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Patients will receive 2 doses of EZN-3042 (and intrathecal cytarabine, conditionally) prior to initiating systemic therapy with vincristine, doxorubicin, prednisone and PEG-asparaginase. Patients with CNS 1 or 2 will also receive intrathecal methotrexate, and patients with CNS 3 will also receive triple intrathecal therapy (methotrexate, hydrocortisone, and cytarabine).

Dose will be assigned at study entry. To be given as a 2 hour intravenous infusion on days -5, -2, 8, 15, 22 and 29. Dose levels: L0 (level zero): 1.5 mg/kg, L1: 2.5 mg/kg, L2: 5 mg/kg, L3: 6.5 mg/kg

EZN-3042

Given intrathecally on day -6. Patients who may have received intrathecal chemotherapy within 7 days of day 0 as part of their prior maintenance chemotherapy (e.g. before the diagnosis of relapse) or as part of the diagnostic workup will not receive this dose of IT cytarabine. If given, dose is defined by age:

1-1.99 years: 30 mg 2-2.99 years: 50 mg

Greater than or equal to 3 years: 70 mg.

Cytarabine is also part of the triple intrathecal therapy given to CNS 3 patients on Days 8, 15, 22 and 29. Dose is defined by age:

1. - 1.99 years: 16 mg
2. - 2.99 years: 20 mg
3. - 8.99 years: 24 mg

Greater than or equal to 9 years: 30 mg

60 mg/m2/day given intravenous infusion (IV) over 15 minutes on day 1.

40 mg/m2/day divided BID or TID given orally on days 1 through 29. For patients who are unable to tolerate prednisone orally, substitute IV methylprednisolone at 80% of the oral prednisone dose.

1.5 mg/m2/day (maximum dose 2 mg) given intravenous push over 1 minute or infusion via mini-bag as per institutional policy on days 1, 8, 15 and 22.

2500 IU/m2 intramuscular injection on days 2, 9, 16, 23. If available, Erwinia L-asparaginase may be substituted for pegaspargase in patients with clinically significant prior allergies to pegaspargase.

PEG-asparaginase

Given intrathecally to patients with CNS1 or CNS2 disease at the dose defined by age below on days 15 and 36:

1-1.99 years: 8 mg 2-2.99 years: 10 mg 3-8.99 years: 12 mg

Greater than or equal to 9 years: 15 mg

Given as part of the Triple intrathecal therapy to patients with CNS 3 disease at the doses defined by age below on days 8, 15, 22 and 29:

1. - 1.99 years: 8 mg
2. - 2.99 years: 10 mg
3. - 8.99 years: 12 mg

Greater than or equal to 9 years: 15 mg

Given as part of the Triple intrathecal therapy to patients with CNS 3 disease at the doses defined by age below on days 8, 15, 22 and 29:

1. - 1.99 years: 8 mg
2. - 2.99 years: 10 mg
3. - 8.99 years: 12 mg

Greater than or equal to 9 years: 15 mg

Elizabeth Raetz, MD

William Carroll, MD

An experimental drug called EZN-3042 targets survivin, a protein expressed in leukemia cells at relapse that promotes the leukemia cells to grow. The main goal of this phase I study is to find out the dose of EZN-3042 that can be safely given without serious side effects both alone and in combination with standard chemotherapy drugs during re-induction.

This is a phase I multi-site study of the new investigational agent EZN-3042, which is highly effective at blocking survivin and inhibiting survivin protein expression. Survivin plays pivotal roles in tumor formation by inhibiting cell death and regulating cell cycle progression. The primary objective is to study EZN-3042 in children with relapsed acute lymphoblastic leukemia (ALL). Patients will receive 2 doses of EZN-3042 (and intrathecal cytarabine, conditionally) prior to initiating systemic therapy with vincristine, doxorubicin, prednisone and PEG-asparaginase. Patients with CNS 1 or 2 will also receive intrathecal methotrexate, and patients with CNS 3 will also receive triple intrathecal therapy (methotrexate, hydrocortisone, and cytarabine). Blood and bone marrow specimens will be drawn to measure minimal residual disease (MRD), pharmacokinetic levels of EZN-3042 and survivin expression. The study will follow a standard 3+3 dose escalation design. We hypothesize that EZN-3042 will be safe, tolerable and biologically active, when given both alone and in combination with standard re-induction chemotherapy.

EZN-3042 Administered With Re-induction Chemotherapy in Children With Relapsed Acute Lymphoblastic Leukemia (ALL)

A Phase I Study Evaluating the Safety, Tolerability and Biological Activity of EZN-3042, a Survivin mRNA Antagonist, Administered With Re-induction Chemotherapy in Children With Relapsed Acute Lymphoblastic Leukemia (ALL)

To determine the recommended dose of EZN-3042 administered weekly in combination with re-induction chemotherapy. Based on disease response at Day 36 and toxicity profile assessed until 30 days after discontinuation of study drug.

To evaluate primary target engagement of EZN-3042 we will examine survivin transcript and protein expression before (Day -6) and after EZN-3042 administration (Day 0) in enriched bone marrow blasts in children with relapsed B-precursor leukemia.

Enzon Pharmaceuticals, Inc.

Therapeutic Advances in Childhood Leukemia Consortium

The definitions of AE and SAE used to collect information do not differ from the clinicaltrials.gov definitions.

Dose Level 1 is the starting dose level. Patients will receive 2 doses of EZN-3042 at 2.5 mg/m2/day (and intrathecal cytarabine, conditionally) prior to initiating systemic therapy with vincristine, doxorubicin, prednisone and PEG-asparaginase, and then Day 8, 15, 22, and 29. If MTD is exceeded at dose level 1, the dose level will be deescalated to Dose Level 0.

EZN Dose Level 1

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Prior HSCT

The study was terminated early because Enzon Pharmaceuticals decided to halt development of EZN-3042.

Peggy Romano, BA, CCRP

Study deescalated to Dose Level 0 at 1.5 mg/kg after 2 patients at Dose Level 1 experienced DLTs.

EZN Dose Level 0

6 patients were enrolled at Dose Level 1. Dose level deescalated to Dose level 0 after 2 patients in Dose Level 1 experienced dose limiting toxicities. No patients were accrued on Dose level 0 prior to study closure.

Maximum Tolerated Dose of EZN-3042

Five patients provided samples for pharmacokinetic analysis.

Number of Participants Who Showed a Decrease From Day -6 in Survivin Transcript Expression After EZN-3042 Administration

If the MTD is not exceeded at dose level 1, the dose will be escalated to dose level 2 at 5mg/m2/day. Dose will be administered following the same dosing schedule as Dose level 1.

EZN Dose Level 2

If the MTD is not exceeded at Dose Level 2, the dose will be escalated to Dose Level 3 at 6.5 mg/kg following the same dosing schedule as Dose Level 1 and 2.

EZN Dose Level 3

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
EZN-3042 Administered With Re-induction Chemotherapy in Children With Relapsed Acute Lymphoblastic Leukemia (ALL)	NCT01186328	Lymphoblastic L... Lymphoblastic L... Leukemia, Lymph... Leukemia, Lymph...	EZN-3042 Cytarabine Doxorubicin Prednisone Vincristine PEG-asparaginas... Methotrexate Hydrocortisone	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium
EZN-3042 Administered With Re-induction Chemotherapy in Children With Relapsed Acute Lymphoblastic Leukemia (ALL)	NCT01186328	Lymphoblastic L... Lymphoblastic L... Leukemia, Lymph... Leukemia, Lymph...	EZN-3042 Cytarabine Doxorubicin Prednisone Vincristine PEG-asparaginas... Methotrexate Hydrocortisone	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium

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