Clinical trial NCT01186328
Conditions: Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, Acute, Childhood Leukemia, Lymphoblastic, Acute, T Cell Leukemia, Lymphoblastic, Acute
Keywords: Relapse T cell Lymphoblastic Leukemia EZN3042 Refractory Precursor B Pre B cell Survivin Acute Childhood Pediatric
Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
Start date: 2010-08-24; Completion date: 2012-01-10
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: 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).
Interventions: intervention 1: EZN-3042 intervention 2: Cytarabine intervention 3: Doxorubicin intervention 4: Prednisone intervention 5: Vincristine intervention 6: PEG-asparaginase intervention 7: Methotrexate intervention 8: Hydrocortisone
Intervention descriptions: intervention 1: 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 intervention 2: 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 intervention 3: 60 mg/m2/day given intravenous infusion (IV) over 15 minutes on day 1. intervention 4: 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. intervention 5: 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. intervention 6: 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. intervention 7: 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 intervention 8: 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

Protocol documents: