Clinical trial NCT02393859: Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)
Official title: Phase 3 Trial to Investigate the Efficacy, Safety, and Tolerability of Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects With HR First Relapse B-precursor ALL
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia, Acute Lymphoblastic
Keywords: ALL
High-risk first relapse B-precursor ALL
Precursor Cell Lymphoblastic Leukemia
Neoplasms
Lymphoproliferative Disorders
Immunoproliferative Disorders
Antibodies, Bispecific
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2015-03-20
Enrollment: 111
Sex: ALL
Minimum age (years): 0
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: B-precursor ALL is an aggressive malignant disease. Therapy is usually stratified according to risk characteristics to ensure that appropriate treatment is administered to patients with high-risk of relapse. In general, pediatric treatment regimens are more intense than those employed in adults and include courses of combination chemotherapy. Standard of care chemotherapy is associated with considerable toxicity. There is a lack of novel treatment options for subjects who relapse or are refractory to treatment. Therefore, innovative therapeutic approaches are urgently needed. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. This study will evaluate the event-free survival (EFS) after treatment with blinatumomab when compared to standard of care (SOC) chemotherapy. The effect of blinatumomab on overall survival and reduction of minimal residual disease compared to SOC chemotherapy will also be investigated.

Detailed description: Patients will be randomized in a 1:1 ratio to receive either one cycle of blinatumomab or one block of standard high-risk consolidation chemotherapy. Blinatumomab is administered as a continuous intravenous infusion (CIVI). One cycle of blinatumomab treatment includes 4 weeks of CIVI of blinatumomab. After completing consolidation therapy, the patients should undergo alloHSCT depending on their bone marrow status. The patients will be followed up until the last subject on study is 36 months following alloHSCT or has died, whichever is first.

Eligibility criteria: Inclusion Criteria:

* Subjects with Philadelphia chromosome negative (Ph-) high-risk (HR) first relapse B-precursor acute lymphoblastic leukemia (ALL; as defined by International Berlin-Frankfurt-Muenster study group/International study for treatment of childhood relapsed ALL \[I-BFM SG/IntReALL\] criteria)
* Subjects with bone marrow blast percentage \< 5% (M1) or bone marrow blast percentage \< 25% and ≥5% (M2) marrow at the time of randomization,
* Age \> 28 days and \< 18 years at the time of informed consent/assent
* Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated
* Availability of the following material from relapse diagnosis for central analysis of minimal residual disease (MRD) by polymerase chain reaction (PCR): clone-specific primers and reference deoxyribonucleic acid (DNA), as well as primer sequences and analyzed sequences of clonal rearrangements (cases with isolated extramedullary relapse or cases with technical and/or logistic hurdles to obtain and process bone marrow material are exempt from providing this material. In these cases, central MRD analysis only by Flow is permitted).

Exclusion Criteria:

* Clinically relevant central nervous system (CNS) pathology requiring treatment (eg, unstable epilepsy). Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully treated prior to enrollment
* Peripheral neutrophils \< 500/μL prior to start of treatment
* Peripheral platelets \< 50,000/μL prior to start of treatment
* Currently receiving treatment in another investigational device or drug study or less than 4 weeks since ending treatment on another investigational device or drug study(s), procedures required by IntReALL high-risk (HR) guidelines are allowed
* Chemotherapy related toxicities that have not resolved to ≤ grade 2 (except for parameters defined in Exclusion Criteria 202, 203, 204, and 217)
* Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
* Abnormal renal or hepatic function prior to start of treatment (day 1) as defined below
* Abnormal serum creatinine based on age/gender
* Total bilirubin \> 3.0 mg/dL prior to start of treatment (unless related to Gilbert's or Meulengracht disease)
* Documented infection with human immunodeficiency virus (HIV)
* Known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing (excluding asparaginase)
* Post-menarchal female subject who is pregnant or breastfeeding, or is planning to become pregnant or breastfeed while receiving protocol-specified therapy and for at least 12 months after the last dose of chemotherapy
* Post-menarchal female subject who is not willing to practice true sexual abstinence or use a highly effective form of contraception while receiving protocol-specified therapy and for at least 12 months after the last dose of chemotherapy
* Sexually mature male subject who is not willing to practice true sexual abstinence or use a condom with spermicide while receiving protocol-specified therapy and for at least 6 months after last dose of chemotherapy. In countries where spermicide is not available, a condom without spermicide is acceptable
* Sexually mature male subject who is not willing to abstain from sperm donation while receiving protocol-specified therapy and for at least 6 months after last dose of chemotherapy
* Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject's and investigator's knowledge
* History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion
* Placed into an institution due to juridical or regulatory ruling.

Primary outcomes:
measure: Kaplan Meier Estimate: Event-Free Survival (EFS; Primary Analysis)
timeFrame: As of the primary analysis data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months.
measure: Kaplan Meier Estimate: EFS (Final Analysis)
timeFrame: At final analysis, overall median follow-up time for EFS was 51.9 months.
Secondary outcomes:
measure: Kaplan Meier Estimate: Overall Survival (OS)
timeFrame: At final analysis, overall median follow-up time for OS was 55.2 months.
measure: Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation
timeFrame: Up to End of Treatment (Cycle 1, Day 29)
measure: Cumulative Incidence of Relapse (CIR)
timeFrame: At final analysis, the overall maximum follow-up time was 82.0 months.
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs)
timeFrame: From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
measure: Number of Participants With TEAEs of Interest
timeFrame: From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
measure: Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values
timeFrame: Up to Day 29 (± 2 days).
measure: Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)
timeFrame: From the date of alloHSCT until death/censor date; median follow up time was 1742.0 days for blinatumomab and 1619.0 days for HC3.
measure: Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only)
timeFrame: Day 1 to Day 29.
measure: Pharmacokinetics: Concentration at Steady State (Css) (Blinatumomab Arm Only)
timeFrame: Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15
measure: Pharmacokinetics: Clearance (CL) (Blinatumomab Arm Only)
timeFrame: Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15
Other outcomes:
Locations:
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Research Site
state: Buenos Aires
city: Randwick
country: Australia
facility: Research Site
state: New South Wales
city: Westmead
country: Australia
facility: Research Site
state: New South Wales
city: South Brisbane
country: Australia
facility: Research Site
state: Queensland
city: Parkville
country: Australia
facility: Research Site
state: Victoria
city: Graz
country: Austria
facility: Research Site
city: Innsbruck
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Brussels
country: Belgium
facility: Research Site
city: Brussels
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liege
country: Belgium
facility: Research Site
city: Curitba
country: Brazil
facility: Research Site
state: Paraná
city: Porto Alegre
country: Brazil
facility: Research Site
state: Rio Grande Do Sul
city: Sao Paulo
country: Brazil
facility: Research Site
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Research Site
state: São Paulo
city: Praha 5
country: Czechia
facility: Research Site
city: Kobenhavn O
country: Denmark
facility: Research Site
city: Bordeaux Cedex
country: France
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Lyon
country: France
facility: Research Site
city: Marseille cedex 5
country: France
facility: Research Site
city: Montpellier cedex 05
country: France
facility: Research Site
city: Nantes cedex 1
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Strasbourg Cedex
country: France
facility: Research Site
city: Vandoeuvre les Nancy
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Duesseldorf
country: Germany
facility: Research Site
city: Erlangen
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Frankfurt am Main
country: Germany
facility: Research Site
city: Freiburg
country: Germany
facility: Research Site
city: Giessen
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Jena
country: Germany
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Münster
country: Germany
facility: Research Site
city: Tübingen
country: Germany
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: Würzburg
country: Germany
facility: Research Site
city: Goudi
country: Greece
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Petah Tikva
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Tel Hashomer
country: Israel
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Monza (MB)
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Mexico
country: Mexico
facility: Research Site
state: Distrito Federal
city: Guadalajara
country: Mexico
facility: Research Site
state: Jalisco
city: Monterrey
country: Mexico
facility: Research Site
state: Nuevo León
city: Rotterdam
country: Netherlands
facility: Research Site
city: Utrecht
country: Netherlands
facility: Research Site
city: Oslo
country: Norway
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Zabrze
country: Poland
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Porto
country: Portugal
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Cluj-Napoca
country: Romania
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Malaga
country: Spain
facility: Research Site
state: Andalucía
city: Sevilla
country: Spain
facility: Research Site
state: Andalucía
city: Santander
country: Spain
facility: Research Site
state: Cantabria
city: Barcelona
country: Spain
facility: Research Site
state: Cataluña
city: Barcelona
country: Spain
facility: Research Site
state: Cataluña
city: Valencia
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: Santiago de Compostela
country: Spain
facility: Research Site
state: Galicia
city: Boadilla del Monte
country: Spain
facility: Research Site
state: Madrid
city: El Palmar
country: Spain
facility: Research Site
state: Murcia
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Basel
country: Switzerland
facility: Research Site
city: Zuerich
country: Switzerland
facility: Research Site
city: Adana
country: Turkey
facility: Research Site
city: Antalya
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Kayseri
country: Turkey
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Bristol
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Locatelli F, Eckert C, Hrusak O, Buldini B, Sartor M, Zugmaier G, Zeng Y, Pilankar D, Morris J, von Stackelberg A. Blinatumomab overcomes poor prognostic impact of measurable residual disease in pediatric high-risk first relapse B-cell precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2022 Aug;69(8):e29715. doi: 10.1002/pbc.29715. Epub 2022 Apr 28.
citation: Blinatumomabe em pacientes pediátricos com leucemia linfoblástica aguda B em primeira recidiva de alto risco: um estudo de custo-efetividade. van Beurden-Tan CHY, Ribeiro RA, Seber A, de Martino Lee ML, Marçola M, Schuetz R, Loggetto SR, Maiolino A. Jornal Brasileiro de Economia da Saúde 14(1): 41-50. 10.21115/JBES.v14.n1.p41-50
citation: Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Moricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):843-854. doi: 10.1001/jama.2021.0987.
citation: Caillon M, Brethon B, van Beurden-Tan C, Supiot R, Le Mezo A, Chauny JV, Majer I, Petit A. Cost-Effectiveness of Blinatumomab in Pediatric Patients with High-Risk First-Relapse B-Cell Precursor Acute Lymphoblastic Leukemia in France. Pharmacoecon Open. 2023 Jul;7(4):639-653. doi: 10.1007/s41669-023-00411-4. Epub 2023 Apr 18.