Calaspargase Pegol or Pegaspargase and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia
Condition: Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia; Childhood B Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 3

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.
    

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 #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.
    

Intervention name(s): Calaspargase Pegol-mknl; Cyclophosphamide; Cytarabine; Daunorubicin Hydrochloride; Dexamethasone; Doxorubicin Hydrochloride; Laboratory Biomarker Analysis; Mercaptopurine; Methotrexate; Pegaspargase; Pharmacological Study; Prednisone; Radiation Therapy; Thioguanine; Vincristine Sulfate
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Other; Drug; Drug; Drug; Other; Drug; Radiation; Drug; Drug
Intervention description(s): Given IV; Given IV; Given IV, IT, PO, or SC; Given IV; Given PO or IV; Given IV; Correlative studies; Given PO; Given IV, IT, or PO; Given IV; Correlative studies; Given IV or PO; Some patients undergo RT; Given PO; Given IV
Other intervention name(s): Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl); Asparlas; Calaspargase Pegol; EZN-2285; SC-PEG E. Coli L-Asparaginase; Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Cerubidin; Cerubidine; Cloridrato de Daunorubicina; Daunoblastin; Daunoblastina; Daunoblastine; Daunomycin Hydrochloride; Daunomycin, hydrochloride; Daunorubicin.HCl; Daunorubicini Hydrochloridum; FI-6339; Ondena; RP-13057; Rubidomycin Hydrochloride; Rubilem; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycadron; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron; Decadron DP; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone Intensol; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Dxevo; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; TaperDex; Visumetazone; ZoDex; 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI); ADM; Adriacin; Adriamycin; Adriamycin Hydrochloride; Adriamycin PFS; Adriamycin RDF; ADRIAMYCIN, HYDROCHLORIDE; Adriamycine; Adriblastina; Adriblastine; Adrimedac; Chloridrato de Doxorrubicina; DOX; DOXO-CELL; Doxolem; Doxorubicin HCl; Doxorubicin.HCl; Doxorubin; Farmiblastina; FI 106; FI-106; hydroxydaunorubicin; Rubex; 3H-Purine-6-thiol; 6 MP; 6 Thiohypoxanthine; 6 Thiopurine; 6-Mercaptopurine; 6-Mercaptopurine Monohydrate; 6-MP; 6-Purinethiol; 6-Thiopurine; 6-Thioxopurine; 6H-Purine-6-thione, 1,7-dihydro- (9CI); 7-Mercapto-1,3,4,6-tetrazaindene; Alti-Mercaptopurine; Azathiopurine; Bw 57-323H; Flocofil; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptina; Mercaptopurinum; Mercapurin; Mern; NCI-C04886; Puri-Nethol; Purimethol; Purine, 6-mercapto-; Purine-6-thiol (8CI); Purine-6-thiol, monohydrate; Purinethiol; Purinethol; U-4748; WR-2785; Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate; Mexate-AQ; MTX; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; L-Asparaginase with Polyethylene Glycol; Oncaspar; Oncaspar-IV; PEG-Asparaginase; PEG-L-Asparaginase; PEG-L-Asparaginase (Enzon - Kyowa Hakko); PEGLA; Polyethylene Glycol L-Asparaginase; Polyethylene Glycol-L-Asparaginase; .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltasone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Orasone; Panafcort; Panasol-S; Paracort; Perrigo Prednisone; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisone Intensol; Prednisonum; Prednitone; Promifen; Rayos; Servisone; SK-Prednisone; Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; 2-Amino 6MP; 2-Amino-1,7-dihydro-6H-purine-6-thione; 2-Amino-6-mercaptopurine; 2-Amino-6-purinethiol; 2-Aminopurin-6-thiol; 2-Aminopurine-6(1H)-thione; 2-Aminopurine-6-thiol; 2-Aminopurine-6-thiol Hemihydrate; 2-Mercapto-6-aminopurine; 6-Amino-2-mercaptopurine; 6-Mercapto-2-aminopurine; 6-Mercaptoguanine; 6-TG; 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI); BW 5071; Lanvis; Tabloid; Thioguanine Hemihydrate; Thioguanine Hydrate; Tioguanin; Tioguanine; Wellcome U3B; WR-1141; X 27; Kyocristine; Leurocristine Sulfate; Leurocristine, sulfate; Oncovin; Vincasar; Vincosid; Vincrex; Vincristine, sulfate
Intervention MeSH terms: Cytarabine; Dexamethasone; Dexamethasone acetate; Prednisone; Cortisone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Pegaspargase; Thioguanine; BB 1101; 2-Aminopurine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment