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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 #4, 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 #4, 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.

Official Title
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A Pilot Study of Intravenous EZN-2285 (SC-PEG E. Coli L-asparaginase) or Intravenous Oncaspar® in the Treatment of Patients With High-Risk Acute Lymphoblastic Leukemia (ALL)

Conditions
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Acute Lymphoblastic Leukemia, Adult B Acute Lymphoblastic Leukemia, Childhood B Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Calaspargase Pegol-mknl
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Drug: Dexamethasone
* Drug: Doxorubicin Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Mercaptopurine
* Drug: Methotrexate
* Drug: Pegaspargase
* Other: Pharmacological Study
* Drug: Prednisone
* Radiation: Radiation Therapy
* Drug: Thioguanine
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (combination chemotherapy)<br>Patients receive calaspargase pegol 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 4 years. | Drug: Calaspargase Pegol-mknl<br>* Given IV<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IV, IT, PO, or SC<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IV, IT, or PO<br>* Other names: WR-19039;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Prednisone<br>* Given IV or PO<br>* Other names: SK-Prednisone;Radiation: Radiation Therapy<br>* Some patients undergo RT<br>* Other names: Therapy, Radiation;Drug: Thioguanine<br>* Given PO<br>* Other names: X 27;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Active Comparator: Arm II (combination chemotherapy)<br>Patients receive pegaspargase 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 4 years. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IV, IT, PO, or SC<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IV, IT, or PO<br>* Other names: WR-19039;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Prednisone<br>* Given IV or PO<br>* Other names: SK-Prednisone;Radiation: Radiation Therapy<br>* Some patients undergo RT<br>* Other names: Therapy, Radiation;Drug: Thioguanine<br>* Given PO<br>* Other names: X 27;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) (Half-life of SC-PEG E. Coli L-asparaginase (EZN-2285) Compared to Pegaspargase During Induction and Consolidation Therapy) | 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. | Post Day 29 of Induction and Post Day 22 of Consolidation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics (PD) | Plasma Asparaginase Concentration During consolidation and induction. | Day 29 of consolidation and induction | 
| Percentage of Participants With Minimal Residual Disease (MRD)<0.01% at the End of Induction | Percentage of participants with Negative MRD (MRD<0.01%). | End of induction (Day 29) | 
| Percentage of Participants With Complete Remission at the End of Induction | Complete Remission (CR) rate; where CR is defined as M1 marrow (< 5% lymphoblasts in the bone marrow) | End of induction (Day 29) | 
| Percentage of Participants With Event-free Survival (EFS) | 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. | 5 Years | 
| Asparaginase Level | 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 | Days 4, 15, 22 and 29 of Induction | 
| Plasma and CSF Concentrations of Asparagine in ug/ml | The plasma and CSF concentrations of asparagine in ug/ml after administration of EZN-2285 compared to Oncaspar. | 25 Days Post-dose (Day 29) | 
| Immunogenicity | Number of Patients with Positive Immunogenicity tests | 25 Days Post-dose (Day 29) | 
| Toxicities During Post Induction Intensification Therapy (All Grades) | 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. | Up to 5 years | 
| Relationship Between PK and Presence of Antibodies | Patients with presence of Antibodies. | Day 29 of consolidation |