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

Primary Purpose

B-ALL

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Blinatumomab
Sponsored by
Amgen Research (Munich) GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-ALL focused on measuring Blinatumomab, B-ALL, adult ALL, relapsed ALL, refractory ALL, Leukemia, ALL, Lymphatic diseases, Lymphoproliferative disorders, bispecific antibody, anti-CD19, Immunotherapeutic treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with B-precursor ALL relapsed after at least induction and consolidation or having refractory disease
  • More than 5% blasts in bone marrow
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Life expectancy of ≥ 12 weeks

Exclusion Criteria:

  • History or presence of clinically relevant central nervous system (CNS) pathology
  • Infiltration of cerebrospinal fluid (CSF) by ALL
  • Autologous/allogeneic hematopoietic stem cell transplantation (HSCT) within six weeks/three months prior to start of blinatumomab treatment
  • Active Graft-versus-Host Disease (GvHD)
  • Patients with Philadelphia chromosome (Ph)+ ALL eligible for treatment with dasatinib or imatinib
  • Cancer chemotherapy within two weeks prior to start of blinatumomab treatment
  • Immunotherapy (e.g. rituximab) within four weeks prior to start of blinatumomab treatment
  • Infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive)
  • Pregnant or nursing women
  • Previous treatment with blinatumomab

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Blinatumomab 15 μg

Blinatumomab 5/15 μg

Blinatumomab 5/15/30 μg

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment
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
Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
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.
Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment
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%
Percentage of Participants With a Minimal Residual Disease (MRD) Response During the Core Study
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.
Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) After Treatment With Blinatumomab
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
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
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
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.
Number of Participants With Treatment-emergent Adverse Events
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.
Steady State Blinatumomab Concentration
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 of Blinatumomab
Clearance was calculated as R0/Css; where R0 is the infusion rate (μg/m^2/hr) and Css is the steady state concentration.
Serum Cytokine Peak Levels
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.

Full Information

First Posted
September 23, 2010
Last Updated
January 23, 2017
Sponsor
Amgen Research (Munich) GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT01209286
Brief Title
Study of the BiTE® Blinatumomab (MT103) in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2016
Overall Recruitment Status
Completed
Study Start Date
October 2010 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
October 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amgen Research (Munich) GmbH

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-ALL
Keywords
Blinatumomab, B-ALL, adult ALL, relapsed ALL, refractory ALL, Leukemia, ALL, Lymphatic diseases, Lymphoproliferative disorders, bispecific antibody, anti-CD19, Immunotherapeutic treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Blinatumomab 15 μg
Arm Type
Experimental
Arm Description
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.
Arm Title
Blinatumomab 5/15 μg
Arm Type
Experimental
Arm Description
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.
Arm Title
Blinatumomab 5/15/30 μg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Blinatumomab
Other Intervention Name(s)
AMG103, MT103, BLINCYTO™
Intervention Description
Continuous intravenous infusion over four weeks per treatment cycle
Primary Outcome Measure Information:
Title
Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
Description
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.
Time Frame
Within the first 2 cycles of treatment, 12 weeks
Secondary Outcome Measure Information:
Title
Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment
Description
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
Time Frame
Within the first 2 cycles of treatment, 12 weeks
Title
Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
Description
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.
Time Frame
Within the first 2 cycles of treatment, 12 weeks
Title
Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment
Description
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%
Time Frame
Within the first 2 cycles of treatment, 12 weeks
Title
Percentage of Participants With a Minimal Residual Disease (MRD) Response During the Core Study
Description
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.
Time Frame
During the core study treatment period (up to 30 weeks).
Title
Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) After Treatment With Blinatumomab
Description
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 Frame
Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days
Title
Time to Hematological Relapse
Description
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.
Time Frame
Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days.
Title
Relapse-free Survival
Description
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.
Time Frame
Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days.
Title
Overall Survival
Description
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.
Time Frame
Up to the data cut-off date of 15 October 2012; maximum follow up time was 667 days.
Title
Number of Participants With Treatment-emergent Adverse Events
Description
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.
Time Frame
From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle; median treatment duration was 55.7 days.
Title
Steady State Blinatumomab Concentration
Description
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.
Time Frame
Samples were collected at predose and at 48 hours following start of infusion, when dose is escalated and on Days 8, 15, 22, and 29 of the first 2 cycles.
Title
Clearance of Blinatumomab
Description
Clearance was calculated as R0/Css; where R0 is the infusion rate (μg/m^2/hr) and Css is the steady state concentration.
Time Frame
Samples were collected at predose and at 48 hours following start of infusion, when dose is escalated and on Days 8, 15, 22, and 29 of the first 2 cycles.
Title
Serum Cytokine Peak Levels
Description
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.
Time Frame
Samples were collected prior to treatment start (baseline), and at 2, 6, 24, and 48 hours after drug infusion start, and at these same time points when dose is escalated in each treatment cycle.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with B-precursor ALL relapsed after at least induction and consolidation or having refractory disease More than 5% blasts in bone marrow Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Life expectancy of ≥ 12 weeks Exclusion Criteria: History or presence of clinically relevant central nervous system (CNS) pathology Infiltration of cerebrospinal fluid (CSF) by ALL Autologous/allogeneic hematopoietic stem cell transplantation (HSCT) within six weeks/three months prior to start of blinatumomab treatment Active Graft-versus-Host Disease (GvHD) Patients with Philadelphia chromosome (Ph)+ ALL eligible for treatment with dasatinib or imatinib Cancer chemotherapy within two weeks prior to start of blinatumomab treatment Immunotherapy (e.g. rituximab) within four weeks prior to start of blinatumomab treatment Infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive) Pregnant or nursing women Previous treatment with blinatumomab
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Max Topp, MD
Organizational Affiliation
University of Wuerzburg
Official's Role
Principal Investigator
Facility Information:
City
Frankfurt
Country
Germany
City
Freiburg
Country
Germany
City
Hannover
Country
Germany
City
Kiel
Country
Germany
City
Münster
Country
Germany
City
Regensburg
Country
Germany
City
Tübingen
Country
Germany
City
Ulm
Country
Germany
City
Würzburg
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
28533941
Citation
Nagele V, Kratzer A, Zugmaier G, Holland C, Hijazi Y, Topp MS, Gokbuget N, Baeuerle PA, Kufer P, Wolf A, Klinger M. Changes in clinical laboratory parameters and pharmacodynamic markers in response to blinatumomab treatment of patients with relapsed/refractory ALL. Exp Hematol Oncol. 2017 May 18;6:14. doi: 10.1186/s40164-017-0074-5. eCollection 2017.
Results Reference
derived
PubMed Identifier
27209293
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.
Results Reference
derived
PubMed Identifier
25385737
Citation
Topp MS, Gokbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Bruggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014 Dec 20;32(36):4134-40. doi: 10.1200/JCO.2014.56.3247. Epub 2014 Nov 10.
Results Reference
derived

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

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