Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Symptoms and General Pathology

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Neoplasm, Residual

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Neoplastic Processes

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Bispecific

Immunoglobulins

Blinatumomab

Immunologic Factors

Participants received blinatumomab as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2 week treatment-free period (defined as one treatment cycle), for up to a maximum of 10 cycles. The initial dose was 15 μg/m\^2/day. A dose increase to 30 μg/m\^2/day was permitted with evidence for insufficient response to blinatumomab treatment.

Administered by continuous intravenous (CIV) over 4 weeks per cycle

Blinatumomab (MT103)

Ralf Bargou, Professor

The purpose of this study is to determine whether the bispecific T-cell engager (BiTE®) Blinatumomab (MT103) is effective in the treatment of ALL patients with minimal residual disease.

The presence of leukemia cells below the cytological detection limit (5% leukemic cells) is defined as minimal residual disease (MRD). If no MRD is detectable (\< 10\^-4 = less than 1 leukemia cell per 10\^4 bone marrow cells) a complete molecular remission is reached. In the last years a series of retrospective studies has shown that MRD in adult ALL is an independent prognostic factor as already demonstrated for childhood leukemia. Diagnostic tools for MRD are polymerase chain reaction (PCR) and/or flow cytometry. PCR analysis can detect fusion transcripts such as bcr/abl and individual clonal rearrangements of immunoglobulins (IgH) and/or T-cell receptor genes (TCR). About 25% of patients with MRD defined by rearrangement comprise a high-risk group with a 94% relapse rate within 3 years. In general for patients with MRD, who are not eligible for allogenic stem cell transplantation, curative treatment is not available. This accounts for MRD defined by the Philadelphia chromosome translocation as well as for MRD defined by rearrangement. The current study is set up to address the question of treating MRD positive ALL with the bispecific anti-cluster of differentiation (CD)19 x anti-CD3 antibody derivative blinatumomab (MT103).

Phase II Study of the BiTE® Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL)

Open-label, Multicenter Phase II Study to Investigate the Efficacy, Safety, and Tolerability of the Bispecific T-cell Engager (BiTE®) MT103 in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia

MRD Response is defined as:

* If Philadelphia Chromosome (Ph) positive (+) or translocation (t) (4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4.
* If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4.

MRD Response is defined as:

* If Philadelphia Chromosome (Ph)+ or t(4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4.
* If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4.

The time to hematological relapse is defined as the time between start of first infusion of blinatumomab and the first result of hematological relapse. Participants without an event of hematological relapse were censored on their last available date of bone marrow aspiration/biopsy.

Hematological relapse is defined as \> 5% leukemia cells in bone marrow. Time to hematological relapse was analyzed using Kaplan-Meier methods.

Time to MRD progression is defined for participants who do not show MRD response at any time during the study as the time from start of first infusion until the first result of MRD progression or hematological relapse, if no MRD progression was diagnosed before hematological relapse. For participants who showed MRD response during the study the time to MRD progression is defined as the time from the date of the first MRD response to the date of MRD relapse. Participants without an event of MRD progression were censored on the day of their last bone marrow aspiration/biopsy. Participants who received a bone marrow transplant were censored on the last day of bone marrow aspiration/biopsy before transplantation.

MRD progression is defined as the increase in the MRD level by 1 log as compared to the baseline level (equal to a 10-fold increase in the number of MRD cells), and had to be confirmed within 6 weeks.

Time to MRD relapse is defined only for participants with an MRD response during the study, defined as the time between the date of the first MRD response and the date of MRD relapse. If a participant experienced hematological relapse without having shown MRD positivity before then the time point of MRD relapse is defined as the time point of hematological relapse. Participants without an event of MRD relapse or hematological relapse were censored on the day of their last available bone marrow aspiration/biopsy. If a participant received a bone marrow transplant the last day of bone marrow aspiration/biopsy before transplantation was used as time point for censoring.

MRD relapse is defined as reappearance of bcr/abl, and/or t(4;11) translocation at any detection level, and/or by individual rearrangements of immunoglobulin or T-cell receptor genes ≥10\^-4 for at least 1 individual marker measured by an assay with a sensitivity of minimum 10\^-4 and should be confirmed within 6 weeks.

The severity (or intensity) of AEs was evaluated according to the grading scale provided in the Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, or according to the following: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death.

The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.

A serious adverse event (SAE) is any untoward medical occurrence or effect that, at any dose results in death, is life-threatening, requires or prolongs hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. In addition, all laboratory abnormalities of grade four severity that occur during or after administration of the investigational drug, any overdose and a pregnancy or fathering were reported as SAEs.

The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using fluorescence-activated cell sorter (FACS)-based cytometric bead array (CBA) system.The limit of detection (LOD) for the cytokine determination was 20 pg/mL, the limit of quantification (LOQ) was 125 pg/mL.

The mean serum concentration of blinatumomab during cycle 1. The LOQ of the assay was 100 pg/mL, and the limit of detection (LOD) was 3 pg/mL.

Amgen Research (Munich) GmbH

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Summary of Adverse Events includes only those participants who received at least one dose of investigational product.

Participants received blinatumomab as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2 week treatment-free period (defined as one treatment cycle), for up to a maximum of 10 cycles. The initial dose was 15 μg/m²/day. A dose increase to 30 μg/m²/day was permitted with evidence for insufficient response to blinatumomab treatment.

Age, Continuous

20-30 years

31-40 years

41-50 years

51-60 years

61-70 years

> 70 years

Age, Customized

Sex: Female, Male

Caucasian

Race/Ethnicity, Customized

bcr/abl translocation above detection limit

t(4;11) translocation above detection limit

Rearrangements of Ig / TCR genes only

Rearrangements of Ig / TCR genes & translocations

bcr/abl: breakpoint cluster region; Ig: immunoglobulin; TCR: T-cell receptor. For bcr/abl above detection limit and t(4;11) translocation above detection limit participants may have rearrangements in addition to translocations.

For Rearrangements of immunoglobulin / TCR genes participants did not show any translocation.

Genetic Alterations

Full Analysis Set included all participants who received ≥ 1 infusion of blinatumomab who completed at least the first treatment cycle and for whom at least one minimal residual disease (MRD) response assessment was available.

Study Director

Percentage of Participants With a Minimal Residual Disease (MRD) Response Within 4 Cycles of Treatment

MRD negativity achieved after cycle 1

MRD negativity achieved after cycle 2

MRD negativity achieved after cycle 3

MRD negativity achieved after cycle 4

Percentage of Participants With an MRD Response After Each Treatment Cycle

Time to Hematological Relapse

Time to MRD Progression

Time to MRD Relapse

Any adverse event

Adverse events of at least CTC grade 3

Treatment-related adverse events

Related adverse events of at least CTC grade 3

Serious adverse evets

Related serious adverse events

AEs leading to discontinuation of blinatumomab

AEs leading to death

Safety analysis set, including all participants who received ≥ 1 infusion of blinatumomab.

Number of Participants With Adverse Events

Start of infusion (N=19)

45 minutes (N=19)

2 hours (N=18)

6 hours (N=19)

12 hours (N=16)

24 hours (N=18)

Day 2 (N=17)

Day 7 (N=18)

Day 14 (N=18)

Day 21 (N=18)

Day 28 (N=17)

Day 35 (N=18)

Participants received blinatumomab 15 μg/m²/day as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2 week treatment-free period.

Participants who received blinatumomab with available pharmacodynamic data.

Change From Screening Value in B-cell Count During Cycle 1

Change From Screening Value in T-cell Count During Cycle 1

IL-2

IL-4

IL-6

IL-8

IL-10

IFN-γ

TNF-α

Participants received blinatumomab 15 μg/m²/day as continuous intravenous infusion at constant flow rate over 4 weeks.

Serum Cytokine Peak Levels in Cycle 1

Participants who received at least 1 infusion of blinatumomab with available pharmacokinetic data.

Serum Blinatumomab Concentration at Steady State

Area Under the Drug Concentration-time Curve From Time Zero to Infinity

Apparent Volume of Distribution

Clearance of Blinatumomab

Terminal Half-life of Blinatumomab

Overall Study

Lymphoma, Non-Hodgkin

Antibodies, Monoclonal

Immunomodulating Agents

Muromonab-CD3

Patients received blinatumomab as continuous intravenous infusion for 4 weeks. Participants with clinical benefit were permitted to continue for another 4 weeks for a total of 8 weeks. Participants with a clinical benefit 4 weeks after completion of the first cycle of treatment could also receive additional treatment approximately 3 months ater the end of infusion at the same dose level.

Doses from 0.5 to 120 µg/m\^2/24hours by continuous intravenous infusion

Ralf Bargou, MD, PhD

The purpose of this study is to determine whether a continuous infusion of Blinatumomab (MT103) is safe in the treatment of relapsed Non-Hodgkin's Lymphoma.

Furthermore, the study is intended to provide pharmacokinetic and pharmacodynamic data of Blinatumomab as well as to get first indication of tumour activity.

Non-Hodgkin's Lymphoma (NHL) represents the 6th most common cancer. Globally, around 165,000 new cases are diagnosed each year, with approximately 90,000 deaths per year. The vast majority of NHLs are B-cell derived (90%) and express common B-cell antigens such as CD19, CD20 and CD22. NHL can be divided into indolent (low-grade) and aggressive (high-grade) lymphomas. Still almost all patients with advanced stage indolent disease will die from their disease. Therefore, a high medical need exists to develop novel agents that further improve the survival of NHL patients.

Blinatumomab (MT103) is a bispecific antibody derivative, anti-CD19 x anti-CD3, designed to link B-cells and T-cells resulting in T-cell activation and a cytotoxic T-cell response against CD19+ cells. Data of prior phase I studies show evidence of biological activity in humans. In vitro and ex-vivo data suggest that a longterm presence of the drug in target tissues may provide antitumour activity.

The study investigates the safety and tolerability of different doses of Blinatumomab administration in a continuous infusion regimen. Maximum tolerated dose (MTD) will be defined in a classical 3+3 dose escalation regimen.

Safety Study of the Bispecific T-cell Engager Blinatumomab (MT103) in Patients With Relapsed NHL

An Open-label, Multi-center Phase I Study to Investigate the Tolerability and Safety of a Continuous Infusion of the Bispecific T-cell Engager MT103 in Patients With Relapsed Non-Hodgkin's Lymphoma (NHL)

Participants reporting at least one occurence of any adverse event including clinical symptoms, laboratory abnormalities, serious adverse events, and treatment-limiting adverse events

The steady state serum concentration (Css), summarized as the observed concentrations collected at least 10 hours after the start of continuous intravenous infusion or within the sampling window at the end of infusion. Concentrations below the lower limit of quantitation (100 pg/mL) were excluded from analysis.

Tumor response was defined according to the Cheson criteria and assessed after 4 and 8 weeks of study treatment using computed tomography (CT) scan (neck, thorax and abdomen/pelvic to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration).

Best clinical response is defined as the best response achieved during the course of the study, with response defined as: Complete Response, Complete Response Unconfirmed, Partial Response, Stable Disease, and Progressive Disease. In this analysis minimal response is set to stable disease as intended in the response categories according to the Cheson criteria. An independent external review by a radiologist (computed tomography scans) and a pathologist (biopsies) was performed to confirm response status.

If no post-baseline tumor assessment was available, the overall clinical response was set to not available.

Tumor response was defined according to the Cheson criteria and assessed after 4 and 8 weeks of study treatment using computed tomography (CT) scan (neck, thorax and abdomen/pelvic to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Minimal response was treated as a separate response category in this analysis. Best clinical response was defined as the best response achieved during the course of the study, whereby the following order was applied: Complete Response, Complete Response Unconfirmed, Partial Response, Minimal Response, Stable Disease, and Progressive Disease.

If no post-baseline tumor assessment was available, the overall clinical response was set to not available.

Participants received blinatumomab ≤ 5 µg/m²/day as continuous intravenous infusion over 4-8 weeks in the first treatment cycle.

Blinatumomab ≤ 5 µg/m²/d

Participants received blinatumomab 15 µg/m²/day as continuous intravenous infusion over 4-8 weeks in the first treatment cycle.

Blinatumomab 15 µg/m²/d

Participants received blinatumomab 30 µg/m²/day as continuous intravenous infusion over 4-8 weeks in the first treatment cycle.

Blinatumomab 30 µg/m²/d

Participants received blinatumomab 60 µg/m²/day without a lower dose as continuous intravenous infusion over 4-8 weeks in the first treatment cycle.

Blinatumomab 60 µg/m²/d Flat

Participants received blinatumomab 60 μg/m²/day as continuous intravenous infusion after initial lower doses of 5 and/or 15 μg/m²/day for a total treatment duration of 4-8 weeks in the first treatment cycle.

Blinatumomab 60 µg/m²/d Step

Participants received blinatumomab 90 µg/m²/day as continuous intravenous infusion over 4-8 weeks in the first treatment cycle.

Blinatumomab 90 µg/m²/d

All participants who received any dose of blinatumomab

Blinatumomab Overall

Total

Race (NIH/OMB)

All participants who received at least one infusion of blinatumomab

Participants who received blinatumomab 5 µg/m²/day as continuous intravenous infusion in the first treatment cycle.

Blinatumomab 5 µg/m²/d

Participants who received blinatumomab 15 µg/m²/day as continuous intravenous infusion in the first treatment cyle.

Participants received blinatumomab 30 µg/m²/day as continuous intravenous infusion in hte first treatment cycle.

Participants received blinatumomab 60 µg/m²/day as continuous intravenous infusion in the first treatment cycle.

Blinatumomab 60 µg/m²/d

Participants received blinatumomab 90 µg/m²/day as continuous intravenous infusion in the first treatment cycle.

Participants who received blinatumomab and had available pharmacokinetic data

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Study of the BiTE® Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL)	NCT00560794	Acute Lymphobla...	Blinatumomab (M...	18 Years -	Amgen Research (Munich) GmbH
Safety Study of the Bispecific T-cell Engager Blinatumomab (MT103) in Patients With Relapsed NHL	NCT00274742	Non-Hodgkin's L...	Blinatumomab (M...	18 Years -	Amgen Research (Munich) GmbH
Safety Study of the Bispecific T-cell Engager Blinatumomab (MT103) in Patients With Relapsed NHL	NCT00274742	Non-Hodgkin's L...	Blinatumomab (M...	18 Years -	Amgen Research (Munich) GmbH

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