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

Primary Purpose

Lymphoblastic Leukemia, Acute, Lymphoblastic Leukemia, Acute, Childhood, Leukemia, Lymphoblastic, Acute, T Cell

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
EZN-3042
Cytarabine
Doxorubicin
Prednisone
Vincristine
PEG-asparaginase
Methotrexate
Hydrocortisone
Sponsored by
Therapeutic Advances in Childhood Leukemia Consortium
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoblastic Leukemia, Acute focused on measuring Relapse, T cell, Lymphoblastic, Leukemia, EZN3042, Refractory, Precursor B, Pre B cell, Survivin, Acute, Childhood, Pediatric

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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.
  • 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 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.

Sites / Locations

  • Childrens Hospital Los Angeles
  • Johns Hopkins University
  • University of Minnesota Children's Hospital
  • Childrens Hospital & Clinics of Minnesota
  • New York University Medical Center
  • St. Jude
  • Sydney Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single Arm

Arm Description

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Disease Response
Possible outcomes are: Complete Remission (CR) defined as M1 bone marrow with no evidence of circulating blasts and with recovery of peripheral counts (ANC > 750 ul and PLT count > 75,000 uL) Complete Remission without Platelet Recovery (CRp) defined as attainment o M1 bone marrow with ANC > 750 uL, but with insufficient recovery of platelets (< 75,000 uL) Partial Remission (PR) defined as complete disappearance of circulating blasts and achievement of M2 marrow, without new sites of extramedullary disease and ANC > 750/uL) Stable Disease (SD) defined as recovery of ANC >750/uL but fails to qualify for CR, CRp, or PR Progressive Disease (PD) defined as an increase of at least 25% in absolute number of circulating leukemic cells, development of new sites of extramedullary disease, or other evidence of PD Induction Death defined as any patient who dies prior to receiving subsequent therapy

Full Information

First Posted
August 19, 2010
Last Updated
May 21, 2019
Sponsor
Therapeutic Advances in Childhood Leukemia Consortium
Collaborators
Enzon Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01186328
Brief Title
EZN-3042 Administered With Re-induction Chemotherapy in Children With Relapsed Acute Lymphoblastic Leukemia (ALL)
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Terminated
Why Stopped
Enzon Pharmaceuticals decided to end its development of EZN-3042.
Study Start Date
August 24, 2010 (Actual)
Primary Completion Date
January 10, 2012 (Actual)
Study Completion Date
January 10, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Therapeutic Advances in Childhood Leukemia Consortium
Collaborators
Enzon Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Single Arm
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
EZN-3042
Other Intervention Name(s)
SPC 3042
Intervention Description
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 Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
ARA-C, cytosine arabinoside, Cytosar, Cytosar-U®, Arabinosylcytosine
Intervention Description
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: - 1.99 years: 16 mg - 2.99 years: 20 mg - 8.99 years: 24 mg Greater than or equal to 9 years: 30 mg
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Adriamycin, Rubex
Intervention Description
60 mg/m2/day given intravenous infusion (IV) over 15 minutes on day 1.
Intervention Type
Drug
Intervention Name(s)
Prednisone
Other Intervention Name(s)
Prednisone Intensol®, Sterapred®, Sterapred® DS, Predone®, Deltasone®
Intervention Description
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 Type
Drug
Intervention Name(s)
Vincristine
Other Intervention Name(s)
Oncovin®, vincristine sulfate, Vincasar Pfs®, VCR, LCR
Intervention Description
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 Type
Drug
Intervention Name(s)
PEG-asparaginase
Other Intervention Name(s)
Oncaspar®, PEG-L-asparaginase
Intervention Description
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 Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Rheumatrex, Trexall, Amethopterin, Methotrexate Sodium, MTX
Intervention Description
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: - 1.99 years: 8 mg - 2.99 years: 10 mg - 8.99 years: 12 mg Greater than or equal to 9 years: 15 mg
Intervention Type
Drug
Intervention Name(s)
Hydrocortisone
Other Intervention Name(s)
Ala-Cort ®, Hydrocortone Phosphate, Solu-Cortef®, Hydrocort Acetate®, Lanacort®, Cortef®, Westcort®, Cortisone, Hydrocortisone Sodium Succinate, Hydrocortisone Sodium Phosphate
Intervention Description
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: - 1.99 years: 8 mg - 2.99 years: 10 mg - 8.99 years: 12 mg Greater than or equal to 9 years: 15 mg
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose of EZN-3042
Description
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.
Time Frame
2 months
Secondary Outcome Measure Information:
Title
Disease Response
Description
Possible outcomes are: Complete Remission (CR) defined as M1 bone marrow with no evidence of circulating blasts and with recovery of peripheral counts (ANC > 750 ul and PLT count > 75,000 uL) Complete Remission without Platelet Recovery (CRp) defined as attainment o M1 bone marrow with ANC > 750 uL, but with insufficient recovery of platelets (< 75,000 uL) Partial Remission (PR) defined as complete disappearance of circulating blasts and achievement of M2 marrow, without new sites of extramedullary disease and ANC > 750/uL) Stable Disease (SD) defined as recovery of ANC >750/uL but fails to qualify for CR, CRp, or PR Progressive Disease (PD) defined as an increase of at least 25% in absolute number of circulating leukemic cells, development of new sites of extramedullary disease, or other evidence of PD Induction Death defined as any patient who dies prior to receiving subsequent therapy
Time Frame
Day 36

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. 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 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elizabeth Raetz, MD
Organizational Affiliation
NYU Langone Health
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
William Carroll, MD
Organizational Affiliation
NYU Langone Health
Official's Role
Study Chair
Facility Information:
Facility Name
Childrens Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Facility Name
University of Minnesota Children's Hospital
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
20892
Country
United States
Facility Name
Childrens Hospital & Clinics of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404-4597
Country
United States
Facility Name
New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
St. Jude
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105-3678
Country
United States
Facility Name
Sydney Children's Hospital
City
Sydney
Country
Australia

12. IPD Sharing Statement

Citations:
PubMed Identifier
24276047
Citation
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.
Results Reference
result
Links:
URL
http://www.tacl.us
Description
Therapeutic Advances in Childhood Leukemia & Lymphoma Consortium web site

Learn more about this trial

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

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