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Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)

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: NCT02393859
Recruitment Status : Active, not recruiting
First Posted : March 20, 2015
Results First Posted : July 13, 2020
Last Update Posted : August 5, 2020
Sponsor:
Information provided by (Responsible Party):
Amgen

Tracking Information
First Submitted Date  ICMJE March 16, 2015
First Posted Date  ICMJE March 20, 2015
Results First Submitted Date  ICMJE June 24, 2020
Results First Posted Date  ICMJE July 13, 2020
Last Update Posted Date August 5, 2020
Actual Study Start Date  ICMJE November 10, 2015
Actual Primary Completion Date July 17, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 24, 2020)
Kaplan Meier Estimate: Event-Free Survival (EFS) [ Time Frame: As of the data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months. ]
EFS is calculated from the time of randomization until the date of relapse or M2 marrow (representative bone marrow aspirate or biopsy with ≥ 5% and < 25% blasts) after having achieved a complete remission (CR), failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with investigational product (IP) or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following:
  • M1 marrow
  • Peripheral blood without blasts
  • Absence of extramedullary leukemic involvement
Months are calculated as days from randomization date to event/censor date, divided by 30.5.
Original Primary Outcome Measures  ICMJE
 (submitted: March 19, 2015)
Event-free survival [ Time Frame: 36 months ]
Event-free survival (EFS) after blinatumomab when compared to standard of care (SOC) chemotherapy
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 23, 2020)
  • Kaplan Meier Estimate: Overall Survival (OS) [ Time Frame: As of the data cutoff date (17 July 2019), overall median follow-up time for OS was 19.5 months. ]
    Overall survival (OS) was calculated from time of randomization until death due to any cause. Participants still alive were censored at the date they were last known to be alive. Months were calculated as days from randomization date to event/censor date, divided by 30.5.
  • Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation [ Time Frame: Up to End of Treatment (Cycle 1, Day 29). Data cutoff date was 17 July 2019. ]
    At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. MRD response was defined as MRD level < 10^-4, by polymerase chain reaction (PCR) or flow cytometry, at the end of treatment with study drug. Participants who were part of the MRD Evaluable Set and were missing the end of treatment (Cycle 1 Day 29) assessment for a respective MRD assessment method were considered not to have achieved a response.
  • Cumulative Incidence of Relapse (CIR) [ Time Frame: As of data cutoff date (17 July 2019), the overall maximum follow-up time was 44.1 months. ]
    CIR estimate, presented as median months to relapse, calculated from date of achievement of first CR, using the cumulative incidence method (Fine JP, Gray RJ:1999). Deaths prior to relapse not considered related to an otherwise undocumented relapse were treated as a competing risk. Participants still alive without a date of relapse were censored at the time of last follow-up. Relapse=presence of ≥1 of the following:
    • isolated bone marrow relapse (M3 marrow [representative bone marrow aspirate or biopsy with ≥25% blasts] in the absence of extramedullary involvement)
    • combined bone marrow relapse (M2 [representative bone marrow aspirate or biopsy with ≥5% and <25% blasts] or M3 marrow and ≥1 extramedullary manifestation of acute lymphoblastic leukemia)
    • central nervous system extramedullary relapse
    • testicular extramedullary relapse
    • extramedullary relapse at other sites
    Months were calculated as days from randomization to event/censor date, divided by 30.5.
  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) [ Time Frame: From first dose of IP through the last dose of IP (up to Day 29) plus 30 days. Data cutoff date was 17 July 2019. ]
    Adverse event (AE): any untoward medical occurrence. Serious AE: an AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Severity was graded according to the Common Terminology Criteria for AEs (CTCAE) version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Investigational product (IP) in the HC3 arm refers to dexamethasone, methotrexate, daunorubicin, erwinase, ifosfamide, asparaginase, and vincristine, and in the blinatumomab arm refers to blinatumomab. Treatment-related refers to the assessment of a relationship between IP and the event.
  • Number of Participants With TEAEs of Interest [ Time Frame: From first dose of IP through the last dose of IP (up to Day 29) plus 30 days. Data cutoff date was 17 July 2019. ]
    TEAEs of interest included capillary leak system (CLS), cytokine release syndrome (CRS), decreased immunoglobulins (DI), elevated liver enzymes (ELE), embolic and thrombotic events (ETE), infections (INF), infusion reactions without considering duration (IRWCD), medication errors (ME), neurologic events (NE), neutropenia and febrile neutropenia (NFN), pancreatitis (PNC), tumor lysis syndrome (TLS), leukoencephalopathy (LE), immunogenicity (IM). Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death.
  • Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values [ Time Frame: Up to Day 29 (± 2 days). Data cutoff date was 17 July 2019. ]
    Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Increases (↑) or decreases (↓) in laboratory value grades (Gr) from baseline (BL) to worst postbaseline (→ PB) grade are presented. NA=not available.
  • Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) [ Time Frame: From the date of alloHSCT until the data cut-off date of 17 July 2019; median follow up time was 652.0 days for blinatumomab and 541.0 days for HC3. ]
    The analysis of 100-day mortality after alloHSCT was assessed for participants who received an alloHSCT while in remission and did not receive any additional anti-leukemic treatment. 100-day mortality after alloHSCT was calculated relative to the date of alloHSCT. The 100-day mortality rate after alloHSCT was defined as the percentage of participants having died up to 100 days after alloHSCT, estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants still alive were censored at the date they were last known to be alive.
  • Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only) [ Time Frame: Day 1 to Day 29. Data cutoff date was 17 July 2019. ]
    Participants receiving blinatumomab had blood samples analyzed for binding antibodies. Samples testing positive for binding antibodies were also tested for neutralizing antibodies. Participants who were binding antibody-positive or neutralizing antibody-positive post-baseline with a negative or no result at baseline are presented.
  • Pharmacokinetics: Concentration at Steady State (Css) [ Time Frame: Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15 ]
  • Pharmacokinetics: Clearance (CL) [ Time Frame: Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 19, 2015)
  • Overall survival [ Time Frame: 36 months ]
    Overall survival (OS) of patients treated with blinatumomab when compared to SOC chemotherapy
  • MRD response [ Time Frame: 4 weeks ]
    MRD response, defined as MRD level < 10-4 at the end of treatment with investigational product(s)
  • Adverse events [ Time Frame: 30 days after the last dose of study treatment or 90 days after alloHSCT (whichever is longer) ]
    Incidence of adverse events (both serious and non-serious), treatment-related adverse events, adverse events of interest, clinically significant changes in laboratory values
  • Survival [ Time Frame: 100 days following alloHSCT ]
    Survival status at 100 days following alloHSCT
  • Anti-blinatumomab antibody [ Time Frame: 4 weeks ]
    Incidence of anti-blinatumomab antibody formation (blinatumomab arm only)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.
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 Leukemia, Acute Lymphoblastic
Intervention  ICMJE
  • Drug: Blinatumomab
    15 μg/m^2/day as a continuous intravenous infusion (CIVI) for 4 weeks
    Other Name: Blincyto, AMG103
  • Drug: Dexamethasone
    10 mg/m^2/day intravenous (IV) on Days 1-6
  • Drug: Vincrisitne
    1.5 mg/m^2/day IV on Days 1 and 6
  • Drug: Daunorubicin
    30 mg/m^2 IV over 24 hours on Day 5
  • Drug: Methotrexate
    1 g/m^2 IV over 36 hours on Day 1
  • Drug: Ifosfamide
    800 mg/m^2 IV for 1 hour on Days 2-4
  • Drug: PEG-asparaginase
    1000 U/m^2 IV for 2 hours or intramuscularly (IM) on Day 6
  • Drug: Erwinia-asparaginase
    In case of allergic reaction to PEG-asparaginase, participants could change to erwinia-asparaginase, 20,000 units/m2 every 48 hours for a total of 6 doses
Study Arms  ICMJE
  • Active Comparator: High Risk Consolidation 3 (HC3) Chemotherapy
    One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).
    Interventions:
    • Drug: Dexamethasone
    • Drug: Vincrisitne
    • Drug: Daunorubicin
    • Drug: Methotrexate
    • Drug: Ifosfamide
    • Drug: PEG-asparaginase
    • Drug: Erwinia-asparaginase
  • Experimental: Blinatumomab
    15 μg/m^2/day as a continuous intravenous infusion (CIVI) for 4 weeks
    Intervention: Drug: Blinatumomab
Publications * Not Provided

*   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
 (submitted: July 23, 2020)
108
Original Estimated Enrollment  ICMJE
 (submitted: March 19, 2015)
320
Estimated Study Completion Date  ICMJE November 14, 2022
Actual Primary Completion Date July 17, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • Abnormal renal or hepatic function prior to start of treatment (day 1) as defined below: a. Serum creatinine levels above upper limit of normal, based on the normal ranges for age and gender of the local laboratories. b. Total bilirubin > 3.0 mg/dL prior to start of treatment (unless related to Gilbert's or Meulengracht disease)
  • 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, and 204)
  • 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
  • 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 6 months after the last dose of blinatumomab or for 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 6 months after the last dose of blinatumomab or for 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 thereafter. 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 thereafter
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Czechia,   Denmark,   France,   Germany,   Greece,   Israel,   Italy,   Mexico,   Netherlands,   Norway,   Poland,   Portugal,   Romania,   Russian Federation,   Spain,   Sweden,   Switzerland,   Turkey,   United Kingdom
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02393859
Other Study ID Numbers  ICMJE 20120215
2014-002476-92 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
URL: https://www.amgen.com/datasharing
Responsible Party Amgen
Study Sponsor  ICMJE Amgen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: MD Amgen
PRS Account Amgen
Verification Date July 2020

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