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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01186328
Recruitment Status : Terminated (The company (Enzon Pharmaceuticals)providing the drug EZN-3042 decided to end its development of EZN-3042.)
First Posted : August 23, 2010
Last Update Posted : May 18, 2015
Enzon Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium

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.

Condition or disease Intervention/treatment Phase
Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, Acute, Childhood Leukemia, Lymphoblastic, Acute, T Cell Leukemia, Lymphoblastic, Acute Drug: EZN-3042 Drug: Cytarabine Drug: Doxorubicin Drug: Prednisone Drug: Vincristine Drug: Pegaspargase Drug: Methotrexate Phase 1

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 prior to initiating systemic therapy with vincristine, doxorubicin, prednisone and PEG-asparaginase. In addition, blood and bone marrow specimens will be drawn to measure minimal residual disease (MRD), pharmacokinetic levels of EZN-3042 and survivan 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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: T2009-007: 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) [IND 108753]
Study Start Date : August 2010
Actual Primary Completion Date : February 2012
Actual Study Completion Date : February 2012

Intervention Details:
    Drug: EZN-3042
    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.
    Drug: Cytarabine
    Given intrathecally on day -6 at the dose defined by age. Age 1-1.99 get 30 mg, age 2-2.99 get 50 mg, and age greater than or equal to 3 get 70 mg.
    Other Names:
    • ARA-C
    • cytosine arabinoside
    • Cytosar
    Drug: Doxorubicin
    60 mg/m2/day given intravenous infusion (IV) over 15 minutes on day 1.
    Other Names:
    • Adriamycin
    • Rubex
    Drug: Prednisone
    40 mg/m2/day divided twice or three times a day given orally on days 1 through 29.
    Other Names:
    • Prednisone Intensol®
    • Sterapred®
    • Sterapred® DS
    Drug: Vincristine
    .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.
    Other Names:
    • Oncovin
    • vincristine sulfate
    • Vincasar Pfs
    • VCR
    Drug: Pegaspargase
    2500 IU/m2 intramuscular injection on days 2, 9, 16, 23.
    Other Names:
    • Oncaspar
    • PEG-L-asparaginase
    Drug: Methotrexate

    Given intrathecally to patients with central nervous system 1 and central nervous system 2 disease at the dose defined by age below on days 15 and 36.

    Age 1-1.99 get 8 mg, age 2-2.99 get 10 mg, age 3-8.99 get 12 mg and greater than or equal to age 9 get 15 mg.

    Other Names:
    • Rheumatrex
    • Trexall
    • Amethopterin
    • Methotrexate Sodium
    • MTX

Primary Outcome Measures :
  1. To determine the safety and tolerability of administering EZN-3042 as a single agent and in combination with chemotherapy, for children with relapsed B-precursor acute lymphoblastic leukemia (ALL) [ Time Frame: 1.5 months ]
  2. To determine the recommended dose of EZN-3042 administered weekly in combination with re-induction chemotherapy. [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Investigate survivin transcript and protein expression before and after EZN-3042 administration in enriched bone marrow blasts [ Time Frame: 2 years ]
  2. To survey RNA and protein expression of proximal and distal components of the apoptotic pathway in sorted bone marrow blasts before and after EZN-3042 administration. [ Time Frame: 2 years ]
  3. Determine levels (transcript and protein) of selected apoptotic proteins and perform gene expression analysis on sorted peripheral blood blasts before and four hours after day 1 chemotherapy is initiated. [ Time Frame: 2 years ]
  4. Compare patterns of survivin expression, levels of apoptotic proteins and gene expression signatures before and after therapy in responders and non-responders. [ Time Frame: 2 years ]
  5. To evaluate the pharmacokinetic (PK) profile of ENZ-3042 when administered as a single agent in pediatric patients. [ Time Frame: 2 years ]
  6. To assess the anti-tumor activity of ENZ-3042 alone and in combination with cytotoxic chemotherapy [ Time Frame: 2 years ]

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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must be ≥1 and ≤ 21 years of age when originally diagnosed with acute lymphoblastic leukemia (ALL).
  • Patients must have a diagnosis of second or greater relapse 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 ≥ 50 for patients > 10 years of age and Lansky ≥ 50 for patients ≤ 10 years of age.
  • 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.
  • Patient's ALT must be < 5 x institutional upper limit of norm (ULN), unless the elevation is suspected to be disease-related.
  • Patient's total bilirubin must be ≤ 1.5 x ULN.
  • Patient's serum albumin must be ≥ 2 g/dL.
  • Patient must have prothrombin time (PT), partial thromboplastin time (PTT) and international normalized ratio (INR) ≤ 1.5 times the ULN.
  • Patient must have a shortening fraction ≥ 27% by echocardiogram or an ejection fraction ≥ 45% by gated nucleotide study.
  • Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
  • Female patients with infants must agree not to breastfeed their infants while on this study.
  • Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.

Exclusion Criteria:

  • 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01186328

  Show 27 Study Locations
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
Enzon Pharmaceuticals, Inc.
Study Chair: Elizabeth Raetz, MD New York University School of Medicine
Study Chair: William Carroll, MD New York University School of Medicine

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium Identifier: NCT01186328     History of Changes
Other Study ID Numbers: T2009-007
First Posted: August 23, 2010    Key Record Dates
Last Update Posted: May 18, 2015
Last Verified: May 2015

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
T cell
Precursor B
Pre B cell

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Acute Disease
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic