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

An Open Label, Multicenter, Phase II Study to Evaluate Efficacy and Safety of the BiTE® Antibody Blinatumomab in Adult Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

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 prognosis. 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 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.

This study consists of a screening period, a treatment period and a follow-up period. Participants receive one to five treatment cycles of blinatumomab at a target dose of 28 μg/day. In the first cycle, the initial dose is 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.

Participants who achieve remission within two cycles of treatment can receive up to three additional cycles of consolidation treatment or proceed to allogeneic HSCT. In the event of progression or relapse within the treatment period, treatment will be terminated. Participants with hematological relapse during the efficacy or safety follow-up period may receive up to three additional cycles of blinatumomab (retreatment) for a maximal total of eight cycles at the investigator´s discretion.

Thirty days after end of the last treatment, participants have an end-of-core-study visit. Following this, there are efficacy follow-up visits at 3, 6, 9, 12, 18 and 24 months at the most after treatment start. Once efficacy follow-up is complete, information on survival collected at least every six months until death or at least until three years after treatment start, whichever occurs earlier (survival follow-up).

Inclusion Criteria:

• Patients with Philadelphia chromosome (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 hematopoietic stem cell transplantation (HSCT)

• 10% or more blasts in bone marrow

• In case of clinical signs of additional extramedullary disease: measurable disease

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Age ≥ 18 years

Exclusion Criteria:

• Patients with Ph-positive ALL
• Patients with Burkitt's Leukemia according to World Health organization (WHO) classification
• History or presence of clinically relevant central nervous system (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 graft versus-host disease (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 investigational medicinal product (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 human immunodeficiency virus (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