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Lymphoblastic Leukemia, AcutePhase 1NCT01186328

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

A Phase 1 study testing EZN-3042, Cytarabine and Doxorubicin in people with Lymphoblastic Leukemia, Acute and Lymphoblastic Leukemia, Acute, Childhood, run by Therapeutic Advances in Childhood Leukemia Consortium at 7 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 1 year to 21 years
What is being tested?
EZN-3042, Cytarabine and Doxorubicin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6 participants
Where
7 sitesin 2 countries
Study dates
24 Aug 2010to 10 Jan 2012
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

7 sites in 2 countries.

7 sites in 2 countries

United States6 sites

  • Johns Hopkins University

    Baltimore, Maryland, 21231

  • Childrens Hospital Los Angeles

    Los Angeles, California, 90027

  • St. Jude

    Memphis, Tennessee, 38105-3678

  • University of Minnesota Children's Hospital

    Minneapolis, Minnesota, 20892

  • Childrens Hospital & Clinics of Minnesota

    Minneapolis, Minnesota, 55404-4597

  • New York University Medical Center

    New York, New York, 10016

Other trials in United States

Australia1 site

  • Sydney Children's Hospital

    Sydney

Other trials in Australia

About this study

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)

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.

Read the 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.

Being tested
EZN-3042, Cytarabine, Doxorubicin, Prednisone, Vincristine
Keywords
Relapse, T cell, Lymphoblastic, Leukemia, EZN3042, Refractory, Precursor B, Pre B cell, Survivin, Acute, Childhood, Pediatric
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Recurrence, Leukemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EZN-3042Drug

    Also called SPC 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. Dose levels: L0 (level zero): 1.5 mg/kg, L1: 2.5 mg/kg, L2: 5 mg/kg, L3: 6.5 mg/kg

  • CytarabineDrug

    Also called ARA-C, cytosine arabinoside, Cytosar, Cytosar-U®

    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

  • DoxorubicinDrug

    Also called Adriamycin, Rubex

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

  • PrednisoneDrug

    Also called Prednisone Intensol®, Sterapred®, Sterapred® DS, Predone®

    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.

  • VincristineDrug

    Also called Oncovin®, vincristine sulfate, Vincasar Pfs®, VCR

    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.

  • PEG-asparaginaseDrug

    Also called Oncaspar®, PEG-L-asparaginase

    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.

  • MethotrexateDrug

    Also called Rheumatrex, Trexall, Amethopterin, Methotrexate Sodium

    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

  • HydrocortisoneDrug

    Also called Ala-Cort ®, Hydrocortone Phosphate, Solu-Cortef®, Hydrocort Acetate®

    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

Study groups in NCT01186328
Study groupRoleWhat they receive
Single ArmExperimentalPatients 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).
Receives: Drug: EZN-3042; Drug: Cytarabine; Drug: Doxorubicin; Drug: Prednisone; Drug: Vincristine; Drug: PEG-asparaginase; Drug: Methotrexate; Drug: Hydrocortisone

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 2 months

Secondary outcomes (1)

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

    To evaluate primary target engagement of EZN-3042 we will examine survivin transcript and protein expression before (Day -6) and after EZN-3042 administration (Day 0) in enriched bone marrow blasts in children with relapsed B-precursor leukemia.

    Measured: Day -6 to Day 0

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Aug 2010 (estimated)
  2. Study start24 Aug 2010
  3. Primary completion10 Jan 2012
  4. Study completion10 Jan 2012

Why it stopped: Enzon Pharmaceuticals decided to end its development of EZN-3042.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
6 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01186328
Sponsor's protocol ID
T2009-007
Status last verified
May 2023
First submitted
19 Aug 2010
Last updated
1 Feb 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 24276047

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing EZN-3042, Cytarabine and Doxorubicin in people with Lymphoblastic Leukemia, Acute and Lymphoblastic Leukemia, Acute, Childhood, run by Therapeutic Advances in Childhood Leukemia Consortium at 7 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 1 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Jul 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose of EZN-3042 (time frame: 2 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01186328, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2024.

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