Trial Information

A Pilot Study of Intravenous EZN-2285 (SC-PEG E. Coli L-asparaginase, IND# 100594) or Intravenous Oncaspar® in the Treatment of Patients With High-Risk Acute Lymphoblastic Leukemia (ALL)

OBJECTIVES:

Primary

- Determine the pharmacokinetic (PK) comparability of SC-PEG E. coli L-asparaginase
(EZN-2285)[As of 12/22/2010, patients no longer receive EZN-2285][As of amendment #6,
patients receive EZN-2285 again.] to pegaspargase given intravenously during induction
and consolidation in patients with high-risk acute lymphoblastic leukemia (ALL)
receiving augmented Berlin-Frankfurt-Munster (BFM) therapy.

Secondary

- Describe the pharmacodynamics of EZN-2285 compared to pegaspargase in these patients.

- Determine, at end of induction therapy by day 29, minimal residual disease for patients
randomized to the EZN-2285-containing regimen compared to the pegaspargase-containing
regimen.

- Determine the complete remission rates for patients receiving EZN-2285, by day 29 of
induction, compared to pegaspargase.

- Assess event-free survival associated with the administration of EZN-2285 compared to
pegaspargase given during augmented post-induction intensification therapy in patients
with high-risk ALL.

- Determine the proportion of patients with an asparaginase level of at least 0.1 IU/mL
and the proportion of patients with that of at least 0.4 IU/mL on days 4, 15, 22, and
29 of induction in both arms.

- Determine the plasma and cerebrospinal fluid concentrations of asparagine after
administration of EZN-2285 compared to pegaspargase.

- Assess the immunogenicity of EZN-2285, including the detection of binding and
neutralizing antibodies, compared to pegaspargase.

- Assess the tolerability and toxicities associated with the administration of EZN-2285
compared to pegaspargase given during augmented post induction intensification therapy
in patients with high-risk ALL .

- Explore the relationship between the terminal PKs of EZN-2285 and the presence of
antibodies.

OUTLINE: This is a multicenter study. Patients are stratified according to response to
induction therapy (slow early responders [SER] vs rapid early responders [RER]. Patients are
randomized to 1 of 2 treatment arms in 2:1 ratio (arm I:arm II) (patients randomized to arm
I receive study drug SC-PEG E. coli L-asparaginase [EZN-2285]*; patients randomized to arm
II receive study drug pegaspargase).

NOTE: *As of 12/22/2010, all patients randomized to receive EZN-2285 will receive
pegaspargase instead.NOTE: *As of amendment #6, patients receive EZN-2285 again.

- Induction therapy** (all patients): Patients receive cytarabine intrathecally (IT) on
day 1; vincristine IV and daunorubicin hydrochloride IV over 15 minutes on days 1, 8,
15, and 22; prednisone*** orally or IV twice a day on days 1-28; study drug IV over 1
hour on day 4; and methotrexate IT on days 8, 15*, 22*, and 29.

Patients are assessed for response on day 8 and/or day 15 and day 29. Patients who achieve
M1 marrow on day 8 or 15 and negative minimum residual disease (MRD) (i.e., < 0.1%) on day
29 are considered RER. Patients who achieve M2 or M3 marrow on day 15 OR MRD ≥ 0.1% but < 1%
on day 29 are considered SER. Patients with M3 bone marrow are removed from the study.
Patients with Very High Risk (VHR) disease are removed from the study. RER and SER proceed
to consolidation therapy. Patients with M2 marrow or M1 marrow with ≥ 1% MRD receive
extended induction therapy.

NOTE: *For patients with CNS3 disease only.

NOTE: ***As of Amendment #6, patients aged less than 10 years receive dexamethasone twice
daily on days 1-14 while patients at least 10 years old receive prednisone twice daily on
days 1-28.

- Extended induction therapy**: Patients receive vincristine IV on days 1 and 8;
prednisone orally or IV twice a day on days 1-14; daunorubicin hydrochloride IV over 15
minutes on day 1; and study drug IV over 1 hour on day 4.

NOTE: **As of Amendment #6, patients aged less than 10 years receive dexamethasone twice
daily on days 1-14 while patients at least 10 years old receive prednisone twice daily on
days 1-28.

Patients are assessed for response on day 43. Patients who achieve M1 and MRD < 1% are
treated as SER (proceed to consolidation therapy). All other patients are removed from
study.

- Consolidation therapy** (all patients): Beginning on day 36 (after completion of
induction therapy) or after completion of extended induction therapy, patients (RER and
SER) receive cyclophosphamide IV over 30 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; oral mercaptopurine on days
1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; study drug IV over 1 hour on
days 15 and 43; and methotrexate IT on days 1, 8, 15*, and 22*. NOTE: As per amendment
#6, CNS3 patients no longer receive cranial radiotherapy as Consolidation therapy.
Patients then proceed to interim maintenance I therapy.

NOTE: *Omit doses for patients with CNS3 disease.

- Interim maintenance I**(all patients): Patients receive vincristine IV and high-dose
methotrexate** IV on days 1, 15, 29, 31, and 43; study drug IV over 1 hour on days 2
and 22; and methotrexate IT on days 1 and 29. Patients then proceed to delayed
intensification I therapy.

- Delayed intensification I** (all patients^): Patients receive vincristine IV on days 1,
8, 15, 43, and 50; dexamethasone orally or IV twice a day on days 1-21 for patients age
1-9, or on days 1-7 and 15-21 for patients age ≥ 10; doxorubicin hydrochloride IV over
15 minutes on days 1, 8, and 15; study drug IV over 1 hour on days 4 and 43;
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,
29, and 36.

Patients treated as RER proceed to maintenance therapy. Patients treated as SER (i.e.,
patients with CNS3 disease at diagnosis, or pre-treated with steroids, or who are RERs with
mixed lineage leukemia [MLL] gene rearrangements) proceed to interim maintenance II followed
by delayed intensification II.

As per amendment #6, an augmented BFM backbone is used with a single delayed intensification
for RERs and a double delayed intensification for SERs. All patients receive discontinuous
dexamethasone (one week on, one week off, one week on) during the Delayed Intensification
phases.

- Interim maintenance II** (SER only): Patients receive vincristine IV, high-dose
methotrexate IV, study drug IV, and methotrexate IT as in interim maintenance I.
Patients who were initially diagnosed with CNS3 disease receive cranial radiotherapy on
days 1-5 and 8-12.

- Delayed intensification II** (SER only): Beginning on day 29, patients (except patients
enrolled prior to Amendment #6) receive 8 daily fractions of cranial radiotherapy(CRT)
(CNS3 patients enrolled after Amendment #6 undergo 10 daily fractions of CRT). All
patients then receive vincristine IV, dexamethasone orally or IV, doxorubicin
hydrochloride IV, study drug IV, cyclophosphamide IV, cytarabine IV or SC, oral
thioguanine, and methotrexate IT as in delayed intensification I. Patients then proceed
to maintenance therapy. As per amendment #6, patients who were initially diagnosed with
CNS3 disease receive cranial radiotherapy on days 1-5 and 8-12. All patients receive
discontinuous dexamethasone (one week on, one week off, one week on) during the Delayed
Intensification phases.

- Maintenance therapy** (all patients): Patients receive vincristine IV on days 1, 29,
and 57; oral dexamethasone on days 1-5, 29-33, and 57-61; oral mercaptopurine on days
1-84; methotrexate IT on day 29; and oral methotrexate on days 8, 15, 22, 29, 36, 43,
50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for up to 2 years (for female
patients) or up to 3 years (for male patients) from the start of interim maintenance I.

NOTE: ** As per amendment #4, most patients receive high-dose methotrexate instead of
Capizzi methotrexate at most stages of therapy. CNS3 patients and SER patients who have
received cranial irradiation receive planned therapy with no modifications.NOTE: As per
amendment #4, the maximum number of intrathecal treatments is limited by RER/SER/CNS3 status
and gender.

Blood and cerebrospinal fluid samples are collected periodically for correlative studies,
including immunogenicity, pharmacokinetic, and pharmacodynamic studies.

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