Clinical Trials /

Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy

NCT03959085

Description:

This phase III trial studies whether inotuzumab ozogamicin added to post-induction chemotherapy for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves outcomes. This trial also studies the outcomes of patients with mixed phenotype acute leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without inotuzumab ozogamicin. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells in a targeted way and delivers calicheamicin to kill them. Other drugs used in the chemotherapy regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin, methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and pegaspargase 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. This trial will also study the outcomes of patients with mixed phenotype acute leukemia (MPAL) and disseminated B lymphoblastic lymphoma (B-LLy) when treated with high-risk ALL chemotherapy. The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The first part of the study includes the first two phases of therapy: Induction and Consolidation. This part will collect information on the leukemia, as well as the effects of the initial treatment, in order to classify patients into post-consolidation treatment groups. On the second part of this study, patients will receive the remainder of the chemotherapy cycles (interim maintenance I, delayed intensification, interim maintenance II, maintenance), with some patients randomized to receive inotuzumab. Other aims of this study include investigating whether treating both males and females with the same duration of chemotherapy maintains outcomes for males who have previously been treated for an additional year compared to girls, as well as to evaluate the best ways to help patients adhere to oral chemotherapy regimens. Finally, this study will be the first to track the outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B LLy) or Mixed Phenotype Acute Leukemia (MPAL) when treated with B-ALL chemotherapy.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • B-Cell Lymphoblastic Lymphoma
  • Mixed Phenotype Acute Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy
  • Official Title: A Phase 3 Randomized Trial of Inotuzumab Ozogamicin (NSC#: 772518) for Newly Diagnosed High-Risk B-ALL; Risk-Adapted Post-Induction Therapy for High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and Disseminated B-LLy

Clinical Trial IDs

  • ORG STUDY ID: AALL1732
  • SECONDARY ID: NCI-2019-02845
  • SECONDARY ID: AALL1732
  • SECONDARY ID: AALL1732
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03959085

Conditions

  • B Acute Lymphoblastic Leukemia
  • B Lymphoblastic Lymphoma
  • Central Nervous System Leukemia
  • Mixed Phenotype Acute Leukemia
  • Testicular Leukemia

Interventions

DrugSynonymsArms
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 I (HR-FAV B-ALL)
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 (HR-FAV B-ALL)
DaunorubicinDAUNOMYCIN, Daunorrubicina, DNR, Leukaemomycin C, Rubidomycin, RUBOMYCIN CArm I (HR-FAV B-ALL)
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 (HR-FAV B-ALL)
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 I (HR-FAV B-ALL)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinArm I (HR-FAV B-ALL)
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 I (HR-FAV B-ALL)
Inotuzumab OzogamicinBesponsa, CMC-544, Way 207294, WAY-207294Arm III (HR B-ALL EXPERIMENTAL)
LeucovorinFolinic acidArm I (HR-FAV B-ALL)
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 I (HR-FAV B-ALL)
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 (HR-FAV B-ALL)
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 (HR-FAV B-ALL)
PegaspargaseL-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-AsparaginaseArm I (HR-FAV B-ALL)
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 I (HR-FAV B-ALL)
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 I (HR-FAV B-ALL)
VincristineLeurocristine, VCR, VincrystineArm I (HR-FAV B-ALL)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm I (HR-FAV B-ALL)

Purpose

This phase III trial studies how well inotuzumab ozogamicin and post-induction chemotherapy work in treating patients with high-risk B-cell lymphoblastic lymphoma (B-ALL), mixed phenotype acute leukemia, and B-lymphoblastic lymphoma (B-LLy). Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a toxic agent called calicheamicin. Inotuzumab attaches to cancer cells in a targeted way and delivers calicheamicin to kill them. Drugs used in chemotherapy, such as cyclophosphamide, cytarabine, doxorubicin, daunorubicin, methotrexate, leucovorin, mercaptopurine, thioguanine, vincristine, and pegaspargase, 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. The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The goal of the part 1 of the study is to collect information about leukemia and the effects of the first two phases of treatment, called Induction and Consolidation on this cancer. Additionally, this study aims to investigate whether treating both males and females with the same duration of chemotherapy maintains outcomes for males who have previously been treated for 3 years from the start of Interim Maintenance in patient with High Risk Favorable (HR-Fav) and HR B-ALL. Another aim is to understand the outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B LLy) receiving HR B-ALL therapy. Finally, another goal of this study is to determine the outcomes of subjects with Mixed Phenotype Acute Leukemia (MPAL) with a favorable early response to treatment using High Risk B-cell Acute Lymphoblastic Leukemia therapy.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine in a randomized manner if the addition of 2 blocks of inotuzumab ozogamicin
      to modified Berlin-Frankfurt-Munster (mBFM) chemotherapy will improve 5 year disease-free
      survival (DFS) in children and young adults with high-risk (HR) B-cell acute lymphoblastic
      leukemia (B-ALL).

      SECONDARY OBJECTIVES:

      I. To describe the 5-year DFS for a favorable risk subset of National Cancer Institute (NCI)
      HR B-ALL (HR favorable [Fav]) when treated with mBFM chemotherapy with a single high-dose
      methotrexate (HD-MTX) interim maintenance (IM) phase and treatment duration of 2 years from
      the start of IM regardless of sex.

      II. To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the
      mBFM chemotherapy backbone in HR B-ALL.

      III. To describe the 5-year event-free survival (EFS) for patients with mixed phenotype acute
      leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi
      escalating intravenous (IV) methotrexate (MTX) without leucovorin rescue plus pegaspargase
      (C-MTX).

      IV. To describe the 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell
      lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM
      phase with C-MTX.

      EXPLORATORY OBJECTIVES:

      I. To describe the therapy administered, disease response, and survival outcomes of patients
      with MPAL who come off protocol therapy due to poor disease response to ALL therapy either
      during Induction, at end of induction (EOI), or at end of consolidation (EOC).

      II. To define the prevalence and significance of minimal marrow disease (MMD) at diagnosis
      and bone marrow minimal residual disease (MRD) at EOI in disseminated B-LLy.

      III. To determine the impact of proposed adherence-enhancing interventions, IP (intervention
      package as used in ACCL1033) versus (vs.) iIP (intensified intervention package) vs. pIP
      (patient/parent-established intervention package), on adherence to oral 6 mercaptopurine in
      children and young adults with ALL.

      OUTLINE: Patients with B-ALL are either assigned to Arm I or randomized to Arm II or III,
      patients with MPAL are assigned to Arm IV, and patients with B-LLy are assigned to Arm V.

      All patients with B-ALL receive Induction and Consolidation therapy:

      INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1 and central nervous system
      (CNS)2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also
      receive vincristine intravenously (IV) over 1 minute on days 1, 8, 15, and 22, daunorubicin
      IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase intramuscularly (IM) or IV over 1-2
      hours on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3
      patients). Patients < 10 years old receive dexamethasone orally (PO) twice daily (BID) or IV
      on days 1-14; patients >= 10 years old receive prednisolone PO BID or IV on days 1-28.
      Treatment continues for 5 weeks in the absence of disease progression or unacceptable
      toxicity.

      CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29,
      cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39,
      mercaptopurine PO once daily (QD) on days 1-14 and 29-42, and methotrexate IT on days 1, 8,
      15, and 22 (CNS3 patients receive methotrexate IT on days 1 and 8). Patients also receive
      vincristine IV over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV over 1-2 hours
      or IM on days 15 and 43. Additionally, patients with testicular disease at diagnosis undergo
      radiation therapy over 12 once daily fractions. Treatment continues for 8 weeks in the
      absence of disease progression or unacceptable toxicity.

      POST-CONSOLIDATION THERAPY: Patients that are < 10 years, have CNS1, no testicular leukemia,
      with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies [4 and 10]), =< 24 hours
      of steroids in the two weeks prior to diagnosis, and EOI MRD < 0.01% are assigned to Arm I.
      Patients with HR B-ALL who are CD22 positive at diagnosis, are randomized to either Arm II or
      III.

      ARM I: HR-FAV B-ALL INTERIM MAINTENANCE: Patients receive vincristine IV over 1 minute on
      days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43,
      leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO QD on days 1-14,
      15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9
      weeks in the absence of disease progression or unacceptable toxicity.

      DELAYED INTENSIFICATION (PART I): 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, and 15,
      doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IV
      over 1-2 hours or IM on day 4. Treatment continues for 8 weeks in the absence of disease
      progression or unacceptable toxicity.

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

      MAINTENANCE: Patients receive methotrexate IT on days 1 and 29 for cycles 1-4, and day 1 for
      subsequent cycles. Patients also receive vincristine IV over 1 minute on day 1, prednisolone
      PO BID or IV on days 1-5, mercaptopurine PO QD on days 1-84, and methotrexate PO on days 8,
      15, 22, (29 excluded in cycles 1-4), 36, 43, 50, 57, 64, 71, and 78. Cycles repeat every 12
      weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

      ARM II: HR B-ALL (CONTROL) INTERIM MAINTENANCE I: Patients receive vincristine IV over 1
      minute on days 1, 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29
      and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, 45-46, mercaptopurine PO QD on days
      1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for
      9 weeks in the absence of disease progression or unacceptable toxicity.

      DELAYED INTENSIFICATION (PART I): 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, and 15,
      doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IV
      over 1-2 hours or IM on day 4. Treatment continues for 8 weeks in the absence of disease
      progression or unacceptable toxicity.

      DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
      day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
      36-39, methotrexate IT on days 29 and 36, vincristine IV over 1 minute on days 43 and 50, and
      pegaspargase IV over 1-2 hours or IM on day 43. Treatment continues for 8 weeks 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, methotrexate IV over 2-15 minutes or 10-15 minutes 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 8 weeks in the absence of disease progression or unacceptable
      toxicity.

      ARM III: HR B-ALL (EXPERIMENTAL) INOTUZUMAB OZOGAMICIN (InO) BLOCK 1: Patients receive
      inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1.
      Treatment continues for 4 weeks 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 over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on
      days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56,
      and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of
      disease progression or unacceptable toxicity.

      InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15.
      Treatment continues for 4 weeks in the absence of disease progression or unacceptable
      toxicity.

      DELAYED INTENSIFICATION (PART I): 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, and 15,
      doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IV
      over 1-2 hours or IM on day 4. Treatment continues for 8 weeks in the absence of disease
      progression or unacceptable toxicity.

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

      ARMS II AND III: HR B-ALL MAINTENANCE: Patients receive vincristine IV over 1 minute on day
      1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on
      days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71 and 78, and
      methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive cranial
      radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease
      progression or unacceptable toxicity. Patients with CNS3 disease undergo cranial radiation
      therapy over 10 fractions during the first 4 weeks.

      ARM IV: MPAL INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also
      receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV
      over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and
      22, pegaspargase IM or IV over 1-2 hours on day 4, and methotrexate IT on days 8 and 29 (and
      on days 15 and 22 for CNS3 patients). Patients < 10 years old receive dexamethasone PO BID or
      IV on days 1-14; patients >= 10 years old receive prednisolone PO BID or IV on days 1-28.
      Treatment continues for 5 weeks in the absence of disease progression or unacceptable
      toxicity.

      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, mercaptopurine PO
      on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22
      for CNS3 patients), vincristine IV over 1 minute on days 15, 22, 43, and 50, and pegaspargase
      IV over 1-2 hours or IM on days 15 and 43. Treatment continues for 8 weeks in the absence of
      disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis
      and continued evidence of testicular disease at end of induction undergo testicular radiation
      over 12 once-daily fractions.

      ARM V: B-LLY INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also
      receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV
      over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and
      22, pegaspargase IM or IV over 1-2 hours on day 4, and methotrexate IT on days 8 and 29 (and
      on days 15 and 22 for CNS3 patients). Patients < 10 years old receive dexamethasone PO BID or
      IV on days 1-14; patients >= 10 years old receive prednisolone PO BID or IV on days 1-28.
      Treatment continues for 5 weeks in the absence of disease progression or unacceptable
      toxicity.

      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, mercaptopurine PO
      on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22
      CNS3 patients), vincristine IV over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV
      over 1-2 hours or IM on days 15 and 43. Treatment continues for 8 weeks in the absence of
      disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis
      and continued evidence of testicular disease at end of induction undergo testicular radiation
      therapy over 12 once-daily fractions.

      ARM IV AND V: MPAL AND B-LLY INTERIM MAINTENANCE I: Patients receive vincristine IV over 1
      minute on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29,
      and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, methotrexate IT on days 1
      and 29 and mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56. Treatment continues
      for 9 weeks in the absence of disease progression or unacceptable toxicity.

      DELAYED INTENSIFICATION (PART I): 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, and 15,
      doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IV
      over 1-2 hours or IM on day 4. Treatment continues for 8 weeks in the absence of disease
      progression or unacceptable toxicity.

      DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
      day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
      36-39, methotrexate IT on days 29 and 36, vincristine IV over 1 minute on days 43 and 50, and
      pegaspargase IV over 1-2 hours or IM on day 43. Treatment continues for 8 weeks 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, methotrexate IV or infusion over 2-15 minutes or 10-15 minutes 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 8 weeks in the absence of disease progression or unacceptable
      toxicity.

      MAINTENANCE: Patients receive vincristine IV over 1 minute on days 1, prednisolone PO BID or
      IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29
      (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71, and 78, and methotrexate IT on days 1
      (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every
      12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
      Patients with CNS3 disease at diagnosis undergo cranial radiation therapy for 10 fractions
      over 4 weeks.

      After completion of study treatment, patients are followed up at 4 weeks, then every 3 months
      for 2 years, every 4-6 months for the third year, then every 6-12 months for years 4-5.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (HR-FAV B-ALL)ExperimentalSee detailed description for Arm I
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Prednisolone
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
Arm II (HR B-ALL CONTROL)Active ComparatorSee detailed description for Arm II.
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Prednisolone
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
Arm III (HR B-ALL EXPERIMENTAL)ExperimentalSee detailed description for Arm III.
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Inotuzumab Ozogamicin
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
Arm IV (MPAL)ExperimentalSee detailed description for Arm IV.
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Prednisolone
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate
ARM V (B-LLY)ExperimentalSee detailed description for Arm V.
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Leucovorin
  • Leucovorin Calcium
  • Methotrexate
  • Pegaspargase
  • Prednisolone
  • Thioguanine
  • Vincristine
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility
             studies (Part A) prior to treatment and enrollment on AALL1732. Note that central
             confirmation of MPAL diagnosis must occur within 7 business days after enrollment for
             MPAL patients. If not performed within this time frame, patients will be taken off
             protocol.

          -  APEC14B1 is not a requirement for B-LLy patients but for institutional compliance
             every patient should be offered participation in APEC14B1. B LLy patients may directly
             enroll on AALL1732 and MUST submit eligibility studies as outlined.

          -  White blood cell count (WBC) criteria for patients with B-ALL (within 7 days prior to
             the start of protocol-directed systemic therapy):

               -  Age 1-9.99 years: WBC >= 50,000/uL

               -  Age 10-24.99 years: Any WBC

               -  Age 1-9.99 years: WBC < 50,000/uL with:

                    -  Testicular leukemia

                    -  CNS leukemia (CNS3)

                    -  Steroid pretreatment.

          -  White blood cell count (WBC) criteria for patients with MPAL (within 7 days prior to
             the start of protocol-directed systemic therapy):

               -  Age 1-24.99 years: any WBC.

          -  Patient has newly diagnosed B-ALL or MPAL (by World Health Organization [WHO] 2016
             criteria) with > 25% blasts on a bone marrow (BM) aspirate;

               -  OR If a BM aspirate is not obtained or is not diagnostic of acute leukemia, the
                  diagnosis can be established by a pathologic diagnosis of acute leukemia on a BM
                  biopsy;

               -  OR A complete blood count (CBC) documenting the presence of at least 1,000/uL
                  circulating leukemic cells if a bone marrow aspirate or biopsy cannot be
                  performed.

          -  Patient has newly diagnosed B-LLy Murphy stages III or IV.

          -  Patient has newly diagnosed B-LLy Murphy stages I or II with steroid pretreatment.

          -  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.

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

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

        Exclusion Criteria:

          -  Patients with Down syndrome are not eligible (patients with Down syndrome and B-ALL
             are eligible for AALL1731, regardless of NCI risk group).

          -  Patients with known Charcot-Marie-Tooth disease.

          -  With the exception of steroid pretreatment or the administration of intrathecal
             cytarabine, patients must not have received any prior cytotoxic chemotherapy for the
             current diagnosis of B-ALL, MPAL, or B-LLy or for any cancer diagnosed prior to
             initiation of protocol therapy on AALL1732.

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

          -  Patients with acute undifferentiated leukemia (AUL) are not eligible.

          -  For Murphy stage III/IV B-LLy patients, or stage I/II patients with steroid
             pretreatment, 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.

          -  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 women who plan to breastfeed their infants while on study and for 2 months
             after the last dose of inotuzumab ozogamicin.

          -  Sexually active patients of reproductive potential who have not agreed to use an
             effective contraceptive method for the duration of study participation. For those
             patients randomized to inotuzumab ozogamicin, there is a minimum of 8 months after the
             last dose of inotuzumab ozogamicin for females and 5 months after the last dose of
             inotuzumab ozogamicin for males.
      
Maximum Eligible Age:24 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Improvement in 5-year disease-free survival (DFS) after adding 2 blocks of inotuzumab ozogamicin (InO) to Berlin-Frankfurt-Munster (mBFM) chemotherapy in children and young adults with High-Risk (HR) B-ALL
Time Frame:From end of consolidation (EOC) to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years
Safety Issue:
Description:Power calculations are based on detecting an improvement in post consolidation DFS with the addition of InO to standard therapy for high risk (HR) B-acute lymphoblastic leukemia (ALL). All survival time analyses assume a Weibull distribution with shape parameter of 0.6 (based on historical data). Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using intent-to-treat (ITT) analysis based on randomized group.

Secondary Outcome Measures

Measure:5-year DFS for favorable risk subset of NCI HR B-ALL (HR favorable) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD MTX) Interim Maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex
Time Frame:From EOC to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.
Measure:Incidence of adverse events for the integration of inotuzumab ozogamicin into the mBFM chemotherapy backbone in HR B-ALL
Time Frame:Up to 5 years
Safety Issue:
Description:Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Will be monitored and reported.
Measure:5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi escalating intravenous MTX without leucovorin rescue plus pegaspargase (C-MTX)
Time Frame:From study entry to first event (induction failure, Induction death, end of induction (EOI) minimal residual disease (MRD) >= 5%, EOC MRD >= 0.01%, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.
Measure:5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX
Time Frame:From study entry to first event (progressive disease, induction death, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Oncology Group

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