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Blinatumomab in Treating Younger Patients With Relapsed B-cell Acute Lymphoblastic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02101853
Recruitment Status : Active, not recruiting
First Posted : April 2, 2014
Last Update Posted : April 5, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE March 28, 2014
First Posted Date  ICMJE April 2, 2014
Last Update Posted Date April 5, 2021
Actual Study Start Date  ICMJE December 8, 2014
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2020)
  • Disease free survival (DFS) of high-risk (HR) and intermediate-risk (IR) relapse patients [ Time Frame: From randomization to first event (treatment failure, relapse, second malignancy, death) or last follow-up for those who are event-free, assessed up to 10 years ]
    Comparison of DFS rates between treatment arms will be based on log rank test. Interim analysis will be conducted to monitor for efficacy and futility. The efficacy stopping boundaries are based on the O' Brien-Fleming spending function. The futility boundaries are based on testing the alternative hypothesis at the 0.024 level.
  • DFS of low risk (LR) relapse patients [ Time Frame: From randomization to first event (relapse, second malignancy, death) or last follow-up for those who are event-free, assessed up to 10 years ]
    Comparison of DFS rates between treatment arms will be based on log rank test. Interim analysis will be conducted to monitor for efficacy and futility. The efficacy stopping boundaries are based on the O' Brien-Fleming spending function. The futility boundaries are based on testing the alternative hypothesis at the 0.039 level.
Original Primary Outcome Measures  ICMJE
 (submitted: March 28, 2014)
  • 2-year DFS of HR and IR relapse patients [ Time Frame: From start of Block 2 of therapy to event (treatment failure, relapse, second malignancy, death) or last follow-up for those who are event-free, assesses at 2 years ]
  • 3-year DFS of LR relapse patients [ Time Frame: From start of Block 3 of therapy to first event (relapse, second malignant neoplasm, remission death) or last followup for those who are event-free, assessed at 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2020)
  • Overall survival (OS) of HR and IR relapse patients [ Time Frame: From randomization to death or last follow-up, assessed up to 10 years ]
    Comparison of OS rates between treatment arms will be based on log rank test.
  • OS of lLR relapse patients [ Time Frame: From randomization to death or last follow-up, assessed up to 10 years ]
    Comparison of OS rates between treatment arms will be based on log rank test.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2014)
  • Rates of MRD positivity (> 0.01%) [ Time Frame: Up to 12 weeks ]
    Will be compared at the end of Block 2 and 3 between randomized arms for HR and IR relapse patients.
  • Morphologic CR rate [ Time Frame: Up to 10 years ]
  • MRD negativity (< 0.01%) rate [ Time Frame: Up to 12 weeks ]
    Will be compared at the end of Block 2 and 3 between randomized arms for HR and IR relapse patients.
  • Proportion of patients that proceed to HSCT after treatment with blinatumomab (for treatment failure patients not previously receiving blinatumomab) [ Time Frame: Up to 10 years ]
  • Feasibility of rapid taper of immune suppression for subset of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no aGVHD defined as < 25% rate of grade III-IV aGVHD [ Time Frame: Up to 10 years ]
    The observed rates of grade III-IV aGVHD among this subset will be calculated with 95% confidence intervals and compared descriptively to target rates.
  • Safety of rapid taper of immune suppression for subset of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no aGVHD defined as < 5% rate of treatment-related mortality (TRM) [ Time Frame: Up to 10 years ]
    The observed rates of TRM among this subset will be calculated with 95% confidence intervals and compared descriptively to target rates.
Current Other Pre-specified Outcome Measures
 (submitted: March 26, 2020)
  • Rates of minimal residual disease (MRD) positivity (> 0.01%) [ Time Frame: Up to 12 weeks ]
    The rates will be compared at the end of Block 2 and 3 between randomized arms for HR and IR relapse patients.
  • Hematologic complete remission rate (for treatment failure patients not previously receiving blinatumomab) [ Time Frame: Up to 12 weeks ]
    The observed rate will be calculated among patients with treatment failure who did not previously receive blinatumomab.
  • MRD negativity (< 0.01%) rate (for treatment failure patients not previously receiving blinatumomab) [ Time Frame: Up to 12 weeks ]
    The observed rate will be calculated among patients with treatment failure who did not previously receive blinatumomab.
  • Proportion of patients that proceed to hematopoietic stem cell transplant (HSCT) after treatment with blinatumomab (for treatment failure patients not previously receiving blinatumomab) [ Time Frame: Up to 12 weeks ]
    The observed rate will be calculated among patients with treatment failure who did not previously receive blinatumomab.
  • Feasibility of rapid taper of immune suppression for subset of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no acute graft versus host disease (aGVHD) [ Time Frame: Up to 10 years ]
    The observed rate of grade III-IV aGVHD among this subset will be calculated with 95% confidence intervals and compared descriptively to target rate.
  • Safety of rapid taper of immune suppression for subset of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no aGVHD defined as < 5% rate of treatment-related mortality (TRM) [ Time Frame: Up to 10 years ]
    The observed rate of TRM among this subset will be calculated with 95% confidence intervals and compared descriptively to target rate.
  • Blinatumomab pharmacokinetics (PK) [ Time Frame: Days 2 and 14 of cycle 1 ]
    Blinatumomab PK will be evaluated by summarizing blinatumomab steady state concentrations and systemic clearance obtained from non-compartmental analysis. In addition, a population PK approach using a non-linear mixed effect model will also be used to assess blinatumomab PK. Exposure-response analyses will be performed to explore associations among blinatumomab exposure, relevant clinical covariates and clinical measures of safety and efficacy.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Blinatumomab in Treating Younger Patients With Relapsed B-cell Acute Lymphoblastic Leukemia
Official Title  ICMJE Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)
Brief Summary This randomized phase III trial studies how well blinatumomab works compared with standard combination chemotherapy in treating patients with B-cell acute lymphoblastic leukemia that has returned after a period of improvement (relapsed). Immunotherapy with blinatumomab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether standard combination chemotherapy is more effective than blinatumomab in treating relapsed B-cell acute lymphoblastic leukemia.
Detailed Description

PRIMARY OBJECTIVES:

I. To compare disease free survival (DFS) of high-risk (HR) and intermediate-risk (IR) relapse B-cell acute lymphoblastic leukemia (B-ALL) patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR randomization). (Closed to enrollment effective September 18, 2019) II. To compare the DFS of low risk (LR) relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization). (Closed to enrollment effective September 30, 2019)

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) of HR and IR relapse B-ALL patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR randomization).

II. To compare OS of LR relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization).

EXPLORATORY OBJECTIVES:

I. To compare the rates of minimal residual disease (MRD) >= 0.01% at the end of block 2 and block 3 for HR and IR relapse B-ALL patients in HR/IR randomization.

II. To estimate, for treatment failure (TF) patients not previously receiving blinatumomab, the hematologic complete remission rate (CR), rate of MRD < 0.01%, and proportion able to proceed to hematopoietic stem cell transplant (HSCT) in CR after treatment with blinatumomab.

III. To assess the feasibility and safety of rapid taper of immune suppression for the subset of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no acute graft versus host disease (aGVHD).

IV. To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-response relationships for measures of safety and effectiveness.

OUTLINE:

All patients receive Block 1 over 4 weeks.

BLOCK 1: Patients receive dexamethasone orally (PO) twice daily (BID) or intravenously (IV) on days 1-5 and 15-19; vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22; pegaspargase IV over 1-2 hours on days 3 and 17; mitoxantrone hydrochloride IV over 15-30 minutes on days 1-2, and methotrexate intrathecally (IT) on day 1. Patients with central nervous system (CNS) 1 or CNS2 also receive methotrexate IT on day 8. Patients with CNS3 or isolated CNS relapse also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8, 15, and 22. High risk and intermediate risk patients are then assigned to randomization R1. Low risk patients are assigned to randomization R2.

RANDOMIZATION R1 (HR and IR patients): Patients are randomized to 1 of 2 treatment arms. Effective 09/18/2019, HR/IR patients not yet randomized are not eligible for post-Induction therapy on AALL1331 and will be removed from protocol therapy. Patients receiving therapy on Arm A prior to Amendment #10A who have not yet received day 22 treatment on Block 3 will be offered the opportunity to cross over to Arm B to receive blinatumomab.

ARM A: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT if eligible. Patients with persistent testicular involvement after Block 1 receive testicular radiation during the Block 2.

ARM B: Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT if eligible. Patients with persistent testicular involvement after Block 1 receive testicular radiation during the first block of blinatumomab.

RANDOMIZATION R2 (LR patients): Patients are then randomized to 1 of 2 treatment arms.

ARM C: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance. CNS3 patients receive chemoradiation post-Maintenance Cycle 1. Patients with persistent testicular involvement after Block 1 receive testicular radiation during Block 2.

ARM D: Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance. CNS3 patients receive chemoradiation post Maintenance Cycle 1. Patients with persistent testicular involvement after Block 1 receive testicular radiation during Block 2.

BLOCK 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; methotrexate IV over 36 hours on day 8; leucovorin calcium IV or PO on days 10-11; pegaspargase IV over 1-2 hours on day 9 or 10; cyclophosphamide IV over 15-30 minutes on days 15-19; and etoposide IV over 1-2 hours on days 15-19. Patients with CNS1 or CNS2 also receive methotrexate IT on day 8. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 22.

BLOCK 3: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; cytarabine IV over 3 hours every 12 hours on days 1, 2, 8, and 9; asparaginase intramuscularly (IM) or IV over 1 hour on days 2, 4, 9, 11, and 23; methotrexate IT on day 1and IV over 36 hours on day 22; leucovorin calcium PO or IV on days 24-25. Patients with CNS1 or CNS2 also receive methotrexate IT on day 22. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 22.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28. Patients with CNS1 or CNS2 also receive methotrexate IT on days 15 and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 15 and 29.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV continuously on days 1-28. Patients with CNS1 or CNS2 also receive methotrexate IT on days 8 and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 29.

BLINATUMOMAB BLOCK 3: Patients receive blinatumomab IV continuously on days 1-28 and dexamethasone PO or IV on day 1.

CONTINUATION 1 & 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; mercaptopurine tablet PO on days 1-42; methotrexate PO on days 8, 15, 29, and 36; or; cyclophosphamide IV over 15-30 minutes on days 43 and 50; etoposide IV over 1-2 hours on days 43 and 50; thioguanine PO once daily on days 43-49; and cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 44-47 and 51-54. Patients with CNS1 or CNS2 also receive methotrexate IT on days 1 and 43, methotrexate PO every 6 hours for 4 doses on day 22, leucovorin calcium PO every 6 hours for 2 doses on day 24. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1 and 43 ; methotrexate IV over 36 hours on day 22; and leucovorin calcium IV or PO every 6 hours on days 24-25.

MAINTENANCE: Patients receive dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; vincristine sulfate IV over 1 minute on days 1, 29, and 57; mercaptopurine tablet PO on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Patients with CNS1 or CNS2 also receive methotrexate IT on day 1. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. Cycles repeat every 12 weeks for up to 2 years since the beginning of treatment in the absence of disease progression or unacceptable toxicity.

MAINTENANCE CHEMORADIATION (LR CNS3 PATIENTS ONLY): Following maintenance cycle 1, patients receive 1800 cGy cranial radiation; dexamethasone PO BID or IV on days 1-7 and 15-21; vincristine sulfate IV over 1 minute on days 1, 8 and 15; and pegaspargase IV over 1-2 hours on day 1. Patients then resume maintenance with cycle 2 and beyond.

After completion of study treatment, patients are followed up annually for 10 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Recurrent B Acute Lymphoblastic Leukemia
Intervention  ICMJE
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    Undergo allogeneic HSCT
    Other Names:
    • Allogeneic
    • Allogeneic Hematopoietic Cell Transplantation
    • Allogeneic Stem Cell Transplantation
    • HSC
    • HSCT
    • Stem Cell Transplantation, Allogeneic
  • Drug: Asparaginase
    Given IM or IV
    Other Names:
    • 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
  • Biological: Blinatumomab
    Given IV
    Other Names:
    • Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody
    • Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103
    • Blincyto
    • MEDI-538
    • MT-103
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-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
  • Drug: Cytarabine
    Given IT and IV or SC
    Other Names:
    • .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
  • Drug: Dexamethasone
    Given PO or IV
    Other Names:
    • 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
    • Dxevo
    • Fluorodelta
    • Fortecortin
    • Gammacorten
    • Hexadecadrol
    • Hexadrol
    • Lokalison-F
    • Loverine
    • Methylfluorprednisolone
    • Millicorten
    • Mymethasone
    • Orgadrone
    • Spersadex
    • TaperDex
    • Visumetazone
    • ZoDex
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16
    • VP 16-213
    • VP-16
    • VP-16-213
    • VP16
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Leucovorin Calcium
    Given IV or PO
    Other Names:
    • 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
  • Drug: Mercaptopurine
    Given PO
    Other Names:
    • 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
  • Drug: Methotrexate
    Given IT, IV, and PO
    Other Names:
    • 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
  • Drug: Mitoxantrone
    Given IV
    Other Names:
    • Dihydroxyanthracenedione
    • Mitozantrone
  • Drug: Mitoxantrone Hydrochloride
    Given IV
    Other Names:
    • CL 232315
    • DHAD
    • DHAQ
    • Dihydroxyanthracenedione Dihydrochloride
    • Mitoxantrone Dihydrochloride
    • Mitoxantroni Hydrochloridum
    • Mitozantrone Hydrochloride
    • Mitroxone
    • Neotalem
    • Novantrone
    • Onkotrone
    • Pralifan
  • Drug: Pegaspargase
    Given IV
    Other Names:
    • 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
  • Other: Pharmacological Study
    Correlative studies
  • Radiation: Radiation Therapy
    Undergo cranial radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • ENERGY_TYPE
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
  • Drug: Therapeutic Hydrocortisone
    Given IT
    Other Names:
    • Aeroseb-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
    • Rectoid
  • Drug: Thioguanine
    Given PO
    Other Names:
    • 2-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 27
  • Drug: Vincristine
    Given IV
    Other Names:
    • Leurocristine
    • VCR
    • Vincrystine
  • Drug: Vincristine Sulfate
    Given IV
    Other Names:
    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate
Study Arms  ICMJE
  • Active Comparator: Arm A (HR and IR control)
    Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Drug: Asparaginase
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
    • Drug: Leucovorin Calcium
    • Drug: Methotrexate
    • Drug: Mitoxantrone
    • Drug: Mitoxantrone Hydrochloride
    • Drug: Pegaspargase
    • Other: Pharmacological Study
    • Drug: Therapeutic Hydrocortisone
    • Drug: Vincristine
    • Drug: Vincristine Sulfate
  • Experimental: Arm B (HR and IR blinatumomab)
    Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Biological: Blinatumomab
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Other: Laboratory Biomarker Analysis
    • Drug: Methotrexate
    • Other: Pharmacological Study
    • Drug: Therapeutic Hydrocortisone
  • Active Comparator: Arm C (LR control)
    Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
    Interventions:
    • Drug: Asparaginase
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Other: Pharmacological Study
    • Radiation: Radiation Therapy
    • Drug: Therapeutic Hydrocortisone
    • Drug: Thioguanine
    • Drug: Vincristine
    • Drug: Vincristine Sulfate
  • Experimental: Arm D (LR blinatumomab)
    Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
    Interventions:
    • Biological: Blinatumomab
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Other: Pharmacological Study
    • Radiation: Radiation Therapy
    • Drug: Therapeutic Hydrocortisone
    • Drug: Thioguanine
    • Drug: Vincristine
    • Drug: Vincristine Sulfate
Publications * Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. doi: 10.1001/jama.2021.0669.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: December 17, 2014)
598
Original Estimated Enrollment  ICMJE
 (submitted: March 28, 2014)
438
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • First relapse of B-ALL, allowable sites of disease include isolated bone marrow, combined bone marrow and CNS and/or testicular, and isolated CNS and/or testicular; extramedullary sites are limited to the CNS and testicles
  • No waiting period for patients who relapse while receiving standard maintenance therapy
  • Patients who relapse on frontline therapy in phases other than maintenance must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
  • Cytotoxic therapy: at least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy, or maintenance chemotherapy, or intrathecal chemotherapy (methotrexate strongly preferred) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status
  • Biologic (anti-neoplastic) agent: at least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
  • Stem cell transplant or rescue: patient has not had a prior stem cell transplant or rescue
  • Patient has not had prior treatment with blinatumomab
  • With the exception of intrathecal chemotherapy (methotrexate strongly preferred; cytarabine is permissible) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status, patient has not received prior relapse-directed therapy (i.e., this protocol is intended as the INITIAL treatment of first relapse)
  • Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • 1 to < 2 years: =< 0.6 mg/dL
    • 2 to < 6 years: =< 0.8 mg/dL
    • 6 to < 10 years: =< 1 mg/dL
    • 10 to < 13 years: =< 1.2 mg/dL
    • 13 to < 16 years: =< 1.5 mg/dL (males) and =< 1.4 mg/dL (females)
    • >= 16 years: =< 1.7 mg/dL (males) and =< 1.4 mg/dL (females)
  • Direct bilirubin < 3.0 mg/dL
  • Shortening fraction of >= 27% by echocardiogram, or
  • Ejection fraction of >= 50% by radionuclide angiogram
  • All patients and/or their parent or legal guardian 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

Exclusion Criteria:

  • Patients with Philadelphia chromosome positive/breakpoint cluster region protein (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1)+ ALL are not eligible
  • Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia are not eligible
  • Patients with T-lymphoblastic leukemia (T-ALL)/lymphoblastic lymphoma (T-LL) are not eligible
  • Patients with B-lymphoblastic lymphoma (B-LL) are not eligible
  • Patients with known optic nerve and/or retinal involvement are not eligible; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement
  • Patients known to have one of the following concomitant genetic syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome
  • Patients with known human immunodeficiency virus (HIV) infection
  • Patients with known allergy to mitoxantrone, cytarabine, or both etoposide and etoposide phosphate (Etopophos)
  • Lactating females who plan to breastfeed
  • 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
  • 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 pre-existing significant central nervous system pathology that would preclude treatment with blinatumomab, including: history of severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination/movement disorder, or autoimmune disease with CNS involvement are not eligible; patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible; (patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved)
  • Patients with uncontrolled seizure disorder are not eligible; (patients with seizure disorders that do not require antiepileptic drugs, or are well controlled with stable doses of antiepileptic drugs remain eligible)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 30 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02101853
Other Study ID Numbers  ICMJE NCI-2014-00631
NCI-2014-00631 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
s15-00970
COG-AALL1331
AALL1331 ( Other Identifier: Children's Oncology Group )
AALL1331 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
U10CA098543 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Patrick A Brown Children's Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP