Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)
Condition: Leukemia, Acute Lymphoblastic
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
Intervention: Blinatumomab; Dexamethasone; Vincrisitne; Daunorubicin; Methotrexate; Ifosfamide; PEG-asparaginase; Erwinia-asparaginase
Intervention description: 15 μg/m^2/day as a continuous intravenous infusion (CIVI) for 4 weeks; 10 mg/m^2/day intravenous (IV) on Days 1-6; 1.5 mg/m^2/day IV on Days 1 and 6; 30 mg/m^2 IV over 24 hours on Day 5; 1 g/m^2 IV over 36 hours on Day 1; 800 mg/m^2 IV for 1 hour on Days 2-4; 1000 U/m^2 IV for 2 hours or intramuscularly (IM) on Day 6; 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
Intervention MeSH terms: Dexamethasone; Methotrexate; Daunorubicin; Asparaginase; Ifosfamide; Blinatumomab; Pegaspargase
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 111.0
Sex: All
Minimum age: 0 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: ALL; High-risk first relapse B-precursor ALL; Precursor Cell Lymphoblastic Leukemia; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Antibodies, Bispecific

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.
    

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.