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

Participants received blinatumomab 15 μg/m²/day as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, followed by 15 μg/m²/day starting from Week 2 of treatment.

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, a dose of 15 μg/m²/day in the subsequent 7 days, followed by 30 μg/m²/day starting from Week 3 of treatment.

Continuous intravenous infusion over four weeks per treatment cycle

Max Topp, MD

The purpose of this study is to determine whether the bispecific T-cell engager blinatumomab is effective, safe and tolerable in the treatment of patients with relapsed/refractory B-precursor ALL.

Relapsed/refractory B-precursor ALL in adult patients is an aggressive malignant disease with dismal prognosis and unmet medical need. Additional therapeutic approaches are urgently needed. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. The purpose of this study is to investigate the efficacy, safety and tolerability of different doses of the bispecific T-cell engager blinatumomab in adult patients with relapsed/refractory B-precursor ALL. Patrticipants will receive up to five 4-week cycles of intravenous blinatumomab treatment.

Study of the BiTE® Blinatumomab (MT103) in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

An Open Label, Multicenter, Exploratory Phase II Study to Evaluate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab in Adult Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria:

Complete Response/Remission (CR):

* Less than or equal to 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullar disease
* Full recovery of peripheral blood counts:

  * Platelets \> 100,000/μL
  * Hemoglobin ≥ 11 g/dL
  * Absolute neutrophil count (ANC) \> 1,500/μL

Complete Remission with only Partial Hematological Recovery (CRh\*):

* Less than or equal to 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullar disease
* Partial recovery of peripheral blood counts:

  * Platelets \> 50,000/μL
  * Hemoglobin ≥ 7 g/dL
  * ANC \> 500/μL.

At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Complete Response/Remission (CR) was defined by the following criteria:

* Less than or equal to 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullar disease
* Full recovery of peripheral blood counts:

  * Platelets \> 100,000/μL
  * Hemoglobin ≥ 11 g/dL
  * Absolute neutrophil count (ANC) \> 1,500/μL

At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Complete remission with only partial hematological recovery (CRh\*) was defined by the following criteria:

* Less than or equal to 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullar disease
* Partial recovery of peripheral blood counts:

  * Platelets \> 50,000/μL
  * Hemoglobin ≥ 7 g/dL
  * ANC \> 500/μL.

At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Partial remission was defined by the following criteria:

• Bone marrow blasts ≤ 25%

A minimal residual disease (MRD) response is defined as MRD \< 10\^-4 blasts/nucleated cells based on polymerase chain reaction (PCR) evaluation of individual rearrangements of immunoglobulin or T cell receptor genes.

The percentage of participants who underwent immediate allogeneic HSCT (defined as those in remission who undergo HSCT without receiving any other treatments) after having discontinued or completed the core study.

Time to hematological relapse was measured for participants who achieved a CR or CRh\* during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their day of death.

Hematological Relapse was defined as:

* Proportion of blasts in bone marrow \> 5%
* Extramedullary relapse.

Time to hematological relapse was analyzed by Kaplan-Meier methods.

Relapse-free survival was measured only for participants who achieved a CR or CRh\* during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse-free survival was estimated using Kaplan-Meier methods.

Overall survival was measured for all participants from the date of first infusion of blinatumomab until the date of death due to any cause. Participants who did not die were censored on the last documented visit date. Overall survival was estimated using Kaplan-Meier methods.

Adverse events were evaluated for severity according to the grading scale provided in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 and according to the following:

Grade I (mild); Grade 2 (moderate); Grade 3 (severe - significantly limits the patient's ability to perform routine activities despite symptomatic therapy; Grade 4 (life-threatening); Grade 5 (death).

The investigator used medical judgment to determine if there was a causal relationship (ie, certain, probable, possible, unlikely, not related) between an adverse event and blinatumomab.

A serious adverse event is any untoward medical occurrence or effect, that at any dose:

resulted in death, was life-threatening, required or prolonged hospitalization, resulted in persistent or significant disability or incapacity, is a congenital anomaly or birth defect or is a medically important condition.

The steady state concentration of blinatumomab was summarized as the observed concentrations collected at least 10 hours after the intravenous infusion was started for cycle 1 and cycle 2, respectively. Actual doses administered were used in the analysis.

Concentrations below the limit of detection (3 pg/mL) were set to zero before data analysis and concentrations below the lower limit of quantitation (50 pg/mL) were excluded from analysis.

Clearance was calculated as R0/Css; where R0 is the infusion rate (μg/m\^2/hr) and Css is the steady state concentration.

The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) is 125 pg/mL and the limit of detection (LOD) is 20 pg/mL.

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

Blinatumomab 15 μg

Blinatumomab 5/15 μg

Blinatumomab 5/15/30 μg

All participants who received blinatumomab by continuous intravenous infusion during the core study.

Blinatumomab Overall

Total

Race (NIH/OMB)

Number of Prior Relapses

Primary Refractory

Relapsed

Relapsed / refractory Status

Yes, Sibling

Yes, Unrelated

Yes, Haploidentical (mother/father)

No prior allogeneic HSCT

Prior Allogeneic Hematopoietic Stem cell Transplantation (HSCT)

Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.

Full analysis set (FAS), defined as participants who received any infusion of the assigned study medication, who completed at least the first treatment cycle and for whom at least one response assessment was available after the start of treatment.

Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

ABlinatumomab 5/15/30 μg

Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment

Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment

Percentage of Participants With a Minimal Residual Disease (MRD) Response During the Core Study

Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) After Treatment With Blinatumomab

Blinatumimab Overall

Participants who reached complete remission or complete remission with partial hematological recovery during the core study.

Relapse-free Survival

Overall Survival

Any adverse event (AE)

Serious adverse events

Serious adverse events of at least CTC grade 3

Serious related adverse events

AEs leading to interruption of blinatumomab

Safety analysis set, defined as all participants who received any infusion of blinatumomab.

Number of Participants With Treatment-emergent Adverse Events

Participants receiving blinatumomab 5 μg/m²/day.

Blinatumomab 5 μg

Participants receiving blinatumomab 15 μg/m²/day.

Participants receiving blinatumomab 30 μg/m²/day.

Blinatumomab 30 μg

Participants who received blinatumomab and who had available pharmacokinetic data.

Steady State Blinatumomab Concentration

All participants who received blinatumomab.

IL-6: Cycle 1 (N=35)

IL-6: Cycle 2 (N=22)

IL-6: Cycle 3 (N=11)

IL-10: Cycle 1 (N=35)

IL-10: Cycle 2 (N=22)

IL-10: Cycle 3 (N=11)

IFN-Ɣ: Cycle 1 (N=35)

IFN-Ɣ: Cycle 2 (N=22)

IFN-Ɣ: Cycle 3 (N=11)

IL-2: Cycle 1 (N=35)

IL-2: Cycle 2 (N=22)

IL-2: Cycle 3 (N=11)

TNF-α: Cycle 1 (N=35)

TNF-α: Cycle 2 (N=22)

TNF-α: Cycle 3 (N=11)

Participants who received blinatumomab and who had evaluable pharmacodynamic 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
Study of the BiTE® Blinatumomab (MT103) in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)	NCT01209286	B-ALL	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
Clinical Study With Blinatumomab in Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)	NCT01466179	Acute Lymphobla...	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
Clinical Study With Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)	NCT01741792	Diffuse Large B...	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
Study of the BiTE® Blinatumomab (MT103) in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)	NCT01209286	B-ALL	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
Clinical Study With Blinatumomab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)	NCT01741792	Diffuse Large B...	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
Confirmatory Phase II Study of Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL)	NCT01207388	B-cell Acute Ly...	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH

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