Phase II Study of Blinatumomab in Patients with B-cell Lineage Acute Lymphocytic Leukemia with Positive Minimal Residual Disease
The goal of this clinical research study is to learn if Blinacyto (blinatumomab) can help to control ALL with positive MRD. The safety of this drug will also be studied.
Disease Group: Leukemia
Treatment Agent: Blinatumomab,Dexamethasone
Treatment Location: Only at MDACC
Primary Objectives: To evaluate the clinical efficacy of blinatumomab in patients B-cell acute lymphoblastic leukemia in complete morphologic remission with positive minimal residual disease (MRD) in terms of relapse-free survival RFS. Secondary Objectives: To evaluate other efficacy endpoints such as event-free and overall survival and MRD negativity rate overall and after the first cycle, as well as safety of blinatumomab in this setting. Background Minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). Persistence or reappearance of minimal residual disease (MRD) after induction chemotherapy is the most important adverse prognostic factor in patients with B-lineage acute lymphoblastic leukemia (ALL) and identifies chemorefractory disease. More than 90% of patients who fail to clear MRD after chemotherapy experience a clinical relapse despite continued chemotherapy. The median time to relapse of patients with MRD+ disease is 4-5 months. The only option to cure these patients is allogeneic hematopoietic stem cell transplantation (HSCT), but the outcome is suboptimal.8Therefore, the development of novel therapies with an alternative mode of action for the treatment of molecularly refractory B-lineage ALL is urgently needed. Blinatumomab The Bispecific T-cell Engaging (BiTE) antibody blinatumomab represents the first agent in a class that redirects host T-cells to cell surface antigen-expressing cancer cells. Blinatumomab contains the variable domains of a CD19 antibody and a CD3 antibody which are joined by a non-immunogenic linker. Upon binding to CD19, the cytotoxic T cells become activated and induce cell death via the pore-forming perforin system. The drug was initially administered as an intermittent infusion two to three times weekly, but lack of activity and serious neurologic toxicity caused the schedule of administration to be abandoned. Based on the short half-life of the drug and the mechanism of action, continuous infusion over several weeks were investigated. This drastically improved the activity of the drug, particularly in ALL, and helped reduce adverse effects. Background Drug Information Blinatumomab Blinatumomab will be supplied as 3 mL single-use glass injection vials containing a sterile, preservative-free, white to off-white, lyophilized powder for intravenous (IV) administration following reconstitution with sterile water for injection (sWFI). Each vial contains a target of 30.3 ìg blinatumomab (nominal) formulated with 25 mM citric acid monohydrate 15% (W/V) trehalose dihydrate, 200 mM lysine hydrochloride and 0.1% (W/V), polysorbate 80, pH 7. Since blinatumomab will be administered via continuous intravenous route, it needs to be stabilized at low concentrations to prevent absorption to surfaces. Therefore, the IV bag must be conditioned by prior addition of a product-specific diluent (IV solution stabilizer), resulting in a final diluent concentration of 0.5 mM citrate, 25 mM lysine hydrochloride and 0.002% (w/v) polysorbate 80. Dexamethasone premedication Premedication with dexamethasone is intended to prevent CRS events associated with blinatumomab treatment. Within 1 hour before the start of treatment in each treatment cycle, mandatory premedication with dexamethasone at 20 mg IV is required for the prevention of CRS resulting from blinatumomab.
IRB Review and Approval Date: 09/14/2015
Recruitment Status: Open
Projected Accrual: N/A
1) Patients at least 18 years of age.
2) Patients with B-lineage ALL in hematologic complete remission (CR) with molecular failure (ie, had never achieved an MRD-negativity status before blinatumomab) or had a molecular relapse (ie, became MRD positive after having been MRD negative) starting at any time point after 3 months of frontline therapy. Molecular disease or minimal residual disease is defined by a value of at least of 1x10^-4 by multicolor flow cytometry.
3) Patients with B-lineage ALL in at least marrow CR in Salvage 1 and beyond with molecular failure at any time point after 1 month of salvage therapy are allowed, including patients who received prior allogeneic stem cell transplantation.
4) Performance status of 0, 1, or 2
5) Adequate organ function with creatinine clearance >/= 30 ml/minute and bilirubin less than or equal to 3.0 mg/dL.
6) No active or co-existing malignancy with life expectancy less than 12 months.
7) Patients with Ph+ ALL can be enrolled in CR1 or CR2 and beyond. A TKI will be added at the discretion of the treating physician. MRD for these patients will be defined by PCR of 0.1% and above (International Scale).
1) Pregnant or nursing women
2) Known to be HIV+
3) Active and uncontrolled disease/infection as judged by the treating physician
4) Unable or unwilling to sign the consent form
5) Active CNS or extramedullary disease
6) Monoclonal antibodies therapy within 2 weeks before study entry
7) Radiotherapy and cancer chemotherapy (except for intrathecal prophylaxis and/or low-dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, steroids) or any investigational drug within 2 weeks before study entry
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