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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Amgen Research (Munich) GmbH
ClinicalTrials.gov Identifier:
NCT01741792
First received: November 28, 2012
Last updated: August 7, 2015
Last verified: August 2015
  Purpose

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).


Condition Intervention Phase
Diffuse Large B-cell Lymphoma
Drug: Blinatumomab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Amgen Research (Munich) GmbH:

Primary Outcome Measures:
  • Overall Objective Response Rate During Treatment Cycle 1 [ Time Frame: During the first 8 weeks ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Percentage of Participants With a Best Overall Response of Complete Response [ Time Frame: During the first 8 weeks ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With a Best Overall Response of Partial Response [ Time Frame: During the first 8 weeks ] [ Designated as safety issue: No ]
    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.

  • Duration of Objective Response [ Time Frame: From first infusion of blinatumomab until the data cut-off date of 10 July 2014; median follow-up time for duration of response was 11.8 months. ] [ Designated as safety issue: No ]
    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.

  • Duration of Complete Response [ Time Frame: From first infusion of blinatumomab until the data cut-off date of 10 July 2014; median follow-up time for duration of response was 11.8 months. ] [ Designated as safety issue: No ]
    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.

  • Duration of Partial Response [ Time Frame: From first infusion of blinatumomab until the data cut-off date of 10 July 2014; median follow-up time for duration of response was 11.8 months. ] [ Designated as safety issue: No ]
    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.

  • Progression-free Survival (PFS) [ Time Frame: From first infusion of blinatumomab until the data cut-off date of 10 July 2014; median time on follow-up for PFS was 15.0 months. ] [ Designated as safety issue: No ]
    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.

  • Overall Survival (OS) [ Time Frame: From the first infusion of blinatumomab until the data cut-off date of 10 July 2014; median time on follow-up for overall survival was 8.5 months. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Adverse Events [ Time Frame: 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. ] [ Designated as safety issue: Yes ]

    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.


  • Blinatumomab Steady State Serum Concentration [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Absolute Numbers and Proportions of Lymphocyte Subpopulations [ Time Frame: up to 28 months ] [ Designated as safety issue: No ]

Enrollment: 25
Study Start Date: July 2012
Estimated Study Completion Date: May 2016
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Blinatumomab
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
Administered by continuous intravenous infusion over 8 weeks in the first cycle and 4 weeks in the second cycle.
Other Names:
  • AMG103
  • MT103
  • BLINCYTO®

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01741792

Locations
Germany
Universitätsmedizin
Göttingen, Germany
Universitätsklinikum des Saarlandes
Homburg, Germany
Universitätsklinikum Schleswig Holstein
Kiel, Germany
Klinikum der Johannes-Gutenberg Universität
Mainz, Germany
Universitätsklinikum
Ulm, Germany
Universititätsklinikum
Würzburg, Germany
Sponsors and Collaborators
Amgen Research (Munich) GmbH
Investigators
Study Chair: Andreas Viardot, MD Universitätsklinikum Ulm
  More Information

No publications provided

Responsible Party: Amgen Research (Munich) GmbH
ClinicalTrials.gov Identifier: NCT01741792     History of Changes
Other Study ID Numbers: MT103-208, 2011-005781-38
Study First Received: November 28, 2012
Results First Received: June 26, 2015
Last Updated: August 7, 2015
Health Authority: Germany: Paul-Ehrlich-Institut

Keywords provided by Amgen Research (Munich) GmbH:
Relapsed DLBCL
Refractory DLBCL
adult DLBCL
Lymphoma
Non-Hodgkin Lymphoma
Lymphatic diseases
Lymphoproliferative disorders
bispecific antibody
anti-CD19
Immunotherapeutic treatment
Immunoproliferative disorders

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on August 31, 2015