Clinical Study With Blinatumomab in Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

• Proportion of patients eligible for allogeneic hematopoietic stem cell transplantation (HSCT) who undergo the procedure after treatment with blinatumomab [ Time Frame: within 17 months ] [ Designated as safety issue: No ]
• CR rate [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• CRh* rate [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Partial remission (PR) rate [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Relapse-free survival [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
• Number of AEs per patient [ Time Frame: up to 8 months ] [ Designated as safety issue: Yes ]
• 100-day mortality after allogeneic HSCT [ Time Frame: within 4 years ] [ Designated as safety issue: Yes ]
• Steady state concentration of blinatumomab (pharmacokinetics) [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Serum cytokine concentrations [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]
• Rate of MRD response [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Rate of MRD complete response [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Time to hematological relapse [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
• Event-free survival [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
• Concentration of peripheral blood lymphocyte subsets [ Time Frame: up to 2 years ] [ Designated as safety issue: No ]

• Proportion of patients eligible for allogeneic hematopoietic stem cell transplantation (HSCT) who undergo the procedure after treatment with blinatumomab [ Time Frame: within 17 months ] [ Designated as safety issue: No ]
• CR rate [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• CRh* rate [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Partial remission (PR) rate [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Relapse-free survival [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
• Number of AEs per patient [ Time Frame: up to 8 months ] [ Designated as safety issue: Yes ]
• 100-day mortality after allogeneic HSCT [ Time Frame: within 4 years ] [ Designated as safety issue: Yes ]
• Steady state concentration of blinatumomab (pharmacokinetics) [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Serum cytokine concentrations [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]
• Rate of MRD response [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Rate of MRD complete response [ Time Frame: within 10 weeks ] [ Designated as safety issue: No ]
• Duration of CR and CRh* [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]

The purpose of this study is to confirm whether the bispecific T cell engager antibody blinatumomab (MT103) is effective and safe in the treatment of patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL).

Relapsed/refractory B-precursor ALL in adult patients is an aggressive malignant disease with dismal prog-nosis. Several studies have reported long term survival to be below 10%. Major prognostic factors are duration of first complete remission (CR1) and age. With current salvage chemotherapy, complete remission (CR) rate is low (20 to 30%) in patients in first salvage with short duration (< one year) of first remission, patients relapsed after first salvage, or patients aged 60 years and older. Duration of CR is usually very short (median disease free survival [DFS]: 2.0-7.5 months). Allogeneic hematopoietic stem cell transplantation (HSCT) may provide a curative treatment option for patients in CR with a satisfactory donor and appropriate clinical status including age, organ function, and remission status. Allogeneic HSCT is not an option in most elderly patients with relapsed ALL. Additional therapeutic approaches are urgently needed.

Blinatumomab (also termed MT 103) is a bispecific single-chain antibody derivative against CD (cluster of differentiation)19 and CD3, designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. In vitro data indicate CD19+ lymphoma and leukemia cell lines to be extremely sensitive to blinatumomab-mediated cytotoxicity.Blinatumomab has the potential to provide meaningful therapeutic benefits to patients compared with existing treatments for this patient population.

The purpose of this study is to confirm whether the bispecific T-cell engager blinatumomab (MT103) is effective and safe in the treatment of patients with relapsed or refractory ALL. Patients will receive up to five 4-week cycles of intravenous blinatumomab treatment.

Inclusion Criteria:

• Patients with Ph-negative B-precursor ALL, with any of the following:
• relapsed or refractory with first remission duration less than or equal to 12 months in first salvage or
• relapsed or refractory after first salvage therapy or
• relapsed or refractory within 12 months of allogeneic HSCT
• 10% or more blasts in bone marrow
• In case of clinical signs of additional extramedullary disease: measurable disease
• ECOG performance status ≤ 2
• Age ≥ 18 years

Exclusion Criteria:

• Patients with Ph-positive ALL
• Patients with Burkitt's Leukemia according to WHO classification
• History or presence of clinically relevant CNS pathology
• Active ALL in the CNS or testes
• Current autoimmune disease or history of autoimmune disease with potential CNS involvement
• Autologous HSCT within six weeks prior to start of blinatumomab treatment
• Allogeneic HSCT within three months prior to start of blinatumomab treatment
• Any active acute GvHD, or active chronic GvHD Grade 2 - 4
• Any systemic therapy against GvHD within two weeks prior to start of blinatumomab treatment
• Cancer chemotherapy within two weeks prior to start of blinatumomab treatment
• Radiotherapy within two weeks prior to start of blinatumomab treatment
• Immunotherapy (e.g., rituximab) within four weeks prior to start of blinatumomab treat-ment
• Any investigational anti-leukemic product within four weeks prior to start of blinatumomab treatment
• Treatment with any other IMP after signature of informed consent
• Eligibility for allogeneic HSCT at the time of enrollment
• Known hypersensitivity to immunoglobulins or to any other component of the IMP formulation
• Abnormal laboratory values indicative of inadequate renal or liver function
• History of malignancy requiring treatment other than ALL within five years prior to start of blinatumomab treatment with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix
• Any concurrent disease or medical condition that is deemed to interfere with the conduct of the study
• Infection with HIV or chronic infection with hepatitis B virus or hepatitis C virus
• Pregnant or nursing women
• Women of childbearing potential not willing to use an effective form of contraception. Male patients not willing to ensure not to beget a child
• Previous treatment with blinatumomab