Clinical Trials /

Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

NCT03007147

Description:

This randomized phase III trial studies how well imatinib mesylate and combination chemotherapy work in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia. Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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. Giving imatinib mesylate and combination chemotherapy may work better in treating patients with Philadelphia chromosome positive acute lymphoblastic leukemia.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
  • Official Title: International Phase 3 Trial in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Testing Imatinib in Combination With Two Different Cytotoxic Chemotherapy Backbones

Clinical Trial IDs

  • ORG STUDY ID: AALL1631
  • SECONDARY ID: NCI-2016-01588
  • SECONDARY ID: AALL1631
  • SECONDARY ID: AALL1631
  • SECONDARY ID: AALL1631
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03007147

Conditions

  • B Acute Lymphoblastic Leukemia
  • BCR-ABL1 Fusion Protein Expression
  • Minimal Residual Disease
  • Philadelphia Chromosome Positive
  • T Acute Lymphoblastic Leukemia
  • Untreated Adult Acute Lymphoblastic Leukemia
  • Untreated Childhood Acute Lymphoblastic 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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm A (imatinib mesylate, EsPhALL 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 A (imatinib mesylate, EsPhALL 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 A (imatinib mesylate, EsPhALL 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 A (imatinib mesylate, EsPhALL chemotherapy)
Dexrazoxane HydrochlorideCardioxane, Totect, ZinecardArm A (imatinib mesylate, EsPhALL chemotherapy)
DoxorubicinAdriablastin, Hydroxyl Daunorubicin, HydroxyldaunorubicinArm A (imatinib mesylate, EsPhALL chemotherapy)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Arm A (imatinib mesylate, EsPhALL chemotherapy)
FilgrastimFILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimArm A (imatinib mesylate, EsPhALL chemotherapy)
IfosfamideAsta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942Arm A (imatinib mesylate, EsPhALL chemotherapy)
Imatinib MesylateCGP 57148, CGP57148B, Gleevec, Glivec, STI 571, STI-571, STI571Arm A (imatinib mesylate, EsPhALL chemotherapy)
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 (imatinib mesylate, EsPhALL 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 A (imatinib mesylate, EsPhALL 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 A (imatinib mesylate, EsPhALL 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 A (imatinib mesylate, EsPhALL chemotherapy)
MethylprednisoloneAdlone, Caberdelta M, DepMedalone, Depo Moderin, Depo-Nisolone, Duralone, Emmetipi, Esametone, Firmacort, Medlone 21, Medrate, Medrol, Medrol Veriderm, Medrone, Mega-Star, Meprolone, Methylprednisolonum, Metilbetasone Solubile, Metrocort, Metypresol, Metysolon, Predni-M-Tablinen, Prednilen, Radilem, Sieropresol, Solpredone, Summicort, Urbason, Veriderm Medrol, WyacortArm A (imatinib mesylate, EsPhALL 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 A (imatinib mesylate, EsPhALL chemotherapy)
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 A (imatinib mesylate, EsPhALL chemotherapy)
Therapeutic HydrocortisoneAeroseb-HC, Barseb HC, Barseb-HC, Cetacort, Cort-Dome, Cortef, Cortenema, Cortifan, Cortisol, Cortispray, Cortril, Dermacort, Domolene, Eldecort, Hautosone, Heb-Cort, HYDROCORTISONE, Hydrocortone, Hytone, Komed-HC, Nutracort, Proctocort, RectoidArm A (imatinib mesylate, EsPhALL chemotherapy)
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-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, Tioguanin, Tioguanine, Wellcome U3B, WR-1141, X 27Arm A (imatinib mesylate, EsPhALL chemotherapy)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm A (imatinib mesylate, EsPhALL chemotherapy)

Purpose

This randomized phase III trial studies how well imatinib mesylate and combination chemotherapy work in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia. Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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. Giving imatinib mesylate and combination chemotherapy may work better in treating patients with Philadelphia chromosome positive acute lymphoblastic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare disease-free survival (DFS) of standard risk pediatric Philadelphia chromosome
      (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib)
      combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or
      the more intensive European (Es)PhALL chemotherapy backbone.

      SECONDARY OBJECTIVES:

      I. To determine the feasibility of administration of imatinib after allogeneic hematopoietic
      stem cell transplantation (HSCT) in high risk Ph+ ALL patients.

      II. To determine event-free survival (EFS) of high risk pediatric Ph+ ALL patients treated
      with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.

      III. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients
      between the two randomized arms.

      IV. To evaluate event free survival (EFS) and overall survival (OS) of all enrolled
      participants.

      V. To evaluate OS in SR patients. VI. To evaluate OS in high risk (HR) patients.

      TERTIARY OBJECTIVES:

      I. To describe the toxicities associated with post-HSCT administration of imatinib.

      II. To evaluate the long-term toxicities in SR patients treated with chemotherapy plus
      imatinib (no transplant), overall and between both randomized arms.

      III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at
      various time points during therapy.

      IV. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT
      and explore the association of these measurements with long-term outcome.

      V. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase
      chain reaction (PCR) assay and next generation sequencing (NGS) assays.

      VI. To determine prognostic significance of IKZF1 gene aberrations and deletions.

      VII. To determine frequency and prognostic significance of p190 and p210 BCR-ABL1 fusion
      variants in pediatric Ph+ ALL.

      VIII. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and
      methotrexate) during the maintenance phase in SR Ph+ ALL patients.

      IX. To identify factors associated with poor adherence. X. To determine association between
      relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).

      XI. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and
      identify factors associated with poor adherence.

      OUTLINE:

      INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days
      1-14.

      INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice
      daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone
      intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22,
      daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate
      intrathecally (IT) on day 29.

      INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide
      IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or
      subcutaneously (SC) on days 1-4, 8-11, 15-18, and 22-25, and methotrexate IT on days 8 and
      22.

      POST-INDUCTION THERAPY: Patients with standard risk are randomized to 1 of 2 arms. Patients
      with high risk are assigned to Arm C.

      ARM A:

      CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21,
      methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose
      methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6,
      dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4,
      leucovorin calcium PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and
      pegaspargase IV over 1-2 hours on day 5, and filgrastim SC on days 7-11 in the absence of
      disease progression or unexpected toxicity.

      CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21,
      methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose
      methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine
      sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin
      calcium PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 5-15 minutes and
      daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase IV over 1-2 hours on
      day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected
      toxicity.

      CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high
      dose cytarabine IV over 3 hours on days 1-2, dexamethasone PO BID or IV on days 1-5,
      etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic
      hydrocortisone IT on day 5, pegaspargase IV over 1-2 hours on day 6, and filgrastim SC on
      days 7-11 in the absence of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days
      1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
      sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
      over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours on day 8 in
      the absence of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63,
      cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV
      over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the
      absence of disease progression or unexpected toxicity.

      INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28,
      methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence
      of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days
      1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
      sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
      over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours on day 8 in
      the absence of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49,
      cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV
      over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the
      absence of disease progression or unexpected toxicity.

      MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO
      once weekly (QW) and IT on days 1 and 43 of courses 1, 2, and 3, and mercaptopurine PO on
      days 1-84. Courses with imatinib mesylate and mercaptopurine repeat every 84 days for up to
      104 weeks from the start of Induction IA in the absence of disease progression or unexpected
      toxicity.

      ARM B:

      INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63,
      vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days 1,
      15, 29, and 43, leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46,
      mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in the absence of
      disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28,
      methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
      sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
      over 1-15 minutes on days 1, 8, and 15, and pegaspargase IV over 1-2 hours on day 4 in the
      absence of disease progression or unexpected toxicity.

      DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56,
      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 sulfate IV over 1 minute on days 43 and 50, and pegaspargase IV over 1-2 hours on
      day 43 in the absence of disease progression or unexpected toxicity.

      INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or
      BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes
      on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2
      hours on days 2 and 22 in the absence of disease progression or unexpected toxicity.

      MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine
      sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV
      for course 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84,
      methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for course 1 and 2). Courses
      repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of
      disease progression or unexpected toxicity.

      ARM C:

      CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine,
      therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone,
      leucovorin calcium, high dose cytarabine, and pegaspargase as in Arm A Consolidation Block 1,
      and filgrastim SC on day 7 in the absence of disease progression or unexpected toxicity.

      CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine,
      therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate,
      ifosfamide, leucovorin calcium, dexrazoxane hydrochloride, daunorubicin hydrochloride,
      pegaspargase, and filgrastim as Arm A Consolidation Block 2 in the absence of disease
      progression or unexpected toxicity.

      CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide,
      methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase, and filgrastim as in Arm
      A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence
      of disease progression or unexpected toxicity.

      HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed
      Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm
      A.

      POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in
      the absence of disease progression or unexpected toxicity.

      After completion of study treatment, patients are followed up every year for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (imatinib mesylate, EsPhALL chemotherapy)ExperimentalSee Detailed Description
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Dexrazoxane Hydrochloride
  • Doxorubicin
  • Etoposide
  • Filgrastim
  • Ifosfamide
  • Imatinib Mesylate
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine
  • Methotrexate
  • Methylprednisolone
  • Pegaspargase
  • Prednisolone
  • Therapeutic Hydrocortisone
  • Thioguanine
  • Vincristine Sulfate
Arm B (imatinib mesylate, COG/BFM chemotherapy)ExperimentalSee Detailed Description.
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Dexrazoxane Hydrochloride
  • Doxorubicin
  • Imatinib Mesylate
  • Leucovorin Calcium
  • Mercaptopurine
  • Methotrexate
  • Methylprednisolone
  • Pegaspargase
  • Prednisolone
  • Thioguanine
  • Vincristine Sulfate
Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)ExperimentalSee Detailed Description
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Dexrazoxane Hydrochloride
  • Doxorubicin
  • Etoposide
  • Filgrastim
  • Ifosfamide
  • Imatinib Mesylate
  • Leucovorin Calcium
  • Mercaptopurine
  • Mercaptopurine
  • Methotrexate
  • Methylprednisolone
  • Pegaspargase
  • Prednisolone
  • Therapeutic Hydrocortisone
  • Thioguanine
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  For patients enrolled on AALL08B1 or APEC14B1 (if open for ALL patients) prior to
             enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled

               -  For patients who have not previously enrolled on AALL08B1 or APEC14B1 (if open
                  for ALL patients) prior to enrollment on AALL1631, a baseline diagnostic sample
                  must be available to develop an MRD probe

               -  In addition, laboratory reports detailing evidence of BCR-ABL1 fusion must be
                  submitted for rapid central review within 72 hours of study enrollment

          -  Newly diagnosed de novo ALL (B-ALL or T-ALL) with definitive evidence of BCR-ABL1
             fusion by karyotype, fluorescence in situ hybridization (FISH) and/or reverse
             transcriptase (RT)-PCR

          -  Patient must have previously started induction therapy, which includes vincristine, a
             corticosteroid, pegaspargase, with or without anthracycline, and/or other standard
             cytotoxic chemotherapy

          -  Patient has not received more than 14 days of multiagent induction therapy beginning
             with the first dose of vinCRIStine

          -  Patient may have started imatinib prior to study entry but has not received more than
             14 days of imatinib

          -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
             Group (ECOG) scores of 0, 1, or 2

          -  Direct bilirubin =< 2.0 mg/dL

          -  Shortening fraction of >= 27% by echocardiogram

          -  Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram

          -  Corrected QT interval, QTc < 480 msec

               -  Note: Repeat echocardiogram is not required if echocardiogram was obtained within
                  21 days of study enrollment

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             mL/min/1.73 m^2

          -  Serum creatinine within normal limits based on age/gender, as follows:

               -  1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)

               -  2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)

               -  6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)

               -  10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)

               -  13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)

               -  >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)

        Exclusion Criteria:

          -  Known history of chronic myelogenous leukemia (CML)

          -  ALL developing after a previous cancer treated with cytotoxic chemotherapy

          -  Active, uncontrolled infection, or active systemic illness that requires ongoing
             vasopressor support or mechanical ventilation

          -  Down syndrome

          -  Pregnancy and breast feeding

               -  Female patients who are pregnant; 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

          -  Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart
             block

          -  Prior treatment with dasatinib, or any BCR-ABL1 inhibitor other than imatinib

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

          -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
             (NCI) requirements for human studies must be met
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease free survival (DFS)
Time Frame:From randomization to first event (relapse, second malignancy, or death in complete remission) or time to last follow-up for patients without events, assessed up to 3 years
Safety Issue:
Description:Will compare the DFS of standard risk Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) patients treated continuous imatinib mesylate with high risk Children's Oncology Group (COG)-ALL chemotherapy backbone or more intensive European (Es)PhALL chemotherapy backbone.

Secondary Outcome Measures

Measure:Imatinib mesylate administration after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk Ph+ ALL patients
Time Frame:Up to 2 years
Safety Issue:
Description:Feasibility of post-HSCT imatinib mesylate is determined based on the proportion of patients who receive at least 75% of intended doses.
Measure:Event free survival (EFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate
Time Frame:From the date of bone marrow for minimal residual disease (MRD) assessment at end-IB to first event or time to last follow-up for patients without events, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood.
Measure:Incidence of grade 3 or higher infections in standard risk Ph+ ALL patients in the two randomized arms evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 3 years
Safety Issue:
Description:The rate of infections during the post IB/pre-maintenance phases of treatment will be compared accounting for follow-up time.
Measure:EFS of all enrolled patients
Time Frame:From enrollment until the first occurrence of: M3 marrow at the end of Induction IA, relapse, second malignancy, or death as a first event, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood.
Measure:Overall survival (OS) of all enrolled patients
Time Frame:From study enrollment to death from any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood. Will be estimated with a maximum standard error of 1.9%.
Measure:OS of standard risk patients
Time Frame:From randomization to death from any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood. Estimates will also be calculated for each of the randomization groups.
Measure:OS of high risk patients
Time Frame:From the date of MRD assessment at end-IB to death from any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood. Estimates will also be calculated for each of the randomization groups.

Details

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

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