Calaspargase Pegol or Pegaspargase and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT00671034

Recruitment Status : Unknown

Verified September 2018 by Children's Oncology Group.
Recruitment status was: Active, not recruiting

First Posted : May 2, 2008

Results First Posted : September 6, 2018

Last Update Posted : March 24, 2020

Sponsor:

Collaborator:

National Cancer Institute (NCI)

Information provided by (Responsible Party):

Children's Oncology Group

Study Description

Brief Summary:

This randomized clinical trial is studying giving calaspargase pegol together with combination chemotherapy to see how well it works compared with giving pegaspargase together with combination chemotherapy in treating younger patients with newly diagnosed high-risk acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Condition or disease	Intervention/treatment	Phase
B-cell Adult Acute Lymphoblastic Leukemia B-cell Childhood Acute Lymphoblastic Leukemia Untreated Adult Acute Lymphoblastic Leukemia Untreated Childhood Acute Lymphoblastic Leukemia	Drug: calaspargase pegol Drug: Pegaspargase Drug: DOXOrubicin Hydrochloride Drug: Cytarabine Drug: Prednisone Drug: methotrexate Drug: cyclophosphamide Drug: mercaptopurine tablet Drug: Dexamethasone Drug: thioguanine Drug: DAUNOrubicin Hydrochloride Drug: vincristine sulfate Radiation: radiation therapy Other: laboratory biomarker analysis Other: pharmacological study	Not Applicable

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Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the pharmacokinetic comparability of EZN-2285 (calaspargase pegol) compared to Oncaspar (pegaspargase) given intravenously during induction and consolidation in patients with high-risk ALL receiving augmented Berlin-Frankfurt-Munster (BFM) therapy.

SECONDARY OBJECTIVES:

I. To describe the pharmacodynamics (PD) of EZN-2285 compared to Oncaspar given intravenously during induction and consolidation in patients with high-risk ALL receiving augmented BFM therapy.

II. To determine end of induction therapy day 29 minimal residual disease (MRD) for patients randomized to the EZN-2285 containing regimen compared to the Oncaspar® containing regimen.

III. To determine the complete remission (CR) rates for patients receiving EZN-2285 by day 29 of induction compared to Oncaspar.

IV. To assess event-free survival (EFS) associated with the administration of EZN-2285 given during augmented post Induction intensification therapy to patients with high-risk ALL compared to Oncaspar.

V. To determine the proportion of patients with an asparaginase level of at least 0.1 IU/mL and the proportion with at least 0.4 IU/mL on days 4, 15, 22 and 29 of induction compared to Oncaspar.

VI. To determine the plasma and cerebrospinal fluid (CSF) concentrations of asparagine after administration of EZN-2285 compared to Oncaspar.

VII. To assess the immunogenicity of EZN-2285 including the detection of binding and neutralizing antibodies compared to Oncaspar.

VIII. To assess the tolerability and toxicities associated with the administration of EZN-2285 given during augmented post induction intensification therapy to patients with high risk ALL compared to Oncaspar.

IX. To explore the relationship between the terminal pharmacokinetics (PK) of EZN-2285 and the presence of antibodies.

OUTLINE: This is a multicenter study. Patients are stratified according to response to induction therapy (slow early responders [SER] vs rapid early responders [RER]. Patients are randomized to 1 of 2 treatment arms in 2:1 ratio (arm I: arm II) (patients randomized to arm I receive study drug calaspargase pegol*; patients randomized to arm II receive study drug pegaspargase).

INDUCTION THERAPY** (ALL PATIENTS): Patients receive cytarabine intrathecally (IT) on day 1; vincristine intravenously (IV) and daunorubicin hydrochloride IV over 15 minutes on days 1, 8, 15, and 22; prednisone orally or IV twice daily (BID) on days 1-28; study drug IV over 1 hour on day 4; and methotrexate IT on days 8, 15*, 22*, and 29. Patients are assessed for response on day 8 and/or day 15 and day 29. Patients who achieve M1 marrow on day 8 or 15 and negative MRD (i.e., < 0.1%) on day 29 are considered RER. Patients who achieve M2 or M3 marrow on day 15 OR MRD >= 0.1% but < 1% on day 29 are considered SER. Patients with M3 bone marrow are removed from the study. RER and SER proceed to consolidation therapy. Patients with M2 marrow or M1 marrow with >= 1% MRD receive extended induction therapy. Patients also receive dexamethasone PO or IV BID on days 1-14 (patients < 10 years) or prednisone BID on days 1-28 (patients >= 10 years)

NOTE: *For patients with CNS3 disease only.

EXTENDED INDUCTION THERAPY**: Patients receive vincristine IV on days 1 and 8; prednisone orally (PO) or IV BID on days 1-14; daunorubicin hydrochloride IV over 15 minutes on day 1; and study drug IV over 1 hour on day 4. Patients are assessed for response on day 43. Patients who achieve M1 and MRD < 1% are treated as SER (proceed to consolidation therapy). All other patients are removed from study.

CONSOLIDATION THERAPY** (ALL PATIENTS): Beginning on day 36 (after completion of induction therapy) or after completion of extended induction therapy, patients (RER and SER) receive cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; study drug IV over 1 hour on days 15 and 43; and methotrexate IT on days 1, 8, 15*, and 22*. Patients then proceed to interim maintenance I therapy.

NOTE: *Omit doses for patients with CNS3 disease.

INTERIM MAINTENANCE I** (ALL PATIENTS): Patients receive vincristine IV and methotrexate** IV on days 1, 11, 21, 31, and 41; study drug IV over 1 hour on days 2 and 22; and methotrexate IT on days 1 and 31. Patients then proceed to delayed intensification I therapy.

DELAYED INTENSIFICATION I** (ALL PATIENTS): Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-21 for patients age 1-9, or on days 1-7 and 15-21 for patients age >= 10; doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15; study drug IV over 1 hour on days 4 and 43; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39; thioguanine PO on days 29-42; and methotrexate IT on days 1, 29, and 36. Patients treated as RER proceed to maintenance therapy. Patients treated as SER (i.e., patients with CNS3 disease at diagnosis, or pre-treated with steroids, or who are RERs with mixed lineage leukemia [MLL] gene rearrangements) proceed to interim maintenance II followed by delayed intensification II.

INTERIM MAINTENANCE II** (SER ONLY): Patients receive vincristine IV, methotrexate IV, study drug IV, and methotrexate IT as in interim maintenance I.

DELAYED INTENSIFICATION II** (SER ONLY): Beginning on day 29, patients (except patients with CNS3 disease) receive 8 daily fractions of cranial radiotherapy. All patients then receive vincristine IV, dexamethasone PO or IV, doxorubicin hydrochloride IV, study drug IV, cyclophosphamide IV, cytarabine IV or SC, thioguanine PO, and methotrexate IT as in delayed intensification I. Patients who were initially diagnosed with CNS3 disease receive cranial radiotherapy on days 1-5 and 8-12. Patients then proceed to maintenance therapy.

MAINTENANCE THERAPY** (ALL PATIENTS): Patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate IT on day 29; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for up to 2 years (for female patients) or up to 3 years (for male patients) from the start of interim maintenance I.

NOTE: ** As per amendment #4A, most patients receive high-dose methotrexate instead of Capizzi methotrexate at most stages of therapy. CNS3 patients and SER patients who have received cranial irradiation receive planned therapy with no modifications.

NOTE: As per amendment #4A, the maximum number of intrathecal treatments is limited by RER/SER/CNS3 status and gender.

Blood and cerebrospinal fluid samples are collected periodically for correlative studies, including immunogenicity, pharmacokinetic, and pharmacodynamic studies.

After completion of study therapy, patients are followed every 2 months for 2 years, every 3 months for 1 year, and then every 6-12 months for 2 years.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	166 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Pilot Study of Intravenous EZN-2285 (SC-PEG E. Coli L-asparaginase, IND# 100594) or Intravenous Oncaspar® in the Treatment of Patients With High-Risk Acute Lymphoblastic Leukemia (ALL)
Study Start Date :	July 2008
Actual Primary Completion Date :	February 1, 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Chronic Lymphocytic Leukemia Leukemia

Drug Information available for: Pegaspargase

Genetic and Rare Diseases Information Center resources: Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma Childhood Acute Lymphoblastic Leukemia Lymphosarcoma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (calaspargase pegol 2100) Patients receive calaspargase pegol 2100 together with combination chemotherapy. Patients receive chemotherapy PO, IV, SC, and IT. Some patients also undergo radiation therapy to the head. Treatment may continue for up to 3 1/2 years.	Drug: calaspargase pegol Given IV Other Names: EZN-2285 SC-PEG2100 E. coli L-asparaginase succinimidyl carbonate monomethoxypolyethylene glycol E. coli L-asparaginase Drug: DOXOrubicin Hydrochloride Given IV Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: Cytarabine Given IV, IT, or SC Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: Prednisone Given IV or PO Other Names: DeCortin Delta Drug: methotrexate Given IV, IT, or PO Other Names: amethopterin Folex methylaminopterin Mexate MTX Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: mercaptopurine tablet Given PO Other Names: 6-mercaptopurine 6-MP Leukerin MP Drug: Dexamethasone Given PO or IV Other Names: Aeroseb-Dex Decadron DM DXM Drug: thioguanine Given PO Other Name: 6-TG Drug: DAUNOrubicin Hydrochloride Given IV Other Names: Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Drug: vincristine sulfate Given IV Other Names: leurocristine sulfate VCR Vincasar PFS Radiation: radiation therapy Some patients undergo RT Other Names: irradiation radiotherapy therapy, radiation Other: laboratory biomarker analysis Correlative studies
Experimental: Arm II (calaspargase pegol 2500) Patients receive calaspargase pegol 2500 together with combination chemotherapy. Patients receive chemotherapy PO, IV, SC, and IT. Some patients also undergo radiation therapy to the head. Treatment may continue for up to 3 1/2 years.	Drug: calaspargase pegol Given IV Other Names: EZN-2285 SC-PEG2500 E. coli L-asparaginase succinimidyl carbonate monomethoxypolyethylene glycol E. coli L-asparaginase Drug: DOXOrubicin Hydrochloride Given IV Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: Cytarabine Given IV, IT, or SC Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: Prednisone Given IV or PO Other Names: DeCortin Delta Drug: methotrexate Given IV, IT, or PO Other Names: amethopterin Folex methylaminopterin Mexate MTX Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: mercaptopurine tablet Given PO Other Names: 6-mercaptopurine 6-MP Leukerin MP Drug: Dexamethasone Given PO or IV Other Names: Aeroseb-Dex Decadron DM DXM Drug: thioguanine Given PO Other Name: 6-TG Drug: DAUNOrubicin Hydrochloride Given IV Other Names: Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Drug: vincristine sulfate Given IV Other Names: leurocristine sulfate VCR Vincasar PFS Radiation: radiation therapy Some patients undergo RT Other Names: irradiation radiotherapy therapy, radiation Other: laboratory biomarker analysis Correlative studies Other: pharmacological study Correlative studies Other Name: pharmacological studies
Active Comparator: Arm III (pegaspargase 2500) Patients receive pegaspargase 2500 together with combination chemotherapy. Patients receive chemotherapy PO, IV, SC, and IT. Some patients also undergo RT to the head. Treatment may continue for up to 3 1/2 years.	Drug: Pegaspargase Given IV Other Names: L-asparaginase with polyethylene glycol Oncaspar PEG-ASP PEG-L-asparaginase Drug: DOXOrubicin Hydrochloride Given IV Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: Cytarabine Given IV, IT, or SC Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside Drug: Prednisone Given IV or PO Other Names: DeCortin Delta Drug: methotrexate Given IV, IT, or PO Other Names: amethopterin Folex methylaminopterin Mexate MTX Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: mercaptopurine tablet Given PO Other Names: 6-mercaptopurine 6-MP Leukerin MP Drug: Dexamethasone Given PO or IV Other Names: Aeroseb-Dex Decadron DM DXM Drug: thioguanine Given PO Other Name: 6-TG Drug: DAUNOrubicin Hydrochloride Given IV Other Names: Cerubidine daunomycin hydrochloride daunorubicin RP-13057 Drug: vincristine sulfate Given IV Other Names: leurocristine sulfate VCR Vincasar PFS Radiation: radiation therapy Some patients undergo RT Other Names: irradiation radiotherapy therapy, radiation Other: laboratory biomarker analysis Correlative studies

Outcome Measures

Primary Outcome Measures :

Pharmacokinetics (PK) (Half-life of SC-PEG E. Coli L-asparaginase (EZN-2285) Compared to Pegaspargase During Induction and Consolidation Therapy) [ Time Frame: Post Day 29 of Induction and Post Day 22 of Consolidation ]
Mean half-life of plasma asparaginase during consolidation and Induction; half-life is defined as the time taken for drug concentration to decrease by half.

Secondary Outcome Measures :

Pharmacodynamics (PD) [ Time Frame: Day 29 of consolidation and induction ]
Plasma Asparaginase Concentration During consolidation and induction.
Percentage of Participants With Minimal Residual Disease (MRD)<0.01% at the End of Induction [ Time Frame: End of induction (Day 29) ]
Percentage of participants with Negative MRD (MRD<0.01%).
Percentage of Participants With Complete Remission at the End of Induction [ Time Frame: End of induction (Day 29) ]
Complete Remission (CR) rate; where CR is defined as M1 marrow (< 5% lymphoblasts in the bone marrow)
Percentage of Participants With Event-free Survival (EFS) [ Time Frame: 5 Years ]
Percentage of participants who were event free. Event Free Probability defined as time from randomization at study entry to first event (induction failure, induction death, relapse, second malignant neoplasm, remission death) or date of last contact for subjects who are event-free.
Asparaginase Level [ Time Frame: Days 4, 15, 22 and 29 of Induction ]
The proportion of patients with an asparaginase level of at least 0.1 IU/mL and the proportion with at least 0.4 IU/mL on Days 4, 15, 22 and 29 of Induction compared to Oncaspar
Plasma and CSF Concentrations of Asparagine in ug/ml [ Time Frame: 25 Days Post-dose (Day 29) ]
The plasma and CSF concentrations of asparagine in ug/ml after administration of EZN-2285 compared to Oncaspar.
Immunogenicity [ Time Frame: 25 Days Post-dose (Day 29) ]
Number of Patients with Positive Immunogenicity tests
Toxicities During Post Induction Intensification Therapy (All Grades) [ Time Frame: Up to 5 years ]
The calculation of AE incidence will be based on the number of patients per AE category. For each patient who has multiple AEs classified to the same category, that patient will be tabulated under the worst toxicity grade for that AE category. The incidence of AEs will be tabulated by treatment arm and by organ class. Special attention will be paid to hypersensitivity, pancreatitis, coagulopathy, infection, neurologic dysfunction and thromboembolic events.
Relationship Between PK and Presence of Antibodies [ Time Frame: Day 29 of consolidation ]
Patients with presence of Antibodies.

Eligibility Criteria

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Ages Eligible for Study:	2 Years to 30 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients must be eligible for and enrolled on AALL08B1 or the successor classification study
Patients must have newly diagnosed high-risk B lymphoblastic leukemia (World Health Organization [WHO] 2008 classification) (also termed B-precursor acute lymphoblastic leukemia)
White blood cell (WBC) >= 50,000/μL for patients age 1-9 OR any WBC count for patients age 10-30 or for patients treated with prior steroids
Patients shall have had no prior cytotoxic chemotherapy with the exception of steroids and intrathecal cytarabine; intrathecal chemotherapy with cytarabine is allowed prior to registration for patient convenience; this is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture; (Note: the CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment) systemic chemotherapy must begin within 72 hours of this intrathecal therapy
Patients receiving prior steroid therapy are eligible for this study; the dose and duration of previous steroid therapy should be carefully documented
Pregnancy tests with a negative result must be obtained in all post-menarchal females
Lactating females must agree that they will not breastfeed a child while on this study

Exclusion Criteria:

Patients with Down syndrome are excluded from this study
Patients with testicular leukemia at diagnosis are excluded from this study
Pregnant female patients are excluded from this study

Contacts and Locations

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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 ClinicalTrials.gov identifier (NCT number): NCT00671034

Locations

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United States, California
Childrens Hospital of Orange County
Orange, California, United States, 92868-3874
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States, 94304
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Connecticut
Connecticut Children's Medical Center
Hartford, Connecticut, United States, 06106
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Illinois
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States, 60614
United States, Indiana
Indiana University Cancer Center
Indianapolis, Indiana, United States, 46202
Indiana University Medical Center
Indianapolis, Indiana, United States, 46202
United States, Maryland
Johns Hopkins University-Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
United States, Michigan
Wayne State University-Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Minnesota
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis, Minnesota, United States, 55404
University of Minnesota Medical Center-Fairview
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New Mexico
University of New Mexico Cancer Center
Albuquerque, New Mexico, United States, 87106
United States, New York
New York University Langone Medical Center
New York, New York, United States, 10016
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Oklahoma
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States, 73104
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
United States, Utah
Primary Children's Hospital
Salt Lake City, Utah, United States, 84113
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	Anne Angiolillo, MD	Children's Oncology Group

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schore RJ, Devidas M, Bleyer A, Reaman GH, Winick N, Loh ML, Raetz EA, Carroll WL, Hunger SP, Angiolillo AL. Plasma asparaginase activity and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase on Children's Oncology Group AALL07P4(.). Leuk Lymphoma. 2019 Jul;60(7):1740-1748. doi: 10.1080/10428194.2018.1542146. Epub 2019 Jan 10.

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Responsible Party:	Children's Oncology Group
ClinicalTrials.gov Identifier:	NCT00671034
Other Study ID Numbers:	AALL07P4 NCI-2009-00317 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) COG-AALL07P4 ( Other Identifier: Children's Oncology Group ) CDR0000594340 ( Other Identifier: Clinical Trials.gov ) AALL07P4 ( Other Identifier: Children's Oncology Group ) AALL07P4 ( Other Identifier: CTEP ) U10CA098543 ( U.S. NIH Grant/Contract )
First Posted:	May 2, 2008 Key Record Dates
Results First Posted:	September 6, 2018
Last Update Posted:	March 24, 2020
Last Verified:	September 2018

Additional relevant MeSH terms:

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Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Cytarabine Dexamethasone Prednisone Cyclophosphamide Doxorubicin Liposomal doxorubicin	Methotrexate Vincristine Daunorubicin Asparaginase Mercaptopurine Pegaspargase Thioguanine Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents

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