Author: Julia Dobke, erstellt am: 2016/03/21, Last modification: 2017/01/18

HR-Blinatumomab A Randomized, Open-label, Controlled Phase 3 Adaptive Trial to Investigate the Efficacy, Safety, and Tolerability of the BiTE Antibody Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects With High-risk First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)
Disease Philadelphia-Chromosom negatives erstes HR-ALL-Rezidiv (B-Vorläufer ALL)
Type Internationale, offene, randomisierte, kontrollierte Phase-3 Studie
Problem / Objectives

Primary objective

  • Event-free survival [ Time Frame: 36 months ]
  • Event-free survival (EFS) after blinatumomab when compared to standard of care (SOC) chemotherapy

Secondary objectives

  • 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)
  • Relapse Incidence [ Time Frame: 36 months ]
  • Cumulative incidence of relapse
  • Css [ Time Frame: 2 weeks ]
  • Population pharmacokinetic (PK) analysis (blinatumomab arm only)
Therapy / Study arms

Patients enrolled in the initial phase of the study 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 for up to 36 months after alloHSCT.

Nach einer Zwischenanalyse wird entschieden, ob das Studiendesign so weítergeführt wird bis zum Ende der Rekrutierung, oder ob eine Anpassung vorgenommen wird, indem die gesamte HR-Konsolidierung (HC1, HC2 und HC3) gegen 3 Zyklen Blinatumomab randomisert wird.

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.
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
  • Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects Wit... Seite 2 von 4
  • 10.10.2016
  • 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. Direct bilirubin > 1.5 mg/dL (for subjects with total bilirubin < 1.50
  • mg/dL, measurement of direct bilirubin is not required) 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
  • 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
  • Known infection with human immunodeficiency virus (HIV)
  • Known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing
  • Post-menarchal female subject who is pregnant or breastfeeding, or is planning to become pregnant or breastfeed while receiving protocolspecified
  • 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 protocolspecified
  • 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
Recruitment mindestens 202, maximal 320
Status seit 31.08.2015
EudraCT 2014-002476-92
Entry Study Register
Principal Investigator amgen

For Amgen:
Gerhard Zugmaier
Executive Medical Director
Amgen Research (Munich) GmbH
Phone: +49 89 895277 335

Studienleitung IntReALL HR

PD Dr. med. Arend von Stackelberg Charité, Campus Virchow-Klinikum Klinik f. Pädiatrie m. S. Onkologie und Hämatologie Augustenburger Platz 1 13353 Berlin Telefon +49 (30) 450 566833 Fax +49 (30) 450 566901

Participants Universitätskinderklinik Berlin, Universitätskinderklinik Düsseldorf, Universitätskinderklinik Essen, Universitätskinderklinik Frankfurt, Universitätskinderklinik Hamburg, Universitätskinderklinik Jena, Universitätskinderklinik Kiel, Universitätskinderklinik München, Universitätskinderklinik Münster, Universitätskinderklinik Tübingen, Universitätskinderklinik Ulm, Universitätskinderklinik Würzburg, Universitätskinderklinik Graz, St. Anna Kinderspital Wien, Universitätskinderklinik Basel, Universitätskinderklinik Zürich
Sponsoring Amgen