whether common polymorphisms in candidate genes are associated with the
frequency of vincristine adverse effects (peripheral neuropathy, syndrome of inappropriate
antidiuretic hormone secretion [SIADH], or constipation) and with anti-leukemic response
(level of end-Induction MRD).

IV. Compare, descriptively, the outcomes of patients treated with combination chemotherapy
vs those treated with matched sibling-related donor hematopoietic stem cell transplantation
(for those with eligible donors).

V. To use deoxyribonucleic acid (DNA) arrays to characterize patterns of gene expression
that predict treatment failure, and to compare gene expression profiles at the time of
relapse with those at initial diagnosis to gain an understanding of the pathways that may be
involved in disease resistance.

OUTLINE: This is a multicenter, randomized study. Patients are randomized to 1 of 2
treatment arms (randomization closed as of 09/2010).

INDUCTION THERAPY 1 (WEEKS 1-5):

ARM I: Patients receive low-dose vincristine intravenously (IV) on days 1, 8, 15, and 22;
prednisone orally (PO) 3 times daily (TID) on days 1-28; doxorubicin hydrochloride IV over
15 minutes on day 1; pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22; cytarabine
intrathecally (IT) on day 1; and methotrexate IT* on days 15 and 29.

ARM II (closed to accrual as of 09/2010)***: Patients receive high-dose vincristine IV on
days 1, 8, 15, and 22 and prednisone, doxorubicin hydrochloride, pegaspargase, cytarabine,
and methotrexate* as in arm I.

NOTE: *Central nervous system (CNS)-positive patients do not receive methotrexate IT. In
both arms, CNS-positive patients receive intrathecal triple therapy (ITT) comprising
methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, 22, and 29.
CNS-positive patients not achieving remission after induction therapy 1 receive one
additional dose of ITT on day 36. Patients in both arms then proceed to induction therapy
2**.

NOTE: **Patients who are CNS-positive at relapse receive induction therapy 3 BEFORE
induction therapy 2.

NOTE: ***Patients already enrolled on arm II are crossover to arm I.

INDUCTION THERAPY 2 (WEEKS 6-10 or 7-11): Once blood counts recover, all patients receive
etoposide phosphate IV over = 1 hour and cyclophosphamide IV over 1 hour on days 1-5;
high-dose methotrexate IV continuously over 24 hours on day 22; leucovorin calcium IV or PO
beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at
least 3 doses; and methotrexate IT* on days 1 and 22. Patients also receive filgrastim
(G-CSF) IV or subcutaneously (SC) beginning on day 6 and continuing until blood counts
recover.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive
ITT on days 1 and 22. Patients with testicular-relapse with persistent testicular disease at
the end of induction therapy 1 undergo testicular radiotherapy once daily (QD), 5 days a
week, for 12 days during induction therapy 2**.

NOTE: **Radiotherapy should be completed before beginning high-dose methotrexate (week 9)
chemotherapy.

All patients then proceed to induction therapy 3.

INDUCTION THERAPY 3 (WEEKS 11-15 or 12-16): All patients receive high-dose cytarabine IV
over 3 hours on days 1, 2, 8, and 9, and asparaginase IM on days 2 and 9. Patients also
receive G-CSF IV or SC beginning on day 10 and continuing until blood counts recover.
Patients with a suitable HLA-matched related donor are removed from study and proceed to
stem cell transplantation. Patients without a suitable HLA-matched related donor proceed to
intensification therapy 1 (as per their randomized arm in induction therapy 1).

INTENSIFICATION THERAPY 1 (WEEKS 16-27 or 17-28):

ARM I: Patients receive low-dose vincristine IV and high-dose methotrexate IV continuously
over 24 hours on day 1; leucovorin calcium IV or orally beginning 42 hours after start of
high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral
mercaptopurine once daily on days 2-6; etoposide phosphate IV over ≥ 1 hour and
cyclophosphamide IV over 1 hour on day 8; and methotrexate IT* on day 15. Treatment repeats
every 21 days for 4 courses (with the exception of IT methotrexate which repeats for only 3
courses).

ARM II: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate,
leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate
IT* as in arm I. (closed to accrual as of 09/2010)

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive
ITT on day 15. ITT repeats every 3 weeks for 3 courses.

NOTE: ** Patients already enrolled on arm II are crossover to arm I.

Patients in both arms then proceed to reinduction therapy (as per their randomized arm in
induction therapy 1).

REINDUCTION THERAPY (WEEKS 28-32 or 29-33):

ARM I: Patients receive low-dose vincristine IV and doxorubicin hydrochloride IV over 15
minutes on days 1, 8, and 15, oral dexamethasone twice daily on days 1-7 and 15-21,
pegaspargase IM on days 2 and 15, and methotrexate IT* on days 1 and 28.

ARM II: Patients receive high-dose vincristine IV on days 1, 8, and 15 and doxorubicin
hydrochloride, dexamethasone, pegaspargase, and methotrexate IT* as in arm I. (closed to
accrual as of 09/2010)

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive
ITT on days 1 and 28.

NOTE: ** Patients already enrolled on arm II are crossover to arm I. Patients in both arms
then proceed to intensification therapy 2 (as per their randomized arm in induction therapy
1).

INTENSIFICATION THERAPY 2 (WEEKS 33-56 or 34-57):

ARM I: Once blood counts recover, patients receive high-dose cytarabine IV over 3 hours on
days 1 and 2; pegaspargase IM on day 2; low-dose vincristine IV on days 22 and 29; high-dose
methotrexate IV on day 22; leucovorin calcium IV or orally beginning 42 hours after start of
high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral
mercaptopurine once daily on days 23-27; etoposide phosphate IV over ≥ 1 hour and
cyclophosphamide IV over 1 hour on day 29; and methotrexate IT* on day 36. Patients also
receive G-CSF IV or SC beginning on day 3 and continuing until blood counts recover.
Treatment repeats every 42 days for 4 courses (with the exception of IT methotrexate which
only repeats for 3 courses).

ARM II: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin calcium,
pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate IT*, and
G-CSF as in arm I. Patients also receive high-dose vincristine IV on days 22 and 29.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive
ITT on day 36. Treatment repeats every 6 weeks for 3 courses.

Patients in both arms then proceed to maintenance therapy (as per their randomized arm in
induction therapy 1).

MAINTENANCE THERAPY (week 57-106 or 58-107):

ARM I: Patients receive methotrexate IT on day 1* and then PO on days 8, 15, 22, 29, and 36;
mercaptopurine PO QD on days 1-42; dexamethasone PO twice daily (BID) on days 1-5; and
low-dose vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64.
Treatment repeats every 70 days for 5 courses.

ARM II: Patients receive methotrexate*, mercaptopurine, dexamethasone, and cyclophosphamide
as in arm I. Patients also receive high-dose vincristine IV on days 43, 50, 57, and 64.

NOTE: *CNS-positive patients receive methotrexate IT on day 1, instead of oral methotrexate.

Beginning in week 1 of the first maintenance therapy course, patients with CNS relapse
undergo cranial radiotherapy QD, 5 days a week, for 10 days. Patients with CNS relapse do
not receive any IT therapy during maintenance therapy.

After completion of study therapy, patients are followed periodically for 5 years.