Dasatinib and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
Condition: Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      This phase II/III trial is studying the side effects and how well giving dasatinib together
      with combination chemotherapy works in treating young patients with newly diagnosed acute
      lymphoblastic leukemia (ALL). Dasatinib 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 or by stopping them from
      dividing. Giving dasatinib together with combination chemotherapy may kill more cancer cells.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To determine the feasibility and toxicity of an intensified chemotherapeutic regimen that
      incorporates dasatinib for treatment of children, adolescents, and young adults (up to age
      30) with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL).

      II. To determine whether the intensification of tyrosine kinase inhibition through the
      addition of dasatinib in Induction (Days 15-28) and substitution of dasatinib for imatinib
      during post-Induction therapy, in the context of intensive cytotoxic therapy (according to
      AALL0031) and a good early response to therapy, will lead to a 3-year event-free survival
      (EFS) of at least 60% in patients with Ph+ ALL.

      SECONDARY OBJECTIVES:

      I. To determine whether the addition of dasatinib during Induction therapy (Days 15-28) will
      decrease levels of minimal residual disease (MRD) present at end of Induction therapy as
      compared with COG AALL0031.

      II. To determine whether early intensified tyrosine kinase inhibitor (TKI) therapy will lower
      end-Consolidation MRD levels as compared to patients on COG AALL0031 that received imatinib
      in Consolidation Blocks 1 and 2 (Cohorts 3-5).

      III. To determine the overall 3-year EFS rate for the whole cohort of Standard- and High-Risk
      patients treated with dasatinib.

      IV. To determine the long-term effects of dasatinib on growth, development, and bone
      metabolism.

      V. To assess BCR-ABL mutation status at time of diagnosis and progression/relapse.

      OUTLINE: This is a multicenter study. Patients are stratified according to risk (standard
      risk vs high risk) at the end of consolidation therapy.

      INDUCTION THERAPY (weeks 1-4): Patients receive initial induction therapy on days 1-14 prior
      to beginning the study. Patients then receive vincristine intravenously (IV) and daunorubicin
      hydrochloride* IV over 15 minutes on days 15 and 22; dasatinib orally (PO) once daily (QD)
      and prednisone PO (or methylprednisolone IV) twice daily (BID) on days 15-28; methotrexate
      intrathecally (IT) on day 29; and some patients receive methotrexate, hydrocortisone, and
      cytarabine IT on days 15 and 22. After completion of induction therapy, patients undergo bone
      marrow aspiration for evaluation of disease. Patients with M1 bone marrow and minimal
      residual disease (MRD) < 1% (standard-risk disease) proceed to block 1 consolidation therapy
      1 week after completion of induction therapy or when blood counts recover (whichever occurs
      later). Patients with M2 or M3 bone marrow or MRD >= 1% (high-risk disease) proceed
      immediately to block 1 consolidation therapy, regardless of blood counts. Patients with
      clinically evident or biopsy-proven testicular leukemia at diagnosis that persists at the end
      of induction therapy undergo 12 fractions of testicular radiotherapy beginning within 4 days
      prior to starting block 1 consolidation therapy.

      NOTE: *Patients who receive initial induction therapy on a DFCI Childhood ALL Consortium
      trial do not receive daunorubicin hydrochloride during induction therapy on this study.

      CONSOLIDATION THERAPY:

      BLOCK 1 CONSOLIDATION THERAPY: (weeks 6-8) Patients receive etoposide IV over 1 hour and
      ifosfamide IV over 1 hour on days 1-5, dasatinib PO on days 1-14 OR on days 1-21, and some
      patients receive methotrexate, hydrocortisone, and cytarabine IT on days 8 and 15. Patients
      also receive filgrastim (G-CSF) subcutaneously (SC) or IV QD beginning on day 6 and
      continuing until blood counts recover.

      After completion of block 1 consolidation therapy, patients proceed to block 2 consolidation
      therapy.

      BLOCK 2 CONSOLIDATION THERAPY: (weeks 9-11) Patients receive high-dose methotrexate IV
      continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses on
      days 2-3; methotrexate, hydrocortisone, and cytarabine IT on day 1; cytarabine IV over 3
      hours every 12 hours for 4 doses on days 2 and 3; and dasatinib PO on days 1-14 OR on days
      1-21. Patients also receive G-CSF SC or IV QD beginning on day 4 and continuing until blood
      counts recover. After completion of block 2 consolidation therapy and recovery of blood
      counts, patients undergo bone marrow aspiration for evaluation of disease. Patients with MRD
      < 0.01% (standard-risk disease) with a matched related donor and who are willing to undergo
      hematopoietic stem cell transplantation (HSCT) proceed to HSCT off study. Standard-risk
      patients without a suitable donor or those who elect not to undergo HSCT proceed to
      post-consolidation therapy. Patients with MRD >= 0.01% (high-risk disease) with a matched
      related or unrelated donor proceed to HSCT off study. High-risk patients without a suitable
      donor proceed to post-consolidation therapy.

      POST-CONSOLIDATION THERAPY:

      REINDUCTION BLOCK 1 THERAPY: (weeks 12-14) Patients receive vincristine IV on days 1, 8, and
      15; daunorubicin hydrochloride IV over 15 minutes on days 1 and 2; cyclophosphamide IV over 1
      hour every 12 hours for 4 doses on days 3 and 4; pegaspargase intramuscularly (IM) on day 4;
      methotrexate, hydrocortisone, and cytarabine IT on days 1 and 15; dexamethasone PO or IV BID
      on days 1-7 and 15-21; and dasatinib PO on days 1-14 OR on days 1-21. Patients also receive
      G-CSF SC or IV QD beginning on day 5 and continuing until blood counts recover.

      After completion of reinduction block 1 therapy, patients proceed to intensification block 1
      therapy.

      INTENSIFICATION BLOCK 1 THERAPY: (weeks 15-23) Patients receive high-dose methotrexate IV
      continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses on
      days 2-3; methotrexate, hydrocortisone, and cytarabine IT on days 1 and 22; etoposide IV over
      1 hour and cyclophosphamide IV over 1 hour on days 22-26; cytarabine IV over 3 hours every 12
      hours for 4 doses on days 43 and 44; asparaginase IM on day 44; and dasatinib PO on days
      1-14, 22-35, and 43-56 OR on days 1-63. Patients also receive G-CSF SC or IV QD beginning on
      day 27 and continuing until blood counts recover. After completion of intensification block 1
      therapy, patients proceed to reinduction block 2 therapy.

      REINDUCTION BLOCK 2 THERAPY: (weeks 24-26) Patients receive reinduction block 2 therapy as
      per reinduction block 1 therapy. After completion of reinduction block 2 therapy, patients
      proceed to intensification block 2 therapy.

      INTENSIFICATION BLOCK 2 THERAPY: (weeks 27-35) Patients receive intensification block 2
      therapy as per intensification block 1 therapy. After completion of intensification block 2
      therapy, patients proceed to maintenance therapy.

      MAINTENANCE THERAPY:

      MAINTENANCE COURSES 1-4: (weeks 36-67) Patients receive high-dose methotrexate IV
      continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses on
      days 2-3; methotrexate, hydrocortisone, and cytarabine IT and vincristine IV on days 1 and
      29; prednisone PO or IV BID on days 1-5 and 29-33; mercaptopurine PO on days 8-28;
      methotrexate PO on days 8, 15, and 22; etoposide IV over 1 hour and cyclophosphamide IV over
      1 hour on days 29-33; and dasatinib PO on days 1-14 and 29-42 OR on days 1-56. Patients also
      receive G-CSF SC or IV QD beginning on day 34 and continuing until blood counts recover.
      Courses repeat every 56 days. After completion of maintenance courses 1-4, patients proceed
      to maintenance course 5.

      MAINTENANCE COURSE 5: (weeks 68-75) Patients receive vincristine IV on days 1 and 29;
      prednisone PO or IV BID on maintenance courses 6-12.

      MAINTENANCE COURSES 6-12: (weeks 76-131) Patients receive vincristine IV on days 1 and 29;
      prednisone PO or IV BID on days 1-5 and 29-33; mercaptopurine PO on days 1-56; methotrexate
      PO on days 1, 8, 15, 22, 29, 36, 43, and 50; and dasatinib PO on days 1-14 and 29-42 OR on
      days 1-56.

      Courses repeat every 56 days. Patients long-term growth, development, and bone metabolism are
      assessed after completion of study therapy and then annually for 5 years.

      After completion of study therapy, patients are followed up periodically for up to 10 years.
    

Intervention name(s): Asparaginase; Cyclophosphamide; Cytarabine; Dasatinib; Daunorubicin Hydrochloride; Dexamethasone; Etoposide; Filgrastim; Hydrocortisone Sodium Succinate; Ifosfamide; Laboratory Biomarker Analysis; Leucovorin Calcium; Mercaptopurine; Methotrexate; Methylprednisolone; Pegaspargase; Prednisone; Radiation Therapy; Vincristine Sulfate
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Biological; Drug; Drug; Other; Drug; Drug; Drug; Drug; Drug; Drug; Radiation; Drug
Intervention description(s): Given IT; Given IV; Given IT or IV; Given PO; Given IV; Given IV or PO; Given IV; Given IV or SC; Given IT; Given IV; Correlative studies; Given IV or PO; Given PO; Given IT, PO, or IV; Given IV; Given IM; Given PO or IV; Some patients undergo cranial RT; Given IV
Other intervention name(s): ASP-1; Asparaginase II; Asparaginase-E.Coli; Colaspase; Elspar; Kidrolase; L-Asnase; L-ASP; L-asparaginase; L-Asparagine amidohydrolase; Laspar; Lcf-ASP; Leucogen; Leunase; MK-965; Paronal; Re-82-TAD-15; Serasa; Spectrila; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; BMS-354825; Dasatinib Hydrate; Dasatinib Monohydrate; Sprycel; Cerubidin; Cerubidine; Cloridrato de Daunorubicina; Daunoblastin; Daunoblastina; Daunoblastine; Daunomycin hydrochloride; Daunomycin, hydrochloride; Daunorubicin.HCl; Daunorubicini Hydrochloridum; FI-6339; Ondena; RP-13057; Rubidomycin Hydrochloride; Rubilem; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycadron; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron; Decadron DP; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone Intensol; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; TaperDex; Visumetazone; ZoDex; Demethyl Epipodophyllotoxin Ethylidine Glucoside; EPEG; Lastet; Toposar; Vepesid; VP 16; VP 16-213; VP-16; VP-16-213; VP16; G-CSF; Neupogen; r-metHuG-CSF; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; (11beta)-21-(3-Carboxy-1-oxopropyl)-11,17-dihydroxypregn-4-ene-3,20-dione, Monosodium Salt; A-Hydrocort; Buccalsone; Corlan; Cortisol sodium succinate; Cortop; Efcortelan; Emergent-EZ; Flebocortid; Hidroc Clora; Hycorace; Hydro-Adreson; Hydrocort; Hydrocortisone 21-Sodium Succinate; Hydrocortisone Na Succinate; Kinogen; Nordicort; Nositrol; Sinsurrene; Sodium hydrocortisone succinate; Solu-Cortef; Solu-Glyc; Asta 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-4942; Adinepar; 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; Wellcovorin; 3H-Purine-6-thiol; 6 MP; 6 Thiohypoxanthine; 6 Thiopurine; 6-Mercaptopurine; 6-Mercaptopurine Monohydrate; 6-MP; 6-Purinethiol; 6-Thiopurine; 6-Thioxopurine; 6H-Purine-6-thione, 1,7-dihydro- (9CI); 7-Mercapto-1,3,4,6-tetrazaindene; Alti-Mercaptopurine; Azathiopurine; BW 57-323H; Flocofil; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptina; Mercaptopurinum; Mercapurin; Mern; NCI-C04886; Puri-Nethol; Purimethol; Purine, 6-mercapto-; Purine-6-thiol (8CI); Purine-6-thiol, monohydrate; Purinethiol; Purinethol; U-4748; WR-2785; Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate; Mexate-AQ; MTX; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Adlone; 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; Wyacort; L-Asparaginase with Polyethylene Glycol; Oncaspar; Oncaspar-IV; PEG-asparaginase; PEG-L-Asparaginase; PEG-L-Asparaginase (Enzon - Kyowa Hakko); PEGLA; Polyethylene Glycol L-Asparaginase; Polyethylene Glycol-L-Asparaginase; .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltasone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Orasone; Panafcort; Panasol-S; Paracort; Perrigo Prednisone; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisone Intensol; Prednisonum; Prednitone; Promifen; Rayos; Servisone; SK-Prednisone; Cancer Radiotherapy; Irradiate; Irradiated; irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Kyocristine; Leurocristine sulfate; Leurocristine, sulfate; Oncovin; Vincasar; Vincosid; Vincrex; Vincristine, sulfate
Intervention MeSH terms: Calcium, Dietary; Leucovorin; Folic Acid; Cytarabine; Dexamethasone; Dexamethasone acetate; Prednisone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cortisone; Cyclophosphamide; Ifosfamide; Isophosphamide mustard; Methotrexate; Etoposide; Vincristine; Etoposide phosphate; Daunorubicin; Asparaginase; Dasatinib; Mercaptopurine; Podophyllotoxin; Pegaspargase; Lenograstim; Prednisolone hemisuccinate; Prednisolone phosphate; BB 1101; Calcium; Levoleucovorin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment