Clinical Trials /

Azacitidine and Combination Chemotherapy in Treating Infants With Acute Lymphoblastic Leukemia and KMT2A Gene Rearrangement

NCT02828358

Description:

This pilot phase II trial studies the side effects of azacitidine and combination chemotherapy in infants with acute lymphoblastic leukemia and KMT2A gene rearrangement. Drugs used in chemotherapy, such as methotrexate, prednisolone, daunorubicin hydrochloride, cytarabine, dexamethasone, vincristine sulfate, pegaspargase, hydrocortisone sodium succinate, azacitidine, cyclophosphamide, mercaptopurine, leucovorin calcium, 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. Giving more than one drug may kill more cancer cells.

Related Conditions:
  • Acute Leukemia of Ambiguous Lineage
  • B-Cell Acute Lymphoblastic Leukemia
  • Mixed Phenotype Acute Leukemia
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine and Combination Chemotherapy in Treating Infants With Acute Lymphoblastic Leukemia and KMT2A Gene Rearrangement
  • Official Title: A Groupwide Pilot Study to Test the Tolerability and Biologic Activity of the Addition of Azacitidine (NSC# 102816) to Chemotherapy in Infants With Acute Lymphoblastic Leukemia (ALL) and KMT2A(MLL) Gene Rearrangement

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-00973
  • SECONDARY ID: NCI-2016-00973
  • SECONDARY ID: AALL15P1
  • SECONDARY ID: AALL15P1
  • SECONDARY ID: AALL15P1
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02828358

Conditions

  • Acute Leukemia of Ambiguous Lineage
  • Childhood B Acute Lymphoblastic Leukemia
  • KMT2A Gene Rearrangement
  • Mixed Phenotype Acute Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, combination chemotherapy)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (azacitidine, combination 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, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (azacitidine, combination 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, RubilemTreatment (azacitidine, combination 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, VisumetazoneTreatment (azacitidine, combination chemotherapy)
Hydrocortisone Sodium Succinate(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-GlycTreatment (azacitidine, combination 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, WellcovorinTreatment (azacitidine, combination 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-2785Treatment (azacitidine, combination 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-19039Treatment (azacitidine, combination 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-AsparaginaseTreatment (azacitidine, combination 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, SteraneTreatment (azacitidine, combination 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 27Treatment (azacitidine, combination chemotherapy)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateTreatment (azacitidine, combination chemotherapy)

Purpose

This pilot phase I trial studies the side effects of azacitidine and combination chemotherapy in infants with acute lymphoblastic leukemia and KMT2A gene rearrangement. Drugs used in chemotherapy, such as methotrexate, prednisolone, daunorubicin hydrochloride, cytarabine, dexamethasone, vincristine sulfate, pegaspargase, hydrocortisone sodium succinate, azacitidine, cyclophosphamide, mercaptopurine, leucovorin calcium, 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. Giving more than one drug may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the tolerability of azacitidine in addition to Interfant-06 standard
      chemotherapy in infants with newly diagnosed acute lymphoblastic leukemia (ALL) with KMT2A
      gene rearrangement (KMT2A-R).

      SECONDARY OBJECTIVES:

      I. To evaluate the biologic activity of azacitidine by pharmacodynamic assessment of global
      deoxyribonucleic acid (DNA) methylation in peripheral blood mononuclear cells (PBMCs) of
      infants treated with azacitidine.

      TERTIARY OBJECTIVES:

      I. To determine the 5 year event-free survival (EFS) of infants with KMT2A-R treated with
      azacitidine in addition to Interfant-06 standard chemotherapy.

      II. To correlate minimal residual disease (MRD) with outcome in the context of the protocol
      therapy.

      III. To perform pharmacokinetic (PK) testing of azacitidine in infants. IV. To test the
      expansion of infant T lymphocytes by stimulation with artificial antigen presenting cells
      identical to those used in chimeric antigen receptor T-cell (CART)-19 production.

      V. To collect pharmacodynamic (PD) data for asparaginase activity following pegaspargase
      administration in infants.

      OUTLINE:

      INDUCTION CHEMOTHERAPY: Patients receive methotrexate intrathecally (IT) on days 1 and 29,
      prednisolone orally (PO) or nasogastrically (NG) three times daily (TID) on days 1-7,
      daunorubicin hydrochloride intravenously (IV) over 1-15 minutes on days 8-9, cytarabine IV
      over 30 minutes on days 8-21 and IT on day 15, dexamethasone PO, NG, or IV TID on days 8-28,
      vincristine sulfate IV over 1 minute on days 8, 15, 22, and 29, pegaspargase IV over 1-2
      hours or intramuscularly (IM) on day 12, and hydrocortisone sodium succinate IT on days 15
      and 29 in the absence of disease progression or unacceptable toxicity. Only patients with
      KMT2A-R continue to post-induction chemotherapy.

      POST-INDUCTION CHEMOTHERAPY:

      AZACITIDINE BLOCK I: Prior to CONSOLIDATION, patients receive azacitidine IV over 10-40
      minutes daily for 5 days in the absence of disease progression or unacceptable toxicity.

      CONSOLIDATION: Following completion of AZACITIDINE BLOCK I, patients receive cyclophosphamide
      IV over 30-60 minutes on days 1 and 29, mercaptopurine PO or NG daily on days 1-28,
      cytarabine IV or subcutaneously (SC) daily on days 3-6, 10-13, 17-20, and 24-27 and IT on day
      10, methotrexate IT on day 24, and hydrocortisone sodium succinate IT on days 10 and 24 in
      the absence of disease progression or unacceptable toxicity.

      AZACITIDINE BLOCK II: Prior to INTERIM MAINTENANCE, patients receive azacitidine as in
      AZACITIDINE BLOCK I

      INTERIM MAINTENANCE: Following completion of AZACITIDINE BLOCK II, patients receive
      mercaptopurine PO or NG daily on days 1-14, methotrexate IV over 24 hours on days 1 and 8 and
      IT on days 2 and 9, hydrocortisone sodium succinate IT on days 2 and 9, leucovorin calcium PO
      or IV on days 2-3 and 9-10, cytarabine IV over 3 hours every 12 hours on days 15-16 and 22-23
      for a total of 8 doses, and pegaspargase IV over 1-2 hours or IM on day 23 in the absence of
      disease progression or unacceptable toxicity.

      AZACITIDINE BLOCK III: Prior to DELAYED INTENSIFICATION PART I, patients receive azacitidine
      as in AZACITIDINE BLOCK I.

      DELAYED INTENSIFICATION PART I: Following completion of AZACITIDINE BLOCK III, patients
      receive pegaspargase IV over 1-2 hours or IM on day 1, dexamethasone PO, NG, or IV TID on
      days 1-14 and 15-21 with a taper on days 15-21, thioguanine PO or NG daily on days 1-28,
      vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22, daunorubicin hydrochloride IV
      over 1-15 minutes on days 1, 8, 15, and 22, cytarabine IV or SC on days 2-5, 9-12, 16-19, and
      23-26 and IT on days 1 and 15, and hydrocortisone sodium succinate IT on days 1 and 15 in the
      absence of disease progression or unacceptable toxicity.

      AZACITIDINE BLOCK IV: Prior to DELAYED INTENSIFICATION PART II, patients receive azacitidine
      as in AZACITIDINE BLOCK I.

      DELAYED INTENSIFICATION PART II: Following completion of AZACITIDINE BLOCK IV, patients
      receive thioguanine PO or NG daily on days 1-14, cyclophosphamide IV over 15-30 minutes on
      days 1 and 15, cytarabine IV or SC on days 2-5 and 9-12 in the absence of disease progression
      or unacceptable toxicity.

      MAINTENANCE: Following DELAYED INTENSIFICATION PART II, patients receive mercaptopurine PO or
      NG on days 1-168, methotrexate IT on day 1 and 92 and PO once weekly on days 8-91 and 98-168,
      hydrocortisone sodium succinate IT on day 1, 57, and 99, and cytarabine IT on day 57.
      Starting on day 169, patients receive mercaptopurine PO or NG on days 1-84 and methotrexate
      PO once weekly. Courses repeat every 84 days for 2 years from the start of INDUCTION
      CHEMOTHERAPY in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, combination chemotherapy)ExperimentalSee Detailed Description
  • Azacitidine
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Dexamethasone
  • Hydrocortisone Sodium Succinate
  • Leucovorin Calcium
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Prednisolone
  • Thioguanine
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health
             Organization [WHO] classification) (also termed B-precursor acute lymphoblastic
             leukemia) or acute leukemia of ambiguous lineage (ALUL), which includes mixed
             phenotype acute leukemia (MPAL); for patients with ALUL, the morphology and
             immunophenotype must be at least 50% B lymphoblastic

          -  Central nervous system (CNS) status must be determined based on a sample obtained
             prior to the administration of any systemic or intrathecal chemotherapy, with the
             exception of steroid pretreatment

        Exclusion Criteria:

          -  Patients with known absence of KMT2A-rearrangement leukemia prior to enrollment

          -  Patients with Down syndrome

          -  Patients with secondary B acute lymphoblastic leukemia (B-ALL) that developed after
             treatment of a prior malignancy with cytotoxic chemotherapy

          -  With the exception of steroid pretreatment or the administration of intrathecal
             methotrexate per protocol dosing, receipt of any other prior cytotoxic chemotherapy
             for either the current diagnosis of B-ALL or any cancer diagnosed prior to the
             initiation of protocol therapy on AALL15P1
      
Maximum Eligible Age:364 Days
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events of azacitidine and combination chemotherapy, graded according to Common Terminology Criteria for Adverse Events 4.0
Time Frame:From the first course of azacitidine administration up to fourth course of azacitidine administration
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Biologic activity, defined as global DNA methylation change in PBMCs
Time Frame:Prior to first course of azacitidine up to day 5 of second course of azacitidine
Safety Issue:
Description:Will calculate the mean long interspersed nucleotide element-1 (LINE-1) methylation for all patients before and after azacitidine and perform paired t-test analysis to determine if there is significant demethylation in the study population for the tested dose level.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

July 3, 2017