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

NCT01186328 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: T2009-007
• Study Type: interventional
• Target: 6
• Locations: 2 countries
• Sites: 7

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.

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

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose of EZN-3042

  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.

  2 months

Secondary Outcomes (1)

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

  Day -6 to Day 0

Study Arms (1)

Single Arm

EXPERIMENTAL

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).

Drug: EZN-3042; Drug: Cytarabine; Drug: Doxorubicin; Drug: Prednisone; Drug: Vincristine; Drug: PEG-asparaginase; Drug: Methotrexate; Drug: Hydrocortisone

Interventions

EZN-3042 DRUG

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

Also known as: SPC 3042

Single Arm

Cytarabine DRUG

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

Also known as: ARA-C, cytosine arabinoside, Cytosar, Cytosar-U®, Arabinosylcytosine

Single Arm

Doxorubicin DRUG

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

Also known as: Adriamycin, Rubex

Single Arm

Prednisone DRUG

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.

Also known as: Prednisone Intensol®, Sterapred®, Sterapred® DS, Predone®, Deltasone®

Single Arm

Vincristine DRUG

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.

Also known as: Oncovin®, vincristine sulfate, Vincasar Pfs®, VCR, LCR

Single Arm

PEG-asparaginase DRUG

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.

Also known as: Oncaspar®, PEG-L-asparaginase

Single Arm

Methotrexate DRUG

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

Also known as: Rheumatrex, Trexall, Amethopterin, Methotrexate Sodium, MTX

Single Arm

Hydrocortisone DRUG

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

Also known as: Ala-Cort ®, Hydrocortone Phosphate, Solu-Cortef®, Hydrocort Acetate®, Lanacort®, Cortef®, Westcort®, Cortisone, Hydrocortisone Sodium Succinate, Hydrocortisone Sodium Phosphate

Single Arm

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients must be ≥1 and ≤ 21 years of age when originally diagnosed with acute lymphoblastic leukemia (ALL).
• Patients must have relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) with ≥25% blasts in the bone marrow (M3), with or without extramedullary disease.
• Patients may have central nervous system 1, 2 or 3 disease.
• Karnofsky Performance Level ≥ 50 for patients \> 10 years of age and Lansky ≥ 50 for patients ≤ 10 years of age.
• Patients must have had 2 or more prior therapeutic attempts defined as:
• Relapse after going into remission from re-induction for the first or subsequent relapse (ie: 2nd , 3rd, 4th…relapse), or
• Refractory disease after first or greater relapse and a single re-induction attempt. \*Please note, Enrollment will be restricted to at most one refractory patient in each cohort of 3 patients per dose level.
• Patients with ALL who are refractory to frontline induction therapy are not eligible.
• Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study.
• Patients who relapse when they are not receiving standard ALL maintenance therapy must have fully recovered from grade 3 or 4 toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Cytotoxic Therapy: It must be at least 14 days since the completion of cytotoxic therapy (excluding hydroxyurea) at the time of study enrollment.
• Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of active Graft-versus-Host Disease (GVHD) and are at least 120 days post-transplant at the time of enrollment.
• Prior anthracycline exposure: Patients must have ≤ 400 mg/m2 lifetime exposure of anthracycline chemotherapy.
• Biologic (anti-neoplastic) therapy: It must be at least 7 days since the completion of therapy with a biologic agent at the time of study enrollment. For agents that have known adverse events occurring 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
• Patients must have a calculated creatinine clearance or radioisotope GRF ≥ 70mL/min/1.73m2 OR a normal serum creatinine based on the institutional normal values according to age.

You may not qualify if:

• Patients with Down syndrome are excluded.
• Patients with B-cell ALL (L3 morphology or evidence of myc translocation by molecular or cytogenetic technique) are not eligible
• Patients who cannot receive asparaginase on this study due to prior pancreatitis, stroke or other toxicity are not eligible.
• Patients with clinically significant prior allergies to PEG asparaginase are eligible if Erwinia L-asparaginase can be substituted. The study will not supply Erwinia.
• Patients who initially receive asparaginase, but must discontinue due to toxicity, remain eligible.
• Patients with documented active and uncontrolled infection at the time of study entry are not eligible.
• Patient will be excluded if they are currently receiving other investigational drugs.
• Patients will be excluded if they are taking strong CYP3A4 inducers or inhibitors.
• Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
• Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Sponsors & Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium: lead
• Enzon Pharmaceuticals, Inc.: collaborator

Study Sites (7)

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21231, United States

Location

University of Minnesota Children's Hospital

Minneapolis, Minnesota, 20892, United States

Location

Childrens Hospital & Clinics of Minnesota

Minneapolis, Minnesota, 55404-4597, United States

Location

New York University Medical Center

New York, New York, 10016, United States

Location

St. Jude

Memphis, Tennessee, 38105-3678, United States

Location

Sydney Children's Hospital

Sydney, Australia

Location

Related Publications (1)

• Raetz EA, Morrison D, Romanos-Sirakis E, Gaynon P, Sposto R, Bhojwani D, Bostrom BC, Brown P, Eckroth E, Cassar J, Malvar J, Buchbinder A, Carroll WL. A phase I study of EZN-3042, a novel survivin messenger ribonucleic acid (mRNA) antagonist, administered in combination with chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. J Pediatr Hematol Oncol. 2014 Aug;36(6):458-63. doi: 10.1097/MPH.0b013e3182a8f58f.

  PMID: 24276047 RESULT

Related Links

• Therapeutic Advances in Childhood Leukemia \& Lymphoma Consortium web site

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Leukemia

Interventions

EZN 3042; SPC 3042; Cytarabine; Doxorubicin; Prednisone; Vincristine; pegaspargase; Methotrexate; Hydrocortisone; hydrocortisone hemisuccinate; hydrocortisone valerate; Cortisone; hydrocortisone sodium phosphate

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Aminopterin; Pterins; Pteridines; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Limitations and Caveats

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

Results Point of Contact

• Title: Peggy Romano, BA, CCRP
• Organization: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) / Children's Hospital Los Angeles

promano@chla.usc.edu

323-361-5505

Study Officials

• Elizabeth Raetz, MD

  NYU Langone Health

  STUDY CHAIR

• William Carroll, MD

  NYU Langone Health

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 19, 2010
• First Posted: August 23, 2010
• Study Start: August 24, 2010
• Primary Completion: January 10, 2012
• Study Completion: January 10, 2012
• Last Updated: February 1, 2024
• Results First Posted: July 24, 2019

Record last verified: 2023-05

Locations

US (6); AU (1)