Clinical trial NCT01741792: Clinical Study With Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Large B-cell Lymphoma
Keywords: Relapsed DLBCL
Refractory DLBCL
adult DLBCL
Lymphoma
Non-Hodgkin Lymphoma
Lymphatic diseases
Lymphoproliferative disorders
bispecific antibody
anti-CD19
Immunotherapeutic treatment
Immunoproliferative disorders
Lead sponsor: Amgen Research (Munich) GmbH
Sponsor class: INDUSTRY
First posted: 2012-12-05
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Objective Response Rate During Treatment Cycle 1
timeFrame: During the first 8 weeks
Secondary outcomes:
measure: Percentage of Participants With a Best Overall Response of Complete Response
timeFrame: During the first 8 weeks
measure: Percentage of Participants With a Best Overall Response of Partial Response
timeFrame: During the first 8 weeks
measure: Duration of Objective Response
timeFrame: From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months.
measure: Duration of Complete Response
timeFrame: From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months.
measure: Duration of Partial Response
timeFrame: From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months.
measure: Progression-free Survival (PFS)
timeFrame: From first infusion of blinatumomab until the end of study; median time on follow-up for PFS was 27.0 months.
measure: Overall Survival (OS)
timeFrame: From the first infusion of blinatumomab until the end of study; median time on follow-up for overall survival was 26.6 months.
measure: Number of Participants With Adverse Events
timeFrame: 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.
measure: Blinatumomab Steady State Serum Concentration
timeFrame: 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)
measure: Leukocyte Counts
timeFrame: 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
measure: Lymphocyte Counts
timeFrame: 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
measure: Monocyte Counts
timeFrame: 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
measure: Granulocyte Count
timeFrame: 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
measure: CD19+ B-Cell Count
timeFrame: 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
measure: CD19+ B-Cells as a Percentage of All Lymphocytes
timeFrame: 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
measure: CD3+ T-Cell Count
timeFrame: 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
measure: CD3+ T-Cells as a Percentage of All Lymphocytes
timeFrame: 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
measure: CD4+ T-Cell Count
timeFrame: 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
measure: CD4+ T-Cells as a Percentage of All Lymphocytes
timeFrame: 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
measure: CD8+ T-Cell Count
timeFrame: 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
measure: CD8+ T-Cells as a Percentage of All Lymphocytes
timeFrame: 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
measure: CD19+ B-Cell to CD3+ T-Cell Ratio
timeFrame: 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
measure: CD4+ T-Cell to CD8+ T-Cell Ratio
timeFrame: 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
measure: CD4+ Naive T Cell Count
timeFrame: 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
measure: CD4+ Naive T Cells as a Percentage of All CD4+ T-Cells
timeFrame: 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
measure: CD4+ Central Memory T-Cell (TCM) Count
timeFrame: 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
measure: CD4+ TCM Cells as a Percentage of All CD4+ T-Cells
timeFrame: 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
measure: CD4+ Effector Memory T-Cell (TEM) Count
timeFrame: 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
measure: CD4+ TEM Cells as a Percentage of All CD4+ T-Cells
timeFrame: 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
measure: CD8+ Naive T-Cell Count
timeFrame: 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
measure: CD8+ Naive T-Cells as a Percentage of All CD8+ T-Cells
timeFrame: 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
measure: CD8+ TCM Cell Counts
timeFrame: 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
measure: CD8+ TCM Cells as a Percentage of All CD8+ T-Cells
timeFrame: 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
measure: CD8+ Effector Memory T-Cell (TEM) Count
timeFrame: 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
measure: CD8+ TEM Cells as a Percentage of All CD8+ T-Cells
timeFrame: 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
measure: CD8+ Terminally Differentiated Effector Memory T-cells (TEMRA) Count
timeFrame: 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
measure: CD8+ TEMRA Cells as a Percentage of All CD8+ T-Cells
timeFrame: 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
Other outcomes:
Locations:
city: Göttingen
country: Germany
facility: Universitätsmedizin
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig Holstein
city: Mainz
country: Germany
facility: Klinikum der Johannes-Gutenberg Universität
city: Ulm
country: Germany
facility: Universitätsklinikum
city: Würzburg
country: Germany
facility: Universititätsklinikum
Study officials:
affiliation: Amgen
name: - MD
role: STUDY_DIRECTOR
References:
citation: Zhu M, Wu B, Brandl C, Johnson J, Wolf A, Chow A, Doshi S. Blinatumomab, a Bispecific T-cell Engager (BiTE((R))) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications. Clin Pharmacokinet. 2016 Oct;55(10):1271-1288. doi: 10.1007/s40262-016-0405-4.
citation: Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, Zettl F, Libicher M, Sayehli C, Stieglmaier J, Zhang A, Nagorsen D, Bargou RC. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016 Mar 17;127(11):1410-6. doi: 10.1182/blood-2015-06-651380. Epub 2016 Jan 11.