A Phase III Randomized Trial for Newly Diagnosed High Risk B-precursor Acute Lymphoblastic Leukemia (ALL) Testing Clofarabine (IND# 73789, NSC# 606869) in the Very High Risk Stratum

Trial Information

A Phase III Randomized Trial for Newly Diagnosed High Risk B-precursor Acute Lymphoblastic Leukemia (ALL) Testing Clofarabine (IND# 73789, NSC# 606869) in the Very High Risk Stratum

PRIMARY OBJECTIVES:

I. To determine if the administration of post-Induction age-adjusted intrathecal triple
therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance (IM)
high-dose methotrexate (IMHDM) backbone will improve 5-year disease-free survival (DFS) of
children with high-risk (HR) acute lymphoblastic leukemia (ALL) compared to age-adjusted
intrathecal (IT) methotrexate (MTX).

II. To determine, in a randomized fashion, if the cyclophosphamide + etoposide-containing
regimen (Experimental Arm 1) or the clofarabine + cyclophosphamide + etoposide-combination
regimen (Experimental Arm 2) will improve the 4-year DFS of children, adolescents, and young
adults with very high-risk (VHR) ALL compared to a modified MBFM-IMHDM regimen that contains
a second IM (Control Arm).

III. To determine, in a randomized fashion, if the cyclophosphamide + etoposide +
clofarabine-containing combination regimen (Experimental Arm 2) will improve the 4-year DFS
of children, adolescents, and young adults with VHR-ALL compared to the cyclophosphamide +
etoposide combination regimen (Experimental Arm 1).

SECONDARY OBJECTIVES:

I. To determine the toxicity and tolerability of post-Induction age-adjusted ITT compared to
age-adjusted IT MTX in children with HR-ALL. To determine the toxicity and tolerability of
Experimental Arms 1 and 2 compared to the Control Arm in children, adolescents, and young
adults with VHR-ALL.

II. To determine whether a single-arm, modified Induction with limited anthracycline
exposure and post-Induction therapy regimen with MBFM-IMIDM and reduced vincristine/steroid
pulse frequency and enhanced supportive care in children with Down syndrome (DS) and HR-ALL
will result in a ≥ 65% 5-year DFS and < 10% Induction mortality, and to gather clinical and
biologic data that will facilitate further study to improve outcomes for this biologically
and clinically unique patient subgroup.

III. To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and
HR-ALL.

IV. To determine if the reduction of minimal-residual disease (MRD) from end-Induction to
end-Consolidation is greater for children, adolescents, and young adults with VHR-ALL
receiving Experimental Arms 1 and/or 2 compared to the Control Arm.

V. To estimate overall survival (OS) rates both overall and by regimen for HR-ALL and
VHR-ALL patients.

VI. To determine if peripheral blood absolute lymphocyte count (ALC) at day 29 of Induction
is predictive of DFS in children, adolescents, and young adults with HR-ALL.

VII. To determine the incidence and prognostic significance of recently discovered recurrent
genomic lesions, including high cytokine receptor-like factor 2 (CRLF2) expression,
CRLF2-activating genomic lesions, janus kinase (JAK) mutations, and IKAROS family zinc
finger 1 (Ikaros) (IKZF1) mutations/deletions, in patients treated on this trial.

VIII. To determine the prognostic significance of molecular risk classifiers using Low
Density Array (LDA) Taqman cards.

IX. To define the frequency of occurrence of key adverse events across all patient subgroups
of HR-ALL in order to provide data for linked correlative biology studies that seek to
develop biomarkers predictive of patients at risk for such events, including the following
specific events: Grade 2 or higher (CNS hemorrhage, pancreatitis, osteonecrosis [ON], and
seizure), Grade 3 or higher (GI bleed, encephalopathy, neuropathy, allergic reaction, ileus,
mucositis/stomatitis, hyperbilirubinemia, and thrombosis), and all grades (transient
ischemic attacks, strokes).

X. To define the differences in the burden of therapy between HR-ALL and VHR-ALL when
treated on the various arms of this study by collecting and comparing the total number of
days admitted to the hospital.

XI. To determine the incidence of ON, defined by magnetic resonance (MR) imaging, and to
characterize the natural history of clinically silent ON in children, adolescents, and young
adults 10 years of age and greater and to assess the role of drugs (i.e., asparaginase and
methotrexate) in addition to corticosteroids, in the risk for development of ON.

XII. To determine if the prevalence of cognitive deficits measured by CogState, in children
(ages 6 to 11 years) with HR- and VHR-ALL at 1 year off therapy, is significantly higher
than the normative population (> 14%) in the following domains: working memory, executive
function, visual motor, processing speed, and visual attention.

XIII. To compare the drug delivery of vincristine, pegaspargase, and methotrexate during
Induction, Consolidation, Delayed Intensification, and Interim Maintenance II in 16-30 year
olds treated on the control arm of the VHR study to that of adolescents and young adults
(AYAs) with ALL treated with the same therapy on the C10403 adult cooperative group trial.

OUTLINE: This is a multicenter study. Patients are stratified according to Down syndrome (no
vs yes).

Induction therapy for ALL patients without Down syndrome (35 days): Patients receive
induction chemotherapy comprising cytarabine intrathecally (IT) on day 1; vincristine
sulfate intravenously (IV) on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 1-15
minutes on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily (BID) on days
1-14 (patients under 10 years old) or prednisone PO or IV BID on days 1-28 (patients at
least 10 years old); pegaspargase IV over 1-2 hours on day 4; and methotrexate IT on days 8
and 29 (plus days 15 and 22 for CNS3).

Patients are stratified according to National Cancer Institute (NCI) ALL risk criteria
(high-risk or standard-risk vs very high-risk). High-risk or standard-risk ALL: Patients are
randomized to 1 of 2 treatment arms.

Consolidation therapy (56 days):

Arm I HR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over
30-60 minutes on days 1 and 29; cytarabine IV or subcutaneously (SC) on days 1-4, 8-11,
29-32, and 36-39; mercaptopurine PO on days 1-4 and 29-42, methotrexate IT on days 1, 8, 15,
and 22; vincristine sulfate IV on days 15, 22, 43, and 50; and pegaspargase IV over 1-2
hours on days 15 and 43. Patients with continuing clinical evidence of testicular leukemia
undergo radiotherapy (RT) once daily, 5 days a week, for approximately 2½ weeks (12
fractions total).

Arm II HR-ALL C: Patients receive intrathecal triple therapy (ITT) comprising methotrexate,
hydrocortisone sodium succinate, and cytarabine on days 1, 8, 15, and 22. Patients also
receive consolidation therapy as patients in arm I HR-ALL C. Patients with testicular
leukemia also undergo RT as in arm I HR-ALL C.

Interim maintenance therapy (63 days):

Arm I HR-ALL IM: Patients receive interim maintenance (IM) therapy comprising vincristine
sulfate IV on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15,
29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; methotrexate
IT on days 1 and 29; and mercaptopurine PO on days 1-56.

Arm II HR-ALL IM: Patients receive ITT on days 1 and 29 and IM therapy as in arm I HR-ALL
IM.

Delayed intensification therapy (56 days):

Arm I HR-ALL DI: Patients receive delayed intensification (DI) therapy comprising
vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-7,
and 15-21; doxorubicin hydrochloride IV on days 1, 8, and 15; methotrexate IT on days 1, 29,
and 36; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60
minutes on day 29; cytarabine IV on days 29-32 and 36-39; and thioguanine PO on days 29-42.

Arm II HR-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in arm I
HR-ALL DI.

Maintenance therapy:

Arm I HR-ALL M: Patients receive maintenance therapy comprising vincristine sulfate IV on
days 1, 29, and 57; methotrexate IT on days 1 (also day 29 of courses 1-4) ; prednisone PO
BID on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; and methotrexate PO on
days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2
years (females) or 3 years (males) in the absence of disease progression or unacceptable
toxicity.

Arm II HR-ALL M: Patients receive ITT on day 1 (also day 29 of courses 1-4) and maintenance
therapy as in arm I HR-ALL M. Treatment repeats every 12 weeks for 2 years (females) or 3
years (males) in the absence of disease progression or unacceptable toxicity.

Very high-risk ALL: Patients are randomized to 1 of 3 treatment arms.

Consolidation therapy part 1 (days 1-28): In all arms, patients receive cyclophosphamide IV
over 30-60 minutes on day 1; cytarabine IV or SC on days 1-4 and 8-11; mercaptopurine PO on
days 1-14; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS patients):
vincristine sulfate IV on days 15 and 22; and pegaspargase IV over 1-2 hours on day 15.
Patients with continuing clinical evidence of testicular leukemia undergo RT once daily, 5
days a week, for approximately 2½ weeks (12 fractions total).

Consolidation therapy part 2 (days 29-57):

Arm A VHR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over
30-60 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39;
mercaptopurine PO on days 29-42; vincristine IV on days 43 and 50; and pegaspargase IV over
1-2 hours on day 43.

Arm B VHR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over
15-30 minutes on days 29-33; etoposide IV over 1-2 hours on days 29-33; vincristine sulfate
IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43.

Arm C VHR-ALL C: Patients receive clofarabine IV over 2 hours on days 29-33 and
consolidation therapy as in arm B VHR-ALL C.

Interim Maintenance I (63 days): In all arms, patients receive vincristine IV on days 1, 15,
29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin
calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO on days 1-56; and
methotrexate IT on days 1 and 29.

Delayed Intensification part 1 (days 1-28): In all arms, patients receive vincristine
sulfate IV on days 1, 8, and 15; dexamethasone PO or IV BID on days 1-7 and 15-21;
doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on day
1; and pegaspargase IV over 1-2 hours on day 4.

Delayed Intensification part 2 (days 29-57):

Arm A VHR-ALL DI: Patients receive DI therapy comprising cyclophosphamide IV over 30-60
minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39;
thioguanine PO on days 29-42; methotrexate IT on days 29 and 36; vincristine sulfate IV on
days 43 and 50; and pegaspargase IV over 1-2 hours on day 43.

Arm B VHR-ALL DI: Patients receive DI therapy comprising cyclophosphamide IV over 15-30
minutes on days 29-33; etoposide IV over 1-2 hours on days 29-33; methotrexate IT on days 29
and 36; vincristine sulfate IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day
43.

Arm C VHR-ALL DI: Patients receive clofarabine IV over 2 hours on days 29-33 and DI therapy
as in arm II B VHR-ALL DI.

Interim Maintenance II (56 days): In all arms, patients receive vincristine sulfate IV and
methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and
22; and methotrexate IT on days 1 and 31.

Maintenance therapy: Patients with CNS3 disease at diagnosis undergo RT once daily over 4
weeks (10 fractions total). In all arms, patients receive vincristine sulfate IV on days 1,
29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; methotrexate PO on days 8, 15,
22, 29, 36, 43, 50, 57, 64, 71, and 78 (except on methotrexate IT days); mercaptopurine PO
on days 1-84; methotrexate IT on day 1 (also day 29 of courses 1 and 2 for CNS patients who
did not receive RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years
(males) in the absence of disease progression or unacceptable toxicities.

High-risk ALL patients with Down syndrome: Patients are stratified according to response to
induction therapy (days 1-14) (rapid early responders [RER; M1 day 15 bone marrow] vs slow
early responders [SER; M2/M3 day 15 bone marrow]).

Induction therapy (days 1-14): All patients receive cytarabine IT on day 1; vincristine
sulfate IV on days 1 and 8, dexamethasone PO or IV BID (patients under 10 years old) or
prednisone PO BID (patients at least 10 years old) on days 1-14, pegaspargase IV over 1-2
hours on day 4; methotrexate IT on day 8; and leucovorin calcium PO on days 10-11.

Induction therapy (day 15-29): RER patients receive induction therapy comprising vincristine
sulfate IV on days 15 and 22; dexamethasone PO BID or prednisone PO BID on days 15-28;
methotrexate IT on day 29 (also days 15 and 22 for CNS3 patients); and leucovorin calcium PO
on days 31-32 (also days 17-18 and 24-25 for CNS3 patients). SER patients receive
daunorubicin hydrochloride IV over 1-15 minutes on day 15 and induction therapy as RER
patients.

Consolidation therapy (56 days): All patients receive cyclophosphamide IV over 30-60 minutes
on days 1 and 29; cytarabine IV over 15-30 minutes or SC on days 1-4, 8-11, 29-32, and
36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43,
and 50; pegaspargase IV over 1-2 hours on days 15 and 43; methotrexate IT on days 1, 8, 15,
and 22; and leucovorin calcium PO on days 3-4, 10-11, 17-18, and 24-25. Patients with
continuing clinical evidence of testicular leukemia undergo RT once daily, 5 days a week,
for approximately 2½ weeks (12 fractions total).

Interim maintenance therapy (63 days): Patients receive vincristine sulfate IV on days 1,
15, 29, and 43; methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium
PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO on days 1-56; and
methotrexate IT on days 1 and 29.

Delayed intensification therapy: Patients receive vincristine sulfate IV on days 1, 8, 15,
43, and 50; dexamethasone PO BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over
1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4 and 43;
cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine
IV over 15-30 minutes or SC on days 29-32 and 36-39; methotrexate IT on days 1, 29, and 36;
and leucovorin calcium PO on days 3-4, 31-32 and 38-39.

Maintenance therapy: Patients with CNS3 disease undergo RT once daily, 5 days a week, for 2
weeks (10 fractions total). Patients receive vincristine IV on day 1; prednisone PO BID on
days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78;
mercaptopurine PO on days 1-84; and methotrexate IT on day 1 (also day 29 of courses 1-4 for
CNS3 patients who did not receive RT). Treatment repeats every 12 weeks for 2 years in the
absence of disease progression or unacceptable toxicity.

Patients undergo peripheral blood and bone marrow collection for correlative studies.
Patients who are at least 10 years old have MRIs during Consolidation, Maintenance, and End
of therapy and blood draws during Consolidation, Delayed Intensification, and Interim
Maintenance II (VHR-ALL only). Patients may also undergo neurocognitive assessment during
consolidation therapy, periodically during maintenance therapy, and at 1 year after
completion of study therapy.

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