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Trial record 66 of 326 for:    "Acute Lymphocytic Leukemia" | "Methotrexate"

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

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ClinicalTrials.gov Identifier: NCT01186328
Recruitment Status : Terminated (Enzon Pharmaceuticals decided to end its development of EZN-3042.)
First Posted : August 23, 2010
Results First Posted : July 24, 2019
Last Update Posted : July 24, 2019
Sponsor:
Collaborator:
Enzon Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium

Tracking Information
First Submitted Date  ICMJE August 19, 2010
First Posted Date  ICMJE August 23, 2010
Results First Submitted Date  ICMJE October 3, 2018
Results First Posted Date  ICMJE July 24, 2019
Last Update Posted Date July 24, 2019
Actual Study Start Date  ICMJE August 24, 2010
Actual Primary Completion Date January 10, 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
Maximum Tolerated Dose of EZN-3042 [ Time Frame: 2 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 20, 2010)
  • 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 ]
  • To determine the recommended dose of EZN-3042 administered weekly in combination with re-induction chemotherapy. [ Time Frame: 2 years ]
Change History Complete list of historical versions of study NCT01186328 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
Disease Response [ Time Frame: Day 36 ]
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
Original Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2010)
  • Investigate survivin transcript and protein expression before and after EZN-3042 administration in enriched bone marrow blasts [ Time Frame: 2 years ]
  • 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 ]
  • 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 ]
  • 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 ]
  • To evaluate the pharmacokinetic (PK) profile of ENZ-3042 when administered as a single agent in pediatric patients. [ Time Frame: 2 years ]
  • To assess the anti-tumor activity of ENZ-3042 alone and in combination with cytotoxic chemotherapy [ Time Frame: 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE EZN-3042 Administered With Re-induction Chemotherapy in Children With Relapsed Acute Lymphoblastic Leukemia (ALL)
Official Title  ICMJE 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)
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lymphoblastic Leukemia, Acute
  • Lymphoblastic Leukemia, Acute, Childhood
  • Leukemia, Lymphoblastic, Acute, T Cell
  • Leukemia, Lymphoblastic, Acute
Intervention  ICMJE
  • 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. Dose levels: L0 (level zero): 1.5 mg/kg, L1: 2.5 mg/kg, L2: 5 mg/kg, L3: 6.5 mg/kg
    Other Name: SPC 3042
  • Drug: Cytarabine

    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

    Other Names:
    • ARA-C
    • cytosine arabinoside
    • Cytosar
    • Cytosar-U®
    • Arabinosylcytosine
  • 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 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.
    Other Names:
    • Prednisone Intensol®
    • Sterapred®
    • Sterapred® DS
    • Predone®
    • Deltasone®
  • Drug: Vincristine
    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.
    Other Names:
    • Oncovin®
    • vincristine sulfate
    • Vincasar Pfs®
    • VCR
    • LCR
  • Drug: PEG-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.
    Other Names:
    • Oncaspar®
    • PEG-L-asparaginase
  • Drug: Methotrexate

    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

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

    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

    Other Names:
    • Ala-Cort ®
    • Hydrocortone Phosphate
    • Solu-Cortef®
    • Hydrocort Acetate®
    • Lanacort®
    • Cortef®
    • Westcort®
    • Cortisone
    • Hydrocortisone Sodium Succinate
    • Hydrocortisone Sodium Phosphate
Study Arms  ICMJE Experimental: Single Arm
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).
Interventions:
  • Drug: EZN-3042
  • Drug: Cytarabine
  • Drug: Doxorubicin
  • Drug: Prednisone
  • Drug: Vincristine
  • Drug: PEG-asparaginase
  • Drug: Methotrexate
  • Drug: Hydrocortisone
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 7, 2012)
6
Original Estimated Enrollment  ICMJE
 (submitted: August 20, 2010)
18
Actual Study Completion Date  ICMJE January 10, 2012
Actual Primary Completion Date January 10, 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries Brazil,   Canada
 
Administrative Information
NCT Number  ICMJE NCT01186328
Other Study ID Numbers  ICMJE T2009-007
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Therapeutic Advances in Childhood Leukemia Consortium
Study Sponsor  ICMJE Therapeutic Advances in Childhood Leukemia Consortium
Collaborators  ICMJE Enzon Pharmaceuticals, Inc.
Investigators  ICMJE
Study Chair: Elizabeth Raetz, MD NYU Langone Health
Study Chair: William Carroll, MD NYU Langone Health
PRS Account Therapeutic Advances in Childhood Leukemia Consortium
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP