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

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ClinicalTrials.gov Identifier: NCT02101853

Recruitment Status : Active, not recruiting

First Posted : April 2, 2014

Results First Posted : December 6, 2022

Last Update Posted : March 22, 2024

View this study on the modernized ClinicalTrials.gov

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

Results First Submitted Date ^ICMJE

September 1, 2022

Results First Posted Date ^ICMJE

December 6, 2022

Last Update Posted Date

March 22, 2024

Actual Study Start Date ^ICMJE

December 17, 2014

Actual Primary Completion Date

June 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Disease Free Survival (DFS) of High-risk (HR) and Intermediate-risk (IR) Relapse Patients [ Time Frame: Up to 2 years from date of randomization ]
DFS rates 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). DFS is calculated as the time from randomization to date of first event (treatment failure, relapse, second malignancy, remission death) or date of last contact. Two-year DFS estimates will be calculated from date of randomization for both Arm A and Arm B. Two-sided 95% confidence intervals will be calculated.
Disease Free Survival (DFS) of Low Risk (LR) Relapse Patients [ Time Frame: Up to 3 years from date of randomization ]
DFS rates of LR relapse B-ALL patients who are randomized following Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR Randomization). DFS is calculated as the time from randomization to date of first event (relapse, second malignancy, remission death) or date of last contact. Three-year DFS estimates will be calculated from date of randomization for both Arm C and Arm D. Two-sided 95% confidence intervals will be calculated.

Original Primary Outcome Measures ^ICMJE

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

Overall Survival (OS) of HR and IR Relapse Patients [ Time Frame: Up to 2 years from date of randomization ]
OS rates 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). OS is calculated as the time from randomization to date of death or date of last contact. Two-year OS estimates will be calculated from date of randomization for both Arm A and Arm B. Two-sided 95% confidence intervals will be calculated.
Overall Survival (OS) of LR Relapse Patients [ Time Frame: Up to 3 years from date of randomization ]
OS rates of LR relapse B-ALL patients who are randomized following Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR Randomization). OS is calculated as the time from randomization to date of death or date of last contact. Three-year OS estimates will be calculated from date of randomization for both Arm C and Arm D. Two-sided 95% confidence intervals will be calculated.

Original Secondary Outcome Measures ^ICMJE

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

Rates of Minimal Residual Disease (MRD) Positivity (> 0.01%) [ Time Frame: Up to 12 weeks ]
The rates at the end of Block 2 and Block 3 will be calculated for the 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 allow the body's immune system to attack and destroy some types of leukemia cells. It is not yet known whether blinatumomab is more effective than standard combination chemotherapy 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) as a part of a treatment regimen prior to allogeneic bone marrow transplantation. (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). (Closed to enrollment effective September 18, 2019) 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 (including 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): LR patients are 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 receive Triple Intrathecal Therapy (ITT) on day 1. Cycles repeat every 12 weeks for up to 2 years from 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:
- AMG 103
- Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody
- Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103
- Blincyto
- MEDI-538
- MEDI538
- MT-103
- MT103
Drug: Cyclophosphamide
Given IV
Other Names:
- (-)-Cyclophosphamide
- 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
- Asta B 518
- B-518
- 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
- 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
- Hemady
- 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 16213
- VP-16
- VP-16-213
- VP16
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
- 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:
- LCR
- 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
- 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
- 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
- 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
- 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

Actual Enrollment ^ICMJE

669

Original Estimated Enrollment ^ICMJE

438

Estimated Study Completion Date ^ICMJE

September 22, 2024

Actual Primary Completion Date

June 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Inclusion Criteria:

Patients >= 1 year and < 31 years of age at the time of relapse will be eligible
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 31 Years (Child, Adult)

Accepts Healthy Volunteers ^ICMJE

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

U.S. FDA-regulated Product

Not Provided

IPD Sharing Statement ^ICMJE

Not Provided

Current Responsible Party

National Cancer Institute (NCI)

Original Responsible Party

Same as current

Current Study Sponsor ^ICMJE

National Cancer Institute (NCI)

Original Study Sponsor ^ICMJE

Same as current

Collaborators ^ICMJE

Not Provided

Investigators ^ICMJE

Principal Investigator:

Patrick A Brown

Children's Oncology Group

PRS Account

National Cancer Institute (NCI)

Verification Date

March 2024

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

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