Clinical Trials /

A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia

NCT03914625

Description:

This phase III trial studies how well blinatumomab works in combination with chemotherapy in treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as blinatumomab, may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as vincristine, dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine, mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, 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. Leucovorin decreases the toxic effects of methotrexate. Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving blinatumomab and combination chemotherapy may work better than combination chemotherapy alone in treating patients with B-ALL. This trial also assigns patients into different chemotherapy treatment regimens based on risk (the chance of cancer returning after treatment). Treating patients with chemotherapy based on risk may help doctors decide which patients can best benefit from which chemotherapy treatment regimens.

Related Conditions:
  • B-Cell Lymphoblastic Leukemia/Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study to Determine the Outcomes of Patients With Localized B Cell Lymphoblastic Lymphoma (B-LLy) When Treated With Standard Risk B-ALL Therapy
  • Official Title: A Phase 3 Trial Investigating Blinatumomab (NSC# 765986) in Combination With Chemotherapy in Patients With Newly Diagnosed Standard Risk or Down Syndrome B-Lymphoblastic Leukemia (B-ALL) and the Treatment of Patients With Localized B-Lymphoblastic Lymphoma (B-LLy)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-02187
  • SECONDARY ID: NCI-2019-02187
  • SECONDARY ID: AALL1731
  • SECONDARY ID: AALL1731
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03914625

Conditions

  • B Acute Lymphoblastic Leukemia
  • B Lymphoblastic Lymphoma
  • Down Syndrome

Interventions

DrugSynonymsArms
Asparaginase Erwinia chrysanthemiCrisantaspase, Crisantaspasum, Erwinase, Erwinaze, L-asparginase (Erwinia )Arm A (SR-Avg control)
BlinatumomabAnti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody, Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103, Blincyto, MEDI-538, MT-103Arm B (SR-Avg experimental)
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, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm A (SR-Avg control)
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 A (SR-Avg control)
DexamethasoneAacidexam, 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, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDexArm A (SR-Avg control)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinArm A (SR-Avg control)
Doxorubicin Hydrochloride5,12-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, RubexArm A (SR-Avg control)
Leucovorinfolinic acidArm A (SR-Avg control)
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, Citrovorum Factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinArm A (SR-Avg control)
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 A (SR-Avg control)
Mercaptopurine Oral Suspension6-MP Oral Suspension, Purixan, XaluprineArm A (SR-Avg control)
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 A (SR-Avg control)
Prednisolone(11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione, .delta.1-Hydrocortisone, Adnisolone, Aprednislon, Capsoid, Cortalone, Cortisolone, Dacortin H, Decaprednil, Decortin H, Delta(1)Hydrocortisone, Delta- Cortef, Delta-Cortef, Delta-Diona, Delta-F, Delta-Phoricol, Delta1-dehydro-hydrocortisone, Deltacortril, Deltahydrocortisone, Deltasolone, Deltidrosol, Dhasolone, Di-Adreson-F, Dontisolon D, Estilsona, Fisopred, Frisolona, Gupisone, Hostacortin H, Hydeltra, Hydeltrasol, Klismacort, Kuhlprednon, Lenisolone, Lepi-Cortinolo, Linola-H N, Linola-H-Fett N, Longiprednil, Metacortandralone, Meti Derm, Meticortelone, Opredsone, Panafcortelone, Precortisyl, Pred-Clysma, Predeltilone, Predni-Coelin, Predni-Helvacort, Prednicortelone, Prednisolonum, Prelone, Prenilone, SteraneArm C (SR-High Control)
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, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-PrednisoneArm A (SR-Avg control)
Thioguanine2-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 27Arm A (SR-Avg control)
VincristineLeurocristine, VCR, VincrystineArm A (SR-Avg control)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm A (SR-Avg control)

Purpose

This phase III trial studies how well blinatumomab works in combination with chemotherapy in treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as blinatumomab, may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as vincristine, dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine, mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, 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. Leucovorin decreases the toxic effects of methotrexate. Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving blinatumomab and combination chemotherapy may work better than combination chemotherapy alone in treating patients with B-ALL. This trial also assigns patients into different chemotherapy treatment regimens based on risk (the chance of cancer returning after treatment). Treating patients with chemotherapy based on risk may help doctors decide which patients can best benefit from which chemotherapy treatment regimens.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine in a randomized manner if the addition of 2 cycles of blinatumomab to
      standard therapy improves disease-free survival (DFS) in patients with standard risk (SR)
      B-ALL and higher risk features (SR-High), and patients with standard-risk average (SR-Avg)
      B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have
      detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of
      induction (EOI).

      II. To confirm that boys in the standard-risk favorable (SR-Fav) subset of B-ALL, with or
      without Down syndrome (DS), will maintain a 5-year DFS of greater than 93% when treated with
      a standard chemotherapy regimen with a treatment duration of 2 years from the start of
      interim maintenance I (IM1).

      SECONDARY OBJECTIVES:

      I. To describe the DFS for patients with SR-Avg B-ALL who are negative for MRD measured by
      flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment
      duration of 2 years from the start of IM1, regardless of sex.

      II. To describe the DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated
      with a standard chemotherapy regimen.

      III. To determine if patients with DS-High achieve a reduction of treatment-related mortality
      (TRM) after replacement of intensive elements of standard chemotherapy (omission of
      anthracyclines in induction, omission of the second month of delayed intensification [DI])
      with 3 cycles of blinatumomab.

      IV. To describe the DFS characterized by the replacement of intensive elements of standard
      chemotherapy with 3 cycles of blinatumomab in patients with DS-High B ALL.

      V. To describe the DFS for patients with localized (Murphy stage I and II) B lymphoblastic
      lymphoma (B-LLy) receiving standard risk B-ALL therapy.

      VI. To compare the change in neurocognitive functioning, as measured by the CogState
      Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4- < 10
      years at the time of diagnosis between children from poor families (defined as presence of
      household material hardship [HMH], including either food, housing or energy insecurity) and
      non-poor families (absence of HMH).

      VII. To describe the impact of blinatumomab on caregiver burden and patient/proxy-reported
      symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study.

      EXPLORATORY OBJECTIVES:

      I. To explore adaptive and innate immune functions and host genetic factors associated with
      severe infectious complications in children with DS B-ALL.

      II. To explore the impact of acute lymphoblastic leukemia (ALL) and its therapy on
      neurocognitive, functional, and quality of life outcomes in patients with DS and ALL, as
      measured by caregiver (parent/legal guardian) questionnaires.

      III. To define the prevalence of minimal marrow disease (MMD) in B-LLy and to correlate MMD
      at diagnosis with outcome in patients with B-LLy.

      OUTLINE: All patients are assigned to, and complete an INDUCTION treatment regimen. Patients
      are then assigned to a CONSOLIDATION treatment regimen. Finally, following CONSOLIDATION,
      patients are either assigned or randomized to 1 of 7 arms.

      NON-DS SR B-ALL INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1,
      vincristine intravenous (IV) push over 1 minute on days 1, 8, 15, and 22, dexamethasone
      orally (PO) or IV twice daily (BID) on days 1-28, pegaspargase IV over 1-2 hours or
      intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29. CNS2 patients also
      receive cytarabine IT twice weekly except during weeks when days 8 and 29 methotrexate is
      administered. Treatment continues for 35 days in the absence of disease progression or
      unacceptable toxicity.

      * After Non-DS SR B-ALL INDUCTION, SR-Fav and SR-Avg patients complete SR CONSOLIDATION,
      while patients with SR-High complete high-risk (HR) CONSOLIDATION.

      DS B-ALL INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1
      minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate
      IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30.
      Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28,
      and patients 10 years of age or older receive prednisone or prednisolone PO or IV BID on days
      1-28. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8
      and 29 IT methotrexate is administered. CNS3 patients also receive methotrexate IT on days 15
      and 22, and leucovorin PO or IV every 6 hours for 2 doses on days 16 and 23. Treatment
      continues for 35 days in the absence of disease progression or unacceptable toxicity.

      * After DS B-ALL INDUCTION, patients without high risk features and MRD < 0.01 % complete SR
      CONSOLIDATION. Patients without high risk features and MRD >= 0.01%, OR with high risk
      features and any MRD complete HR CONSOLIDATION.

      NON-DS B-LLy INDUCTION: Patients receive cytarabine IT on day 1 and twice weekly if CNS2,
      vincristine IV push over 1 minute on days 1, 8, 15, and 22, dexamethasone PO or IV BID on
      days 1-28, pegaspargase IV over 1-2 hours or IM on day 4, and methotrexate IT on days 8 and
      29. Treatment continues for 35 days in the absence of disease progression or unacceptable
      toxicity.

      * After NON-DS B-LLy INDUCTION, all B-LLy patients then complete SR CONSOLIDATION.

      DS B-LLY INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1
      minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate
      IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30.
      Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28,
      and patients 10 years of age or older receive PO or IV prednisone or methylprednisolone on
      days 1-28. Treatment continues for 35 days in the absence of disease progression or
      unacceptable toxicity.

      * After DS B-LLy INDUCTION, patients then complete SR CONSOLIDATION.

      SR CONSOLIDATION: Patients receive vincristine IV push over 1 minute on day 1, mercaptopurine
      PO on days 1-28, and methotrexate IT on days 1, 8, and 15. DS patients also receive
      leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, and 16. Treatment continues for
      28 days in the absence of disease progression or unacceptable toxicity.

      * After SR CONSOLIDATION, patients with MRD undetectable are assigned to ARM A, and patients
      with MRD detectable/indeterminate/unavailable are randomized to ARM A or B. Patients with
      SR-Fav and all B-LLy patients are assigned to treatments identical to that in ARM A.

      HR CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29,
      cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, vincristine IV
      push over 1 minute on days 15, 22, 43, and 50, mercaptopurine PO on days 1-14 and 29-42,
      methotrexate IT on days 1, 8, 15, and 22 , and pegaspargase IV over 1-2 hours or IM on days
      15 and 43. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2,
      9, 16, and 23 (on days 2 and 9 only for DS CNS3 patients). Treatment continues for 56 days in
      the absence of disease progression or unacceptable toxicity.

      * After HR CONSOLIDATION, patients are randomized to ARM C or D. DS B-ALL patients with MRD <
      1% are assigned to an arm including three blocks of blinatumomab.

      ARM A:

        -  INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
           21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted)
           on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
           leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
           in the absence of disease progression or unacceptable toxicity.

        -  DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone
           PO BID or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and
           15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV
           over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29,
           thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or subcutaneously (SC)
           on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2
           doses on days 2 and 30. Treatment continues for 56 days in the absence of disease
           progression or unacceptable toxicity.

        -  INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
           11, 21, 31, and 41, methotrexate IV over 2-5 minutes undiluted or 10-15 minutes diluted
           on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients receive
           leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for
           56 days in the absence of disease progression or unacceptable toxicity.

        -  MAINTENANCE: Non-DS patients receive methotrexate IT on day 1, vincristine IV push over
           1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and
           methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients
           receive vincristine IV push over 1 minute on day 1, methotrexate IT on day 1,
           dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on
           days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78, and leucovorin IV or PO on day 2 if
           DS. Treatment repeats every 84 days until a total duration of therapy of 2 years from
           start of INTERIM MAINTENANCE I is reached in the absence of disease progression or
           unacceptable toxicity.

      ARM B:

        -  BLINATUMOMAB BLOCK I: Patients receive dexamethasone IV or PO on day 1, methotrexate IT
           on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive
           leucovorin IV or PO every 6 hours for 2 doses on day 2. Treatment continues for 35 days
           in the absence of disease progression or unacceptable toxicity.

        -  INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
           21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted)
           on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
           leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
           in the absence of disease progression or unacceptable toxicity.

        -  BLINATUMOMAB BLOCK II: Patients receive methotrexate IT on day 1, and blinatumomab IV
           continuously on days 1-28. DS patients also receive leucovorin PO or IV every 6 hours
           for 2 doses on day 2. Treatment continues for 35 days in the absence of disease
           progression or unacceptable toxicity.

        -  DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone
           PO or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15,
           doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV
           over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29,
           thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32
           and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2
           and 30. Treatment continues for 56 days in the absence of disease progression or
           unacceptable toxicity.

        -  INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
           11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes
           (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS
           patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32.
           Treatment continues for 56 days in the absence of disease progression or unacceptable
           toxicity.

        -  MAINTENANCE: Non-DS patients receive methotrexate IT on day 1 (omit on final 2 cycles),
           vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine
           PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71,
           and 78 (omit day 1 on final 2 cycles). DS patients receive methotrexate IT on day 1
           (omit on final 2 cycles), dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84,
           and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1
           except for final 2 cycles), for DS patients and leucovorin IV or PO every 6 hours for 2
           doses on day 2 (omit on final 2 cycles). Treatment repeats every 84 days until a total
           duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the
           absence of disease progression or unacceptable toxicity.

      ARM C:

        -  INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 15,
           29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on
           days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on day 1 and 29, and leucovorin PO
           or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the
           absence of disease progression or unacceptable toxicity.

        -  DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO BID
           or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50,
           doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or
           IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on
           days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment
           continues for 56 days in the absence of disease progression or unacceptable toxicity.

        -  INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21,
           31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15
           minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and
           pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days
           in the absence of disease progression or unacceptable toxicity.

        -  MAINTENANCE: Patients receive vincristine IV over 1 minute on day 1, prednisone or
           prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84,
           methotrexate IT on days 1 and 29 of cycles 1-2 and on day 1 of subsequent cycles,
           methotrexate PO on days 8, 15, 22, 29 (for cycle 3 and later only), 36, 43, 50, 57, 64,
           71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years
           from start of interim maintenance I is reached in the absence of disease progression or
           unacceptable toxicity.

      ARM D:

        -  BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, methotrexate IT
           on day 1, and blinatumomab IV continuously on days 1-28. Treatment continues for 35 days
           in the absence of disease progression or unacceptable toxicity.

        -  INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29,
           and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days
           1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or IV
           on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of
           disease progression or unacceptable toxicity.

        -  BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28 and methotrexate IT
           on day 1. Treatment continues for 35 days in the absence of disease progression or
           unacceptable toxicity.

        -  DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO or
           IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50,
           doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or
           IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on
           days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment
           continues for 56 days in the absence of disease progression or unacceptable toxicity.

        -  INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21,
           31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15
           minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and
           pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days
           in the absence of disease progression or unacceptable toxicity.

        -  MAINTENANCE: Patients receive methotrexate IT on day 1, vincristine IV over 1 minute on
           day 1, prednisone, prednisolone or methylprednisolone PO or IV on days 1-5,
           mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
           57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of
           2 years from start of interim maintenance I is reached in the absence of disease
           progression or unacceptable toxicity.

      DS-HIGH B-ALL:

        -  BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, blinatumomab IV
           continuously on days 1-28, methotrexate IT on day 1, and leucovorin PO or IV every 6
           hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease
           progression or unacceptable toxicity.

        -  INTERIM MAINTENANCE: Patients receive vincristine IV push over 1 minute on days 1, 15,
           29, and 43, intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43,
           mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-46, methotrexate IT on days 1 and
           29, and leucovorin PO or IV every 6 hours for 2 doses on days 2-4, 16-18, 30-32, and
           44-46. Treatment continues for 63 days in the absence of disease progression or
           unacceptable toxicity.

        -  BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28, methotrexate IT on
           day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues
           for 35 days in the absence of disease progression or unacceptable toxicity.

        -  DELAYED INTENSIFICATION: Patients receive vincristine IV over 1 minute on days 1, 8, and
           15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on
           days 1-7 and 15-21, methotrexate IT on day 1, leucovorin PO or IV every 6 hours for 2
           doses on day 2, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment continues
           for 28 days in the absence of disease progression or unacceptable toxicity.

        -  BLINATUMOMAB BLOCK III: Patients receive blinatumomab IV on days 1-28, methotrexate IT
           on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment
           continues for 35 days in the absence of disease progression or unacceptable toxicity.

        -  MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, prednisone,
           prednisolone or methylprednisolone PO or IV BID on days 1-5, mercaptopurine PO on days
           1-84, methotrexate IT on day 1, methotrexate PO on days 8, 15, 22, 29 (omit day 29 for
           first 3 cycles for patients who do not receive cranial radiotherapy), 36, 43, 50, 57,
           64, 71, and 78, and leucovorin PO on days 2 and 30 (day 30 dose is for cycles 1-3 and
           for patients who do not receive cranial radiotherapy). CNS3 patients receive cranial
           radiotherapy during first 4 weeks of cycle 1. Treatment repeats every 84 days until a
           total duration of therapy of 2 years from start of interim maintenance I is reached in
           the absence of disease progression or unacceptable toxicity.

      All B-LLy patients:

        -  INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
           21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 (diluted) on days
           1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
           leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
           in the absence of disease progression or unacceptable toxicity.

        -  DELAYED INTENSIFICATION: Patients receive vincristine IV push over 1 minute on days 1, 8
           and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on
           days 1-7 and 15-21, methotrexate IT on days 1 and 29, pegaspargase IV over 1-2 hours or
           IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days
           29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients
           additionally receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30.
           Treatment continues for 56 days in the absence of disease progression or unacceptable
           toxicity.

        -  INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
           11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes
           (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS
           patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32.
           Treatment continues for 56 days in the absence of disease progression or unacceptable
           toxicity.

        -  MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, dexamethasone
           PO on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, and
           methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients also
           receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment repeats every
           84 days until a total duration of therapy of 2 years from start of interim maintenance I
           is reached in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 4 weeks until complete
      blood count(CBC)/differential/platelet count recovery, then every 3 months for the first 2
      years, then every 4-6 months for the 3rd year, and every 6-12 months for the 4th and 5th
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (SR-Avg control)Active ComparatorArm A: See detailed description.
  • Asparaginase Erwinia chrysanthemi
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine Oral Suspension
  • Methotrexate
  • Prednisone
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
Arm B (SR-Avg experimental)ExperimentalArm B: See detailed description.
  • Asparaginase Erwinia chrysanthemi
  • Blinatumomab
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine Oral Suspension
  • Methotrexate
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
Arm C (SR-High Control)Active ComparatorArm C: See detailed description.
  • Asparaginase Erwinia chrysanthemi
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine Oral Suspension
  • Methotrexate
  • Prednisolone
  • Prednisone
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
Arm D (SR-High experimental)ExperimentalArm D See detailed description.
  • Asparaginase Erwinia chrysanthemi
  • Blinatumomab
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine Oral Suspension
  • Methotrexate
  • Prednisolone
  • Prednisone
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
B-LLyExperimentalSee detailed description.
  • Asparaginase Erwinia chrysanthemi
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine Oral Suspension
  • Methotrexate
  • Prednisolone
  • Prednisone
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
DS B-ALLExperimentalSee detailed description.
  • Asparaginase Erwinia chrysanthemi
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine Oral Suspension
  • Methotrexate
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
NCI SR or HR DS B-ALLExperimentalSee detailed description.
  • Asparaginase Erwinia chrysanthemi
  • Blinatumomab
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine Oral Suspension
  • Methotrexate
  • Prednisolone
  • Prednisone
  • Vincristine
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening
             (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement
             for B-LLy patients. B-LLy patients may directly enroll on AALL1731 and MUST submit
             eligibility studies.

          -  Age at diagnosis:

               -  Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).

               -  Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).

               -  Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or
                  without DS).

          -  B-ALL patients without DS must have an initial white blood cell count < 50,000/uL
             (performed within 7 days prior to enrollment).

          -  B-ALL patients with DS are eligible regardless of the presenting white blood cell
             count (WBC) (performed within 7 days prior to enrollment).

          -  Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on
             a bone marrow (BM) aspirate;

               -  OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis
                  can be established by a pathologic diagnosis of B-ALL on a BM biopsy;

               -  OR a complete blood count (CBC) documenting the presence of at least 1,000/uL
                  circulating leukemic cells;

               -  OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without
                  Down syndrome.

               -  Note: For B-LLy patients with tissue available for flow cytometry, the criterion
                  for diagnosis should be analogous to B-ALL. For tissue processed by other means
                  (i.e., paraffin blocks), the methodology and criteria for immunophenotypic
                  analysis to establish the diagnosis of B-LLy defined by the submitting
                  institution will be accepted (diagnostic biopsy for B-LLy must be performed
                  within 14 days prior to enrollment).

          -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
             (NCI) requirements for human studies must be met.

          -  All patients and/or their parents or legal guardians must sign a written informed
             consent.

        Exclusion Criteria:

          -  Patient must not have secondary ALL that developed after treatment of a prior
             malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior
             history of transient myeloproliferative disease (TMD) are not considered to have had a
             prior malignancy. They would therefore be eligible whether or not the TMD was treated
             with cytarabine.

          -  With the exception of steroid pretreatment or the administration of intrathecal
             cytarabine, patients must not have received any prior cytotoxic chemotherapy for
             either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to
             initiation of protocol therapy on AALL1731.

          -  For patients receiving steroid pretreatment, the following additional exclusion
             criteria apply:

               -  Non-DS B-ALL patients must not have received steroids for more than 24 hours in
                  the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to
                  initiation of the steroids.

               -  DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV
                  steroids within 4 weeks of diagnosis.

          -  B-ALL patients who do not have sufficient diagnostic bone marrow submitted for
             APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted
             containing > 1,000/uL circulating leukemia cells.

          -  Patient must not have acute undifferentiated leukemia (AUL).

          -  Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be
             known prior to enrollment).

               -  Note: DS patients with CNS3 disease are eligible but will be assigned to the
                  DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior
                  to administration of any systemic or intrathecal chemotherapy, except for steroid
                  pretreatment.

          -  Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular
             disease are eligible but will be assigned to the DS-High B-ALL arm).

          -  For LLy patients, the following additional exclusion criteria apply:

               -  T-Lymphoblastic Lymphoma.

               -  Morphologically unclassifiable lymphoma.

               -  Absence of both B-cell and T-cell phenotype markers in a case submitted as
                  lymphoblastic lymphoma.

               -  CNS positive disease or testicular involvement.

               -  M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow.

          -  Patients with known Charcot-Marie-Tooth disease.

          -  Patients with evidence of a MYC translocation associated with mature (Burkitt) B-cell
             ALL, regardless of blast immunophenotype.

          -  Female patients who are pregnant since fetal toxicities and teratogenic effects have
             been noted for several of the study drugs. A pregnancy test is required for female
             patients of childbearing potential.

          -  Lactating females who plan to breastfeed their infants.

          -  Sexually active patients of reproductive potential who have not agreed to use an
             effective contraceptive method for the duration of their study participation.
      
Maximum Eligible Age:31 Years
Minimum Eligible Age:365 Days
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Post-Consolidation disease free survival (DFS) with addition of 2 cycle of blinatumomab
Time Frame:Time from end of consolidation (EOC) to first event (relapse, second malignant neoplasm, remission death) or censored at date of last contact for those who are disease-free up to 5 years
Safety Issue:
Description:Will be assessed in patients with standard risk (SR) B-lymphoblastic leukemia (B-ALL) and higher risk features, and patients with standard risk average (SR-Avg) B-ALL who are negative for MRD by flow cytometry but have detectable or indeterminate MRD as measured by high throughput sequencing (HTS) at end of induction (EOI). Efficacy design and standard survival analysis methods is used to detect improvement in post-Consolidation DFS due to the addition of 2 cycles of blinatumomab to standard therapy in patients with SR B-ALL and higher risk features, and patients with SR-Avg B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of induction (EOI), and patients with double trisomy of chromosomes 4 and 10 (DT) with MRD (flow) 0.01% - <0.1%.

Secondary Outcome Measures

Measure:DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of interim maintenance (IM)1, regardless of sex
Time Frame:From the start of IM1 up to 2 years
Safety Issue:
Description:
Measure:DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen
Time Frame:5 years
Safety Issue:
Description:Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
Measure:Treatment-related mortality in Down syndrome high risk (DS-high) patients after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of DI) with 3 cycles of blinatumomab
Time Frame:5 years
Safety Issue:
Description:
Measure:DFS of DS-High B-ALL patients when intensive elements of chemotherapy are replaced with 3 cycles of blinatumomab
Time Frame:5 years
Safety Issue:
Description:Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
Measure:DFS of patients with localized B-lymphoblastic lymphoma (B-LLy) receiving standard risk acute lymphoblastic leukemia therapy
Time Frame:5 years
Safety Issue:
Description:Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
Measure:Neurocognitive functioning
Time Frame:Baseline to 2 years after IM1
Safety Issue:
Description:Compare the change in neurocognitive functioning, as measured by the CogState Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4-< 10 years at the time of diagnosis between children from poor families (defined as presence of household material hardship (HMH), including either food, housing or energy insecurity) and non-poor families (absence of HMH).
Measure:Caregiver burden and patient/proxy-reported symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study
Time Frame:Baseline to 2 years after IM1
Safety Issue:
Description:Compare the demands and work limitations on caregivers of children with ALL receiving chemotherapy versus chemotherapy with the addition of blinatumomab and to compare the change in the demands and work limitations over time, measured by the Care of My Child with Cancer questionnaire and the Caregiver Work Limitations questionnaire during post-Induction therapy. Patient/proxy reported symptoms measured by Memorial Symptom Assessment Scale.

Details

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

Last Updated

January 20, 2020