Blinatumomab-Studie

Primary objectives

Phase I study

• to determine the recommended dose of blinatumomab

Phase II study

• to assess the efficacy of blinatumomab

Secondary objectives

Phase I study

• to assess the safety, tolerability, adverse event profile and pharmacokinetics of different dose levels of blinatumomab in different age groups
• to assess the anti-leukemia activity of blinatumomab
• to assess the development of anti-drug antibodies (ADA) to blinatumomab
• to describe the changes in pharmacodynamic markers following treatment with blinatumomab at different dose levels

Phase 2 study

• to asess the safety and tolerability of blinatumomab
• to assess the developemnt of anti-drug antibodies (ADA) to blinatumomab

In the phase I part (dose evaluation) of the study, four different dose levels of blinatumomab will be evaluated. Per dose level there will be included 5 patients plus one substitude patient. Every patient can receive up to five therapy-cycles.
The phase II study is a two stage single larm study. A minimum of 21 patients in the first stage and up to 40 evaluable patients in total will be enrolled.

• Morphologic evidence of B-precursor ALL (pro B-, pre B-, common ALL) with > 25% blasts in bone marrow (M3)
• Age <= 18 years at enrolment (only children age 2-18 will be enroled prior to the identification of the recomended phase II dose)
• Relapsed oder refractory desease: second or later bone marrow relapse, any marrow relapse after HSCT,or, refractory to other treatment: patients in first relapse must have failed to achieve a CR following 3 cycles of reinduction chemotherapy, or, patients who have not achieved a first remission must have failed 3 cycles of induction treatment
• ECOG Performens Status > 2 for patients > 10 years and /Lansky Index > 70% for patients <= 10 years
• Creatinine clearence >= 70/L/min/1,73 m² or a creatinine based on age / gender
• Adequate liver function
• Patient and/or his/her legal represantative have reviewed the patient information /informed consent form and have their questions answered and has given written informed consent
• Intrathecal prophylaxis within 1 week before start of blinatumomab treatment
• Patients with CNS relapse must have a complete CNS response prior of initiating blinatumomab

• Active aute or extensive chronic GvDH
• Evidence of current CNS involvement by ALLL (CNS 2 or CNS3) or testicular involvement by ALL. (Patients with CNS relapse at the time of M3 relapse are not eligible for the phase I part but are eligible for the phase II part of the study, if CNS is sucessfully treated prior to enrolment.) Two successive CSF evaluations at least one week apart following completion of CNS therapy that are CNS 1 are required.
• History of relevant CNS pathology or currant relevant CNS pathology (seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar desease, organic brain syndrome, psychosis, coordination or movement disorder).
• History of autoimmune desase with potential CNS involvement or current autoimmune desase
• Any HSCT within 6 weeks prior to blinatumomab treatment
• Cancer chemotherapy within 2 weeks prior to blinatumomab treatment (exept for intrathecal chemotherapy and / or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methtrexate, glucocorticoids).
• Chemotherapy related toxicities that haven´t resolved <= ° 2
• Radiotherapy within 4 weeks prior treatment with blinatumomab
• Immunotherapy (e.g. rituximab, alemtuzumab) or GvHD prophylaxis within 6 weeks prior to blinatumomab treatment
• Any investigational product within 4 weeks prior to study entry
• Known hypersinsitivity to immune globuline or to any component of the study drug formulation
• Presence of HAMA reactivity (in patients with prior exposure to murine antibodies or proteins)
• Active malignancy other than ALL
• Active severe infection, any other concurrent desease or medical condition that could be exacerbated by the treatment or would seriously complicate compliancew with the protocol
• Known infection with HIV or chronic indfection with hepatitis B virus (Hbs Antigen positive) or hepatitis C (anti-HCV positive)
• Prgenat or nursing female adolescent patients
• Post-menarchal female adolescent patients or mals adolescents patients who are not willing to use an effective form of contraception during tretament phase of the study and at least 3 month after

The study is opened only in a limited number of hospitals and inclusion criteria are narrow. For that, it is recomendes to talk to the national coordinator A. v. Stackelberg first if the patient is eligible, before informing the patient / guardian of the possible enrolment of the patient.