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Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HR First Relapse B-precursor 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. Identifier: NCT02393859
Recruitment Status : Active, not recruiting
First Posted : March 20, 2015
Last Update Posted : November 1, 2019
Information provided by (Responsible Party):

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.

Condition or disease Intervention/treatment Phase
Leukemia, Acute Lymphoblastic Drug: Blinatumomab Drug: Conventional Consolidation Chemotherapy Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 111 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 10, 2015
Actual Primary Completion Date : July 17, 2019
Estimated Study Completion Date : September 23, 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Blinatumomab
Subjects will be randomized to receive either blinatumomab or standard consolidation chemotherapy.
Drug: Blinatumomab
The patient will receive one cycle of blinatumomab, which includes 4 weeks of CIVI of blinatumomab.

Active Comparator: Conventional Consolidation Chemotherapy
Subjects will be randomized to receive either blinatumomab or standard consolidation chemotherapy.
Drug: Conventional Consolidation Chemotherapy
The patient will receive one block of standard consolidation chemotherapy.

Primary Outcome Measures :
  1. Event-free survival [ Time Frame: Minimum 36 months ]
    Event-free survival (EFS) after blinatumomab when compared to standard of care (SOC) chemotherapy

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Minimum 36 months ]
    Overall survival (OS) of patients treated with blinatumomab when compared to SOC chemotherapy

  2. MRD response [ Time Frame: 4 weeks ]
    MRD response, defined as MRD level < 10-4 at the end of treatment with investigational product(s)

  3. 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

  4. Survival [ Time Frame: 100 days following alloHSCT ]
    Survival status at 100 days following alloHSCT

  5. Anti-blinatumomab antibody [ Time Frame: 4 weeks ]
    Incidence of anti-blinatumomab antibody formation (blinatumomab arm only)

  6. Relapse Incidence [ Time Frame: Minimum 36 months ]
    Cumulative incidence of relapse

  7. Css [ Time Frame: 2 weeks ]
    Pharmacokinetic (PK) sampling for blinatumomab concentrations for population PK analysis

  8. Steady-state concentrations [ Time Frame: 2 weeks ]
    Blinatumomab steady-state concentrations

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Subjects with Philadelphia chromosome negative (Ph-) high-risk (HR) first relapse B-precursor ALL (as defined by I-BFM SG/IntReALL criteria)
  • Subjects with M1 or 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 MRD by PCR: clone-specific primers and reference 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 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02393859

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Sponsors and Collaborators
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Study Director: MD Amgen

Additional Information:
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Responsible Party: Amgen Identifier: NCT02393859    
Other Study ID Numbers: 20120215
2014-002476-92 ( EudraCT Number )
First Posted: March 20, 2015    Key Record Dates
Last Update Posted: November 1, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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.
Keywords provided by Amgen:
High-risk first relapse B-precursor ALL
Precursor Cell Lymphoblastic Leukemia
Lymphoproliferative Disorders
Immunoproliferative Disorders
Antibodies, Bispecific
Additional relevant MeSH terms:
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Disease Attributes
Pathologic Processes
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies, Bispecific
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs