Clinical Study With Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Study Overview
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Brief Summary
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The purpose of this study is to confirm whether the bispecific T-cell engager blinatumomab is effective and safe in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Detailed Description
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DLBCL is an aggressive malignant disease which evolves from B-cells and affects mainly the lymphatic tissue. Due to its aggressive nature the disease is characterized by a fast course which is lethal without therapy. Potentially curative therapy options are available even at advanced stages. Standard-first line leads to a high initial response rate (85-90%) and an approximate cure rate of 50% of patients. Patients refractory to or with early relapse after this treatment (10-15%) have a very poor prognosis. Blinatumomab is a bispecific single-chain antibody derivative against CD19 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. This study consisted of a screening period, treatment period, and a follow-up efficacy and survival period. The core study comprises the treatment period to the 30 days after the last infusion. The first cycle consisted of a continuous intravenous (CIV) infusion over 8 weeks. Participants who achieved a Complete Response (CR) or Partial Response (PR) or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval. After the last treatment cycle, efficacy and survival follow-up visits occurred for up to 24 months from treatment start. Participants who relapsed during the follow-up period may have received an additional 8 weeks of treatment. Two dose regimens were assessed in this study. Stage 1 comprised 2 dose cohorts. In Cohort 1, the first 6 participants were to receive blinatumomab in a dose-escalating manner: 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during Cycle 1. In Cohort 2, the next 6 participants enrolled were to receive a constant dose of 112 µg/day blinatumomab. Before the initiation of stage 2, a pre-planned data monitoring committee (DMC) meeting was held to assess the safety profile of Cohort 1 and Cohort 2. The dosing regimen with the more favorable benefit-risk profile was to be selected for Cohort 3.

Official Title
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An Open Label, Multicenter, Exploratory Phase 2 Study to Evaluate the Efficacy and Safety of the Bispecific T-Cell Engager (BiTE®) Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Diffuse Large B-Cell Lymphoma (DLBCL) who are refractory to first or later treatment or have a first relapse or later relapse not eligible for autologous hematopoietic stem cell transplant (HSCT) or relapsed post- autologous-HSCT Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Age ≥ 18 years Life expectancy of ≥ 12 weeks Cerebrospinal fluid (CSF) free of infiltration by DLBCL Exclusion Criteria: History or presence of clinically relevant central nervous system (CNS) pathology as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis Current infiltration of CSF by DLBCL History of autoimmune disease with potential CNS involvement or current autoimmune disease Autologous HSCT within six weeks prior to start of blinatumomab treatment Prior allogeneic HSCT Cancer chemotherapy within two weeks prior to start of blinatumomab treatment Radiotherapy within four weeks prior to start of blinatumomab treatment Immunotherapy (e.g., rituximab) within four weeks prior to start of blinatumomab treatment Any investigational anti-lymphoma product within four weeks prior to start of blinatumomab treatment Treatment with any other investigational product after signature of informed consent Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation Abnormal laboratory values indicative of inadequate renal or liver function History of malignancy other than non-Hodgkin's lymphoma (NHL) 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 Active uncontrolled infection, any other concurrent disease or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator Infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus Pregnant or nursing women Previous treatment with blinatumomab Presence of human anti-murine antibodies (HAMA) at screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab<br>By study design, two dose regimens were assessed in this study. In Stage 1, Cohort 1, participants received blinatumomab in a dose-escalating manner: 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during cycle 1. In Cohort 2, the next participants enrolled and received a constant dose of 112 µg/day blinatumomab. The dosing regimen with the more favorable benefit-risk profile was then selected for Stage 2, Cohort 3. | Drug: Blinatumomab<br>* Administered by continuous intravenous infusion over 8 weeks in the first cycle and 4 weeks in the second cycle.<br>* Other names: BLINCYTO®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Objective Response Rate During Treatment Cycle 1 | Overall response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Overall objective response rate (ORR) is the percentage of participants with a best overall response of complete response (CR) or partial response (PR). Complete response is defined as the disappearance of all evidence of disease and partial response is defined as regression of measureable disease and no new sites. | During the first 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Best Overall Response of Complete Response | Response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Complete response is defined as the disappearance of all evidence of disease. | During the first 8 weeks | 
| Percentage of Participants With a Best Overall Response of Partial Response | Response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Partial response is defined as regression (<50% decrease in size of masses) of measureable disease and no new sites. | During the first 8 weeks | 
| Duration of Objective Response | The time from documentation of the first assessment of either partial or complete response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. | From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months. | 
| Duration of Complete Response | The time from documentation of the first assessment of complete response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. | From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months. | 
| Duration of Partial Response | The time from documentation of the first assessment of partial response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. | From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months. | 
| Progression-free Survival (PFS) | The time from the date of first blinatumomab infusion until the date of diagnosis of progression of lymphoma, the start date of new anti-tumor treatment (excluding any stem cell transplantation) or date of death, whichever is the earliest. Patients alive who did not have progression or new anti-tumor treatment (excluding any stem cell transplantation) were censored at last date of tumor assessment. | From first infusion of blinatumomab until the end of study; median time on follow-up for PFS was 27.0 months. | 
| Overall Survival (OS) | The time from the date of first blinatumomab infusion until death as a result of any cause. Patients still alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. For patients who withdrew their informed consent, only information until the date of withdrawal was analyzed. | From the first infusion of blinatumomab until the end of study; median time on follow-up for overall survival was 26.6 months. | 
| Number of Participants With Adverse Events | Adverse events were evaluated for severity according to the grading scale provided in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. An adverse event or suspected adverse drug reaction was considered serious if it resulted in one of the following outcomes: Resulted in death; Was life-threatening; Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions; Was a congenital anomaly or birth defect; Was a medically important condition. The Investigator used medical judgment to determine whether there was a causal relationship (ie, related [reasonably possible] or unrelated [not reasonably possible]) between an adverse event and blinatumomab. | From the first dose of blinatumomab until up to 30 days after the last dose or until the data cut-off date of 10 July 2014, whichever occurred first; the overall median duration of treatment exposure was 46.8 days. | 
| Blinatumomab Steady State Serum Concentration | Blinatumomab serum levels were analyzed using a validated cluster of differentiation (CD)69 activation bioassay with a lower limit of quantification (LLOQ) of 50 pg/mL. Steady-state concentration (Css) was based on actual dose received, rather than based on cohort or time or day. | Cycle 1: predose; Day 3 and Day 8 (Css for 9 ug/day); Day 15 (Css for 28 ug/day); and Day 29, Day 43 and Day 57 (Css for 112 ug/day) | 
| Leukocyte Counts | Leukocyte (white blood cells) counts were analyzed by differential blood count analysis. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| Lymphocyte Counts | Lymphocyte counts were analyzed by differential blood count analysis. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| Monocyte Counts |  | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| Granulocyte Count |  | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD19+ B-Cell Count | CD19+ B-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD19+ B-Cells as a Percentage of All Lymphocytes | CD19+ B-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD3+ T-Cell Count | CD3+ T-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD3+ T-Cells as a Percentage of All Lymphocytes | CD3+ T-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ T-Cell Count | CD4+ T-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ T-Cells as a Percentage of All Lymphocytes | CD4+ T-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ T-Cell Count | CD8+ T-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ T-Cells as a Percentage of All Lymphocytes | CD8+ T-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD19+ B-Cell to CD3+ T-Cell Ratio | CD19+ B-cells and CD3+ T-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ T-Cell to CD8+ T-Cell Ratio | CD4+ T-cells and CD8+ T-cell counts were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ Naive T Cell Count | CD4+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ Naive T Cells as a Percentage of All CD4+ T-Cells | CD4+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ Central Memory T-Cell (TCM) Count | Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ TCM Cells as a Percentage of All CD4+ T-Cells | Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ Effector Memory T-Cell (TEM) Count | Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD4+ TEM Cells as a Percentage of All CD4+ T-Cells | Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ Naive T-Cell Count | CD8+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ Naive T-Cells as a Percentage of All CD8+ T-Cells | CD8+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ TCM Cell Counts | Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ TCM Cells as a Percentage of All CD8+ T-Cells | Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ Effector Memory T-Cell (TEM) Count | Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ TEM Cells as a Percentage of All CD8+ T-Cells | Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ Terminally Differentiated Effector Memory T-cells (TEMRA) Count | Terminally differentiated effector memory T cells are characterized by the cell-surface expression of CD45RA but not CD197 and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 
| CD8+ TEMRA Cells as a Percentage of All CD8+ T-Cells | Terminally differentiated effector memory T cells are characterized by the cell-surface expression of CD45RA but not CD197 and were analyzed by flow cytometry. | Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed DLBCL, Refractory DLBCL, adult DLBCL, Lymphoma, Non-Hodgkin Lymphoma, Lymphatic diseases, Lymphoproliferative disorders, bispecific antibody, anti-CD19, Immunotherapeutic treatment, Immunoproliferative disorders