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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Amgen Research (Munich) GmbH
ClinicalTrials.gov Identifier:
NCT01209286
First received: September 23, 2010
Last updated: December 23, 2014
Last verified: December 2014
  Purpose

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.


Condition Intervention Phase
B-ALL
Biological: Blinatumomab
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


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

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 [ Time Frame: Within the first 2 cycles of treatment, 12 weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Within the first 2 cycles of treatment, 12 weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Within the first 2 cycles of treatment, 12 weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Within the first 2 cycles of treatment, 12 weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: During the core study treatment period (up to 30 weeks). ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days ] [ Designated as safety issue: No ]
    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 Frame: Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days. ] [ Designated as safety issue: No ]

    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 [ Time Frame: Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days. ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to the data cut-off date of 15 October 2012; maximum follow up time was 667 days. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: Yes ]

    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 [ 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. ] [ Designated as safety issue: No ]

    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 [ 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. ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    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.


Enrollment: 36
Study Start Date: October 2010
Estimated Study Completion Date: December 2016
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Blinatumomab 15 μg
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.
Biological: Blinatumomab
Continuous intravenous infusion over four weeks per treatment cycle
Other Names:
  • AMG103
  • MT103
  • BLINCYTO™
Experimental: Blinatumomab 5/15 μg
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.
Biological: Blinatumomab
Continuous intravenous infusion over four weeks per treatment cycle
Other Names:
  • AMG103
  • MT103
  • BLINCYTO™
Experimental: Blinatumomab 5/15/30 μg
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.
Biological: Blinatumomab
Continuous intravenous infusion over four weeks per treatment cycle
Other Names:
  • AMG103
  • MT103
  • BLINCYTO™

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT01209286

Locations
Germany
Frankfurt, Germany
Freiburg, Germany
Hannover, Germany
Kiel, Germany
Münster, Germany
Regensburg, Germany
Tübingen, Germany
Ulm, Germany
Würzburg, Germany
Sponsors and Collaborators
Amgen Research (Munich) GmbH
Investigators
Principal Investigator: Max Topp, MD Universität Würzburg
  More Information

No publications provided by Amgen Research (Munich) GmbH

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Amgen Research (Munich) GmbH
ClinicalTrials.gov Identifier: NCT01209286     History of Changes
Other Study ID Numbers: MT103-206
Study First Received: September 23, 2010
Results First Received: December 23, 2014
Last Updated: December 23, 2014
Health Authority: Germany: Paul-Ehrlich-Institut

Keywords provided by Amgen Research (Munich) GmbH:
Blinatumomab
B-ALL
adult ALL
relapsed ALL
refractory ALL
Leukemia
ALL
Lymphatic diseases
Lymphoproliferative disorders
bispecific antibody
anti-CD19
Immunotherapeutic treatment

Additional relevant MeSH terms:
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Leukemia
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Antibodies, Bispecific
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 01, 2015