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

Purpose

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	Intervention	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

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: 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]

Resource links provided by NLM:

MedlinePlus related topics: Chronic Lymphocytic Leukemia Leukemia Steroids

Drug Information available for: Prednisone Methotrexate Cytarabine Vincristine sulfate Asparaginase Methotrexate sodium Doxorubicin Doxorubicin hydrochloride Pegaspargase

U.S. FDA Resources

Further study details as provided by Therapeutic Advances in Childhood Leukemia Consortium:

Primary Outcome Measures:

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 ] [ Designated as safety issue: Yes ]
To determine the recommended dose of EZN-3042 administered weekly in combination with re-induction chemotherapy. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Investigate survivin transcript and protein expression before and after EZN-3042 administration in enriched bone marrow blasts [ Time Frame: 2 years ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
To evaluate the pharmacokinetic (PK) profile of ENZ-3042 when administered as a single agent in pediatric patients. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To assess the anti-tumor activity of ENZ-3042 alone and in combination with cytotoxic chemotherapy [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Enrollment:	6
Study Start Date:	August 2010
Estimated Study Completion Date:	June 2012
Primary Completion Date:	February 2012 (Final data collection date for primary outcome measure)

Intervention Details:

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.

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

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

Other Names:

Adriamycin
Rubex

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

.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

2500 IU/m2 intramuscular injection on days 2, 9, 16, 23.

Other Names:

Oncaspar
PEG-L-asparaginase

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

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.

Eligibility

Ages Eligible for Study:	1 Year to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01186328

Show 27 Study Locations

Sponsors and Collaborators

Therapeutic Advances in Childhood Leukemia Consortium

Enzon Pharmaceuticals, Inc.

Investigators

Study Chair:	Elizabeth Raetz, MD	New York University School of Medicine
Study Chair:	William Carroll, MD	New York University School of Medicine

More Information

No publications provided

Responsible Party:	Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier:	NCT01186328 History of Changes
Other Study ID Numbers:	T2009-007
Study First Received:	August 19, 2010
Last Updated:	March 7, 2012
Health Authority:	United States: Food and Drug Administration Canada: Health Canada Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:

EZN3042
Relapse
T cell
Lymphoblastic
Leukemia
Refractory

Precursor B
Pre B cell
Survivan
Acute
Childhood
Pediatric

Additional relevant MeSH terms:

Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Disease
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Pegaspargase
Asparaginase

Cytarabine
Doxorubicin
Methotrexate
Prednisone
Vincristine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors

ClinicalTrials.gov processed this record on June 17, 2013