Clinical Trials /

Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia

NCT02003222

Description:

This randomized phase III trial studies combination chemotherapy with blinatumomab to see how well it works compared to induction chemotherapy alone in treating patients with newly diagnosed breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor tyrosine kinase (ABL)-negative B lineage acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread It is not yet known whether combination chemotherapy is more effective with or without blinatumomab in treating newly diagnosed acute lymphoblastic leukemia.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia
  • Official Title: A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia in Adults

Clinical Trial IDs

  • ORG STUDY ID: NCI-2013-02229
  • SECONDARY ID: NCI-2013-02229
  • SECONDARY ID: E1910
  • SECONDARY ID: ECOG-E1910
  • SECONDARY ID: PE1910_A08PAMDREVW01
  • SECONDARY ID: E1910
  • SECONDARY ID: E1910
  • SECONDARY ID: U10CA180820
  • SECONDARY ID: U10CA021115
  • SECONDARY ID: U24CA196172
  • NCT ID: NCT02003222

Conditions

  • Acute Lymphoblastic Leukemia
  • B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative
  • BCR/ABL1 Fusion Protein Negative
  • Untreated Adult Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
BlinatumomabAnti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody, Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103, Blincyto, MEDI-538, MT-103Arm I (blinatumomab, chemotherapy)
Cyclophosphamide(-)-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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm I (blinatumomab, chemotherapy)
Cytarabine.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-28453Arm I (blinatumomab, chemotherapy)
Daunorubicin HydrochlorideCerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, RubilemArm I (blinatumomab, chemotherapy)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, 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, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, VisumetazoneArm I (blinatumomab, chemotherapy)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Arm I (blinatumomab, chemotherapy)
Mercaptopurine3H-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-2785Arm I (blinatumomab, chemotherapy)
MethotrexateAbitrexate, 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-19039Arm I (blinatumomab, chemotherapy)
PegaspargaseL-Asparaginase with Polyethylene Glycol, Oncaspar, PEG-Asparaginase, PEG-L-Asparaginase, PEG-L-Asparaginase (Enzon - Kyowa Hakko), PEGLA, Polyethylene Glycol L-Asparaginase, Polyethylene Glycol-L-AsparaginaseArm I (blinatumomab, chemotherapy)
Prednisone.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, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisonum, Prednitone, Promifen, Servisone, SK-PrednisoneArm I (blinatumomab, chemotherapy)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Arm I (blinatumomab, chemotherapy)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm I (blinatumomab, chemotherapy)

Purpose

This randomized phase III trial studies combination chemotherapy with blinatumomab to see how well it works compared to induction chemotherapy alone in treating patients with newly diagnosed breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor tyrosine kinase (ABL)-negative B lineage acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread It is not yet known whether combination chemotherapy is more effective with or without blinatumomab in treating newly diagnosed acute lymphoblastic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the overall survival (OS) of blinatumomab in conjunction with chemotherapy to
      chemotherapy alone in patients with BCR-ABL-negative B cell precursor acute lymphoblastic
      leukemia (ALL) who are minimal residual disease (MRD) positive after induction and
      intensification chemotherapy, based on multiparameter flow cytometric (MFC) assessment of
      residual blasts.

      SECONDARY OBJECTIVES:

      I. To compare the relapse-free survival (RFS) of blinatumomab in conjunction with
      chemotherapy to chemotherapy alone in MRD positive patients, MRD negative patients and
      overall population after induction and intensification chemotherapy.

      II. To compare the OS and RFS of those patients who are MRD+ at step 3 randomization/
      registration and then convert to MRD- after 2 cycles of blinatumomab to those patients who
      are MRD- at randomization and remain MRD- after 2 cycles of blinatumomab or consolidation
      chemotherapy.

      III. To assess the toxicities of blinatumomab in this patient population. IV. To assess the
      toxicities of the modified E2993 chemotherapy regimen in this patient population.

      V. To describe the outcome of patients who proceed to allogeneic blood or marrow transplant
      after treatment with or without blinatumomab.

      LABORATORY OBJECTIVES:

      I. To determine differences in MRD kinetics among patients with the BCR/ABL1-like B-lineage
      ALL, and assess the efficacy of blinatumomab in each molecular subgroup.

      II. To evaluate the incidence of anti-blinatumomab antibody formation.

      OUTLINE:

      INDUCTION CHEMOTHERAPY: Patients receive cytarabine intrathecally (IT) on day 1; daunorubicin
      hydrochloride intravenously (IV) over 10-15 minutes on days 1, 8, 15, and 22; vincristine
      sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on days 1-7 (and 15-21
      for patients age < 55 years only); methotrexate IT on day 14; pegaspargase intramuscularly
      (IM) or IV on day 18 (patients age =< 55 years); and CD20 positive patients may optionally
      receive rituximab IV on day 8 and 15. Beginning on day 29, patients with absolute neutrophil
      count (ANC) >= 0.75 x 10^9/L and platelets > 75 x 10^9/L (patients with delayed hematologic
      recovery) (patients with residual disease that is delaying count begin treatment immediately)
      receive cyclophosphamide IV over 30 minutes on days 1 and 29, cytarabine IV over 30 minutes
      or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14,
      29-42, pegaspargase IM or IV on day 15 (patients age < 55 years), patients receiving
      treatment for central nervous system (CNS) 2 or 3 leukemia in course 1 receive methotrexate
      IT on days 1, 8, 15, and 22, and CD20 positive patients may optionally receive rituximab IV
      on days 8 and 15.

      INTENSIFICATION THERAPY: Beginning 4 weeks after the completion of course 2 of induction
      therapy, patients receive intensification therapy comprising high-dose methotrexate IV over 2
      hours on days 1 and 8, and pegaspargase IM or IV on day 9.

      Patients are then randomized to 1 of 2 treatment arms.

      Patients randomized to the blinatumomab group receive blinatumomab IV continuously on days
      1-28. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or
      unacceptable toxicity. Patients may then undergo allogeneic stem cell transplant (SCT) or
      proceed to consolidation therapy per investigator discretion.

      CONSOLIDATION THERAPY: Beginning after the second course of blinatumomab (patients randomized
      to the blinatumomab group) or after intensification therapy (patients not randomized to
      blinatumomab), patients receive cytarabine IV over 30 minutes or SC on days 1-5, etoposide IV
      over 1 hour on days 1-5, methotrexate IT on day 1, and pegaspargase IM or IV on day 5, and
      CD20 positive patients may optionally receive rituximab IV on day 5. Beginning 4 weeks from
      day 1 of course 1, patients receive cytarabine, etoposide, methotrexate, and CD20 positive
      patients may receive rituximab as in course 1. Beginning 4 weeks from day 1 of course 2,
      patients receive daunorubicin hydrochloride IV over 10-15 minutes on day 1, 8, 15, and 22;
      vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone PO daily on days 1-7 (and
      15-21 for patients age < 55 years); methotrexate IT on day 2; cyclophosphamide PO or IV over
      30 minutes on day 29; cytarabine IV over 30 minutes or SC on days 30-33 and 37-40;
      mercaptopurine PO on days 29-42 and CD20 positive patients may receive rituximab on day 8.
      Beginning 8 weeks from day 1 of course 3, patients receive cytarabine, etoposide,
      methotrexate, and CD20 positive patients may optionally receive rituximab as in course 1.
      Patients randomized to blinatumomab repeat course 4 and then receive blinatumomab IV
      continuously on days 1-28.

      MAINTENANCE THERAPY: Within 12 weeks after beginning last course of consolidation therapy,
      patients receive mercaptopurine PO daily, methotrexate PO or IV over 6 hours once weekly for
      2.5 years, vincristine sulfate IV on day 1 every 3 months, prednisone PO on days 1-5 every 3
      months, and methotrexate IT on day 1 every 3 months. Treatment continues for up to 2.5 years
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 2 years,
      every 6 months for 3 years, and then every 12 months for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (blinatumomab, chemotherapy)ExperimentalSee Detailed Description
  • Blinatumomab
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Etoposide
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Prednisone
  • Rituximab
  • Vincristine Sulfate
Arm II (chemotherapy)Active ComparatorSee Detailed Description
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Etoposide
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Prednisone
  • Rituximab
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  PRE-REGISTRATION

          -  Diagnostic bone marrow and peripheral blood specimens must be submitted for
             immunophenotyping and selected molecular testing, and the establishment of BCR/ABL
             status; testing will be performed by the Eastern Cooperative Oncology Group
             (ECOG)-American College of Radiation Imaging Network (ACRIN) Leukemia Translational
             Research Laboratory (LTRL) and reported to the institution

               -  NOTE: IT IS ESSENTIAL THAT A SAMPLE CONTAINING SUFFICIENT BLAST CELLS BE
                  SUBMITTED TO THE ECOG-ACRIN LTRL AT BASELINE SO THAT SUBSEQUENT BONE MARROW
                  ASSESSMENTS OF MRD CAN BE DONE; IN ADDITION TO ALLOWING THE LTRL TO CONFIRM
                  ELIGIBILITY BASED ON BLAST CELL IMMUNOPHENOTYPE AND BCR/ABL STATUS, IT IS ALSO
                  IMPERATIVE THAT AN ADEQUATE NUMBER OF BLASTS BE BANKED FOR ANALYSIS BY DRS
                  MULLIGHAN/WILLMAN. WITHOUT ADEQUATE BASELINE SAMPLES, PATIENTS WILL NOT BE ABLE
                  TO BE TREATED AND RANDOMIZED ON THIS PROTOCOL; IF A BONE MARROW ASPIRATE IS NOT
                  AVAILABLE FOR LTRL SUBMISSION AT BASELINE, IT IS IMPERATIVE THAT DR PAIETTA FROM
                  THE LTRL IS CALLED TO DISCUSS THE PERIPHERAL BLOOD WBC AND BLAST COUNT BEFORE
                  BLOOD ONLY IS SUBMITTED

               -  NOTE: Hydroxyurea can be given for up to 5 days prior to initiation of protocol
                  therapy for control of leukocyte count and/or other symptoms or signs;
                  corticosteroids can be given after pre-registration to the protocol and
                  submission of baseline marrow and blood samples for control of leukocyte count
                  and/or other symptoms or signs prior to initiation of protocol therapy if needed;
                  if corticosteroids are given prior to pre-registration, contact the study chair
                  as the patient may still be eligible to participate

          -  INDUCTION ELIGIBILITY CRITERIA-STEP 1

          -  New diagnosis of B lineage ALL must be made upon bone marrow or peripheral blood
             immunophenotyping; cases with myeloid antigen expression, but unequivocal lymphoid
             immunophenotype, are eligible

          -  Mature B ALL (Burkitt's-like leukemia) is excluded from enrollment in this trial;
             pre-study bone marrow biopsy and aspirate must be completed =< 1 week prior to
             registration

          -  Negativity for the Philadelphia chromosome must be established by conventional
             cytogenetics, fluorescence in situ hybridization (FISH) and/or polymerase chain
             reaction (PCR); patients who are negative for the Philadelphia chromosome by
             conventional cytogenetics must have FISH or PCR performed for BCR/ABL to exclude
             occult translocations

          -  Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if
             adequate number of circulating blasts from peripheral blood; FISH testing for common
             B-lineage ALL abnormalities including t(9;22) (BCR/ABL1), t(12;21) (ETS-variant gene 6
             [ETV6]/runt-related transcription factor 1 [RUNX1]), t(1;19) (pre-B-cell leukemia
             homeobox 1 [PBX1]/transcription factor 3 [TCF3]), +4,+10,+17, (centromeric
             [Cen]4/Cen10/Cen17), t(11q23;var), (myeloid/lymphoid or mixed lineage leukemia [MLL]),
             deletion (del)(9p) (cyclin-dependent kinase inhibitor 2A [CDKN2A]/Cen9), and t(14;var)
             (immunoglobulin heavy chain [IGH] is encouraged); if there are few or no circulating
             blasts and an adequate marrow sample cannot be obtained for cytogenetic analysis, the
             patient may still enroll on the trial

          -  Patient must not have a concurrent active malignancy for which they are receiving
             treatment

          -  Serum direct bilirubin < 2 mg/dl or serum total bilirubin =< 3 (obtained =< 48 hours
             prior to registration); NOTE: the above stipulation for normal hepatic function does
             not apply if liver dysfunction is due to leukemia infiltration

          -  Serum creatinine < 2 mg/dl (obtained =< 48 hours prior to registration); NOTE: the
             above stipulation for normal hepatic function does not apply if liver dysfunction is
             due to leukemia infiltration

          -  Patient should be human leukocyte antigen (HLA) typed (A, B, C, DR and DQ) during
             induction therapy phase or a written explanation for not undergoing HLA typing on the
             flow sheet

          -  Patient must not have intercurrent organ damage or medical problems that will
             jeopardize the outcome of therapy (i.e., psychiatric disorder, drug abuse, pregnancy)

          -  Patients with known human immunodeficiency virus (HIV) infection are eligible if they
             meet all of the following criteria:

               -  No history of acquired immune deficiency syndrome (AIDS)-related complications
                  other than a history of low CD4+ T-cell count (< 200/mm^3) prior to initiation of
                  combination antiretroviral therapy; on study CD4+ T-cell count may not be
                  informative due to leukemia and should not be used as an exclusion criterion if
                  low

               -  Patient must be healthy on the basis of HIV disease with high likelihood of near
                  normal life span were it not for the leukemia

               -  Patient must have serum HIV viral load of < 200 copies/mm^3

               -  Patient must be on combination antiretroviral therapy with minimal
                  pharmacokinetic interactions with study therapy and minimal overlapping clinical
                  toxicity with protocol therapy

               -  Patient must not be receiving protease inhibitors or once daily formulations
                  containing cobicistat, stavudine, or on regimens containing stavudine or
                  zidovudine

               -  It is recommended to utilize a regimen of the integrase inhibitor, dolutegravir,
                  combined with either disoproxil fumarate/emtricitabine or dolutegravir combined
                  with tenofovir alafenamide/emtricitabine

          -  Patient must not have an antecedent hematologic disorder

          -  Patient must have no history of recent myocardial infarction (within three months),
             uncontrolled congestive heart failure, or uncontrolled cardiac arrhythmia

          -  Patient must not have a history or presence of clinically relevant central nervous
             system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe
             brain injuries, dementia; Parkinson's disease, cerebellar disease, organic brain
             syndrome, psychosis, or other significant CNS abnormalities

          -  Patient must have a normal cardiac ejection fraction by pretreatment multigated
             acquisition scan (MUGA) or echocardiogram within 4 weeks prior to registration
             (resting ejection fraction >= 40% or >= 5% increase with exercise), shortening
             fraction by echocardiogram >= 24%, or to within the normal range of values for the
             institution

          -  Patient must not have an active uncontrolled infection

          -  Women must not be pregnant or breast-feeding and must not become pregnant or
             breastfeed during protocol therapy and for at least 3 months after protocol therapy;
             woman of childbearing potential must abstain from sexual activity or be willing to use
             2 highly effective forms of contraception throughout protocol therapy and for at least
             an additional 3 months after the last dose of protocol-specified therapy; all females
             of childbearing potential must have a blood test or urine study within 2 weeks prior
             to registration to rule out pregnancy; a female of childbearing potential is any
             woman, regardless of sexual orientation or whether they have undergone tubal ligation,
             who meets the following criteria: has not undergone a hysterectomy or bilateral
             oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive
             months (i.e., has had menses at any time in the preceding 24 consecutive months)

          -  Men who have a female partner of childbearing potential must be willing to use 2
             highly effective forms of contraception throughout protocol therapy and for at least
             an additional 3 months after the last dose of protocol-specified therapy; men who have
             a pregnant partner must be willing to use a condom during sexual activity throughout
             protocol therapy and for 3 months after the last dose of protocol-specified therapy

          -  ECOG performance score 0-3

          -  Patient must have given written informed consent

          -  POST-INDUCTION THERAPY ELIGIBILITY CRITERIA (PRIOR TO INTENSIFICATION-STEP 2)

          -  ECOG performance status 0-2

          -  Patients must have achieved a CR or CRi

          -  Patients who have achieved a CR or CRi must have maintained peripheral blood evidence
             of a CR or CRi

          -  Patient must be CNS (cerebrospinal fluid [CSF]) negative for leukemia

          -  Patients must have resolved any serious infectious complications related to induction

          -  Any significant medical complications related to induction must have resolved

          -  Serum creatinine =< 2.0 mg/dl (obtained =< 48 hours prior to registration)

          -  Serum direct bilirubin < 2 mg/dL or serum total bilirubin =< 3 (obtained =< 48 hours
             prior to registration)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit
             of normal (ULN) (obtained =< 48 hours prior to registration)

          -  RANDOMIZATION TO BLINATUMOMAB OR NO BLINATUMOMAB-STEP 3

          -  Patients must have an ECOG performance status of 0-2

          -  Patients must have maintained peripheral blood evidence of a remission and must have a
             CR or CRi, confirmed on restaging bone marrow (BM) aspirate and biopsy

          -  Patients must have resolved any serious infectious complications related to therapy

          -  Any significant medical complications related to therapy must have resolved

          -  Direct or total bilirubin < 1.5 x ULN (unless related to Gilbert's or Meulengracht's
             syndrome); the values must be obtained within 48 hours prior to randomization

          -  Serum creatinine < 1.5 x ULN; the values must be obtained within 48 hours prior to
             randomization

          -  Bone marrow aspirates must be submitted for centralized minimal residual disease (MRD)
             assessment performed by the ECOG-ACRIN Leukemia Translational Research Laboratory

          -  MRD results will be reported to the submitting institution

               -  NOTE: FOR MRD ASSESSMENTS, AN ASPIRATE FROM A SEPARATE BONE MARROW ASPIRATION
                  SITE MUST BE SUBMITTED (THE NEEDLE CAN BE RE-DIRECTED THROUGH THE SAME SKIN
                  PUNCTURE SITE); ONLY SUBMIT ASPIRATES FROM THE FIRST PULL OF AN ASPIRATION SITE
                  FOR MRD TESTING; DO NOT SUBMIT SAMPLES FROM THE SECOND OR THIRD PULL OF THE SAME
                  ASPIRATION SITE

               -  In B-lineage ALL, MRD levels in peripheral blood or from a dilute marrow
                  aspiration can be 300% lower, on average, than those in bone marrow at a given
                  time point; submitting a first pull from a separate aspiration site will ensure
                  that MRD determinations used in randomization and trial interpretation are
                  accurate

                    -  NOTE: failure to submit bone marrow aspirates will result in a major
                       violation at the time of an audit

          -  CRITERIA FOR ALLOGENEIC TRANSPLANTATION

          -  A suitable donor must be identified; there are no restrictions on donor type and can
             include a matched sibling, a matched or mismatched unrelated donor, a family haplotype
             matched donor or a cord blood donor (single or double)

          -  Patients should meet the eligibility criteria for RANDOMIZATION TO BLINATUMOMAB OR NO
             BLINATUMOMAB-STEP 3

          -  Patients must be considered reliable enough to comply with the medication regimen and
             follow-up, and have social support necessary to allow this compliance

          -  CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have an ECOG performance status
             of 0-3

          -  CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have maintained peripheral
             blood evidence of a remission and must have a CR or CRi, confirmed on restaging BM
             aspirate and biopsy

          -  CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have resolved any serious
             infectious complications related to therapy

          -  CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Any significant medical complications related
             to therapy must have resolved
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:30 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:Overall survival
Time Frame:Time between randomization and death from any cause, assessed up to 10 years
Safety Issue:
Description:Medians and confidence intervals will be calculated using the Kaplan-Meier method. Comparison of overall survival between treatment arms will be conducted using the one-sided stratified log-rank test with minimal residual disease status, age, CD20 status, rituximab use, and whether patients intend to receive hematopoietic stem cell transplantation or not as stratification factors. A Cox proportional hazards model will be used to assess the effect of treatment and will include receipt of transplant as a time-varying covariate.

Secondary Outcome Measures

Measure:Relapse-free survival
Time Frame:Time from randomization to relapse or death without documentation of relapse, assessed up to 10 years
Safety Issue:
Description:Estimates of relapse-free survival, including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Comparison of relapse-free survival between treatment arms will be conducted using the one-sided stratified log-rank test with minimal residual disease status, age, CD20 status, rituximab use, and whether patients intend to receive hematopoietic stem cell transplantation or not as stratification factors. Stratified on those factors, Cox proportional hazards models, will also be used to assess the treatment effect by adjusting other possible clinical and biological risk factors, including cytogenetic abnormalities and the receipt of transplant (included as a time-varying covariate).
Measure:Minimal residual disease status
Time Frame:Up to 32 weeks
Safety Issue:
Description:Minimal residual disease will be assessed after induction and intensification chemotherapy (but before randomization), after two courses of blinatumomab or consolidation, and prior to the start of the maintenance therapy. The study will have 91% power to detect this difference using two-sided Fisher's exact test at the significance level of 0.05.
Measure:Incidence of adverse events, per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 10 years
Safety Issue:
Description:Classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated or unlikely to be related" to study treatment in the event of an actual relationship developing.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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