Comment Period Extended to 3/23/2015 for Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Clinical Study With Blinatumomab in 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:
NCT01466179
First received: October 28, 2011
Last updated: January 20, 2015
Last verified: January 2015
  Purpose

The purpose of this study is to confirm whether the bispecific T cell engager antibody blinatumomab (MT103) is effective and safe in the treatment of patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL).


Condition Intervention Phase
Acute Lymphoblastic Leukemia
Biological: 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, Phase II Study to Evaluate Efficacy and Safety 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 ]

    Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory.

    Hematological remissions were defined by the following criteria:

    Complete Remission (CR):

    • bone marrow blasts ≤ 5%
    • no evidence of disease
    • full recovery of peripheral blood counts:

      • platelets > 100,000/μL, and
      • absolute neutrophil count (ANC) > 1,000/μL

    Complete Remission With Partial Hematological Recovery (CRh*):

    • bone marrow blasts ≤ 5%
    • no evidence of disease
    • partial recovery of peripheral blood counts:

      • platelets > 50,000/μL, and
      • ANC > 500/μL.


Secondary Outcome Measures:
  • Time to Hematological Relapse (Duration of Response) [ Time Frame: Up to the data cut-off date of 10 October 2013; median observation time was 8.0 months. ] [ Designated as safety issue: No ]

    Time to hematological relapse was measured for participants in remission during the core study (the time from the first infusion through 30 days after the last infusion), from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without 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 date of death.

    Hematological relapse is defined as:

    • proportion of blasts in bone marrow > 5% after documented CR/CRh* or
    • blasts in peripheral blood after documented CR/CRh*.

    Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.


  • Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission [ Time Frame: Up to the data cut-off date of 10 October 2013. Maximum duration on study was 17.8 months. ] [ Designated as safety issue: No ]
    Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT.

  • 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 ]

    Complete Remission was defined by the following criteria:

    • bone marrow blasts ≤ 5%
    • no evidence of disease
    • full recovery of peripheral blood counts:

      • platelets > 100,000/μL, and
      • absolute neutrophil count (ANC) > 1,000/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 ]

    Complete Remission With Partial Hematological Recovery was defined by the following criteria:

    • bone marrow blasts ≤ 5%
    • no evidence of disease
    • partial recovery of peripheral blood counts:

      • platelets > 50,000/μL, and
      • 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 ]
    Partial Remission is defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline.

  • Relapse-free Survival [ Time Frame: Up to the data cut-off date of 10 October 2013; median observation time was 8.9 months. ] [ Designated as safety issue: No ]

    Relapse-free survival was assessed for participants who achieved a complete remission or complete remission with partial hematological recovery 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 and the median observation time was calculated by the reverse Kaplan Meier method.


  • Event-free Survival [ Time Frame: Up to the data cut-off date of 10 October 2013; median observation time was 9.8 months. ] [ Designated as safety issue: No ]

    Event-free survival was calculated from the start date of blinatumomab infusion until the date of bone marrow aspiration at which hematological relapse was first detected, or the date of diagnosis on which the hematological or extramedullary relapse was documented or the date of start of any new therapy for ALL (excluding HSCT), or the date of death, whichever was earlier. Participants who did not achieve complete remission or complete remission with partial hematological recovery during the core study were evaluated as having an event on Day 1. Participants in remission who did not experience hematological relapse, did not receive a new therapy for ALL (excluding HSCT), and did not die were censored on the date of the last available bone marrow aspiration or on the last date of survival follow-up visit, whichever was later.

    Event free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.


  • Overall Survival [ Time Frame: Up to the data cut-off date of 10 October 2013; median observation time was 9.8 months. ] [ Designated as safety issue: No ]
    Overall survival was measured for all participants from the time the participant received the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die 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. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan Meier method.

  • 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 42.2 days. ] [ Designated as safety issue: Yes ]

    Adverse events (AEs) were evaluated for severity according to the the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4, as follows: 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.

    An AE was considered "serious" if it resulted in death, was life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant incapacity or substantial disruption to conduct normal life functions, is a congenital anomaly or birth defect or is a medically important condition.

    Progressive disease was not an adverse event, per the protocol, unless it was more severe than expected for the patient. Therefore, many deaths due to progressive disease were not counted as adverse events.


  • 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant [ Time Frame: From the date of allogeneic HSCT until the data cut-off date of 10 October 2013; median observation time was 7.4 months. ] [ Designated as safety issue: Yes ]

    The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in remission (CR/CRh*) following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT.

    Patients 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.

    The 100-day mortality rate after allogeneic HSCT was defined as the percentage of patients having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods.


  • Serum Blinatumomab Concentration at Steady State [ Time Frame: Samples were taken before treatment start and on Days 3, 8, 10, 15, 22, and 29 after infusion start during Cycles 1 and 2. ] [ Designated as safety issue: No ]
    The steady state concentration of blinatumomab was summarized as the observed concentrations collected at least 10 hours after the start of the IV infusion or dose step for cycle 1 and cycle 2, respectively. Serum concentrations of blinatumomab were measured using a validated bioassay. The lower limit of quantitation (LLOQ) = 50.0 pg/mL.

  • Serum Cytokine Peak Levels [ Time Frame: Serum samples were collected on Days 1 and 8 at 2 hours and 6 hours after treatment start, and on Day 2 (24 hours) and Day 3 (48 hours) of each treatment cycle and on Days 9 and 10 after dose step. ] [ Designated as safety issue: Yes ]

    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-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using enzyme-linked immunosorbent assays or cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the limit of quantification (LOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data < LOQ and > LOD were reported as measured.

    Serum IL-4 levels were below detection limit (< 20 pg/mL) at all time points in all participants studied.


  • Percentage of Participants With a Best Response of Blast Free Hypoplastic or Aplastic Bone Marrow Within 2 Cycles of Treatment [ Time Frame: Within the first 2 cycles of treatment, 12 weeks ] [ Designated as safety issue: No ]

    Blast Free Hypoplastic or Aplastic Bone Marrow was defined as:

    • bone marrow blasts ≤ 5%
    • no evidence of disease
    • insufficient recovery of peripheral counts: platelets ≤ 50,000/μL and/or absolute neutrophil count (ANC) ≤ 500/μL

  • Best Response During the Core Study [ Time Frame: From the first dose of blinatumomab until 30 days after the end of the last infusion during the core study, or until the data cut-off date of 10 October 2013; a maximum of 7.5 months. ] [ Designated as safety issue: No ]

    Complete Remission (CR):

    • bone marrow blasts ≤ 5%
    • no evidence of disease
    • full recovery of peripheral blood counts:

      • platelets > 100,000/μL, and
      • absolute neutrophil count (ANC) > 1,000/μL

    Complete Remission With Partial Hematological Recovery (CRh*):

    • bone marrow blasts ≤ 5%
    • no evidence of disease
    • partial recovery of peripheral blood counts:

      • platelets > 50,000/μL, and
      • ANC > 500/μL

    Blast Free Hypoplastic or Aplastic Bone Marrow:

    • bone marrow blasts ≤ 5%
    • no evidence of disease
    • insufficient recovery of peripheral counts: platelets ≤ 50,000/μL and/or ANC ≤ 500/μL

    Partial Remission:

    • bone marrow blasts 6% to 25% with at least a 50% reduction from Baseline.



Enrollment: 225
Study Start Date: December 2011
Estimated Study Completion Date: June 2017
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Blinatumomab
Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 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. Several studies have reported long term survival to be below 10%. Major prognostic factors are duration of first complete remission (CR1) and age. With current salvage chemotherapy, complete remission (CR) rate is low (20 to 30%) in patients in first salvage with short duration (< one year) of first remission, patients relapsed after first salvage, or patients aged 60 years and older. Duration of CR is usually very short (median disease free survival [DFS]: 2.0-7.5 months). Allogeneic hematopoietic stem cell transplantation (HSCT) may provide a curative treatment option for patients in CR with a satisfactory donor and appropriate clinical status including age, organ function, and remission status. Allogeneic HSCT is not an option in most elderly patients with relapsed ALL. Additional therapeutic approaches are urgently needed.

Blinatumomab is a bispecific single-chain antibody derivative against CD (cluster of differentiation)19 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. In vitro data indicate CD19+ lymphoma and leukemia cell lines to be extremely sensitive to blinatumomab-mediated cytotoxicity. Blinatumomab has the potential to provide meaningful therapeutic benefits to patients compared with existing treatments for this patient population.

This study consists of a screening period, a treatment period and a follow-up period. Participants receive one to five treatment cycles of blinatumomab at a target dose of 28 μg/day. In the first cycle, the initial dose is 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.

Participants who achieve remission within two cycles of treatment can receive up to three additional cycles of consolidation treatment or proceed to allogeneic HSCT. In the event of progression or relapse within the treatment period, treatment will be terminated. Participants with hematological relapse during the efficacy or safety follow-up period may receive up to three additional cycles of blinatumomab (retreatment) for a maximal total of eight cycles at the investigator´s discretion.

Thirty days after end of the last treatment, participants have an end-of-core-study visit. Following this, there are efficacy follow-up visits at 3, 6, 9, 12, 18 and 24 months at the most after treatment start. Once efficacy follow-up is complete, information on survival collected at least every six months until death or at least until three years after treatment start, whichever occurs earlier (survival follow-up).

  Eligibility

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

Inclusion Criteria:

  • Patients with Philadelphia chromosome (Ph)-negative B-precursor ALL, with any of the following:

    • relapsed or refractory with first remission duration less than or equal to 12 months in first salvage or
    • relapsed or refractory after first salvage therapy or
    • relapsed or refractory within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT)
  • 10% or more blasts in bone marrow
  • In case of clinical signs of additional extramedullary disease: measurable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Age ≥ 18 years

Exclusion Criteria:

  • Patients with Ph-positive ALL
  • Patients with Burkitt's Leukemia according to World Health organization (WHO) classification
  • History or presence of clinically relevant central nervous system (CNS) pathology
  • Active ALL in the CNS or testes
  • Current autoimmune disease or history of autoimmune disease with potential CNS involvement
  • Autologous HSCT within six weeks prior to start of blinatumomab treatment
  • Allogeneic HSCT within three months prior to start of blinatumomab treatment
  • Any active acute graft versus-host disease (GvHD), or active chronic GvHD Grade 2 - 4
  • Any systemic therapy against GvHD within two weeks prior to start of blinatumomab treatment
  • Cancer chemotherapy within two weeks prior to start of blinatumomab treatment
  • Radiotherapy within two weeks prior to start of blinatumomab treatment
  • Immunotherapy (e.g., rituximab) within four weeks prior to start of blinatumomab treat-ment
  • Any investigational anti-leukemic product within four weeks prior to start of blinatumomab treatment
  • Treatment with any other investigational medicinal product (IMP) after signature of informed consent
  • Eligibility for allogeneic HSCT at the time of enrollment
  • Known hypersensitivity to immunoglobulins or to any other component of the IMP formulation
  • Abnormal laboratory values indicative of inadequate renal or liver function
  • History of malignancy requiring treatment other than ALL 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
  • Any concurrent disease or medical condition that is deemed to interfere with the conduct of the study
  • Infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus
  • Pregnant or nursing women
  • Women of childbearing potential not willing to use an effective form of contraception. Male patients not willing to ensure not to beget a child
  • 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: NCT01466179

  Hide Study Locations
Locations
United States, California
City of Hope
Duarte, California, United States, 91010-3000
University of California Los Angeles
Los Angeles, California, United States, 90095-1678
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
University of Chicago
Chicago, Illinois, United States, 60637
United States, Massachusetts
Dana Farber Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Roswell Park Cancer Streets
Buffalo, New York, United States, 14263
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
France
CHU d'Angers
Angers, France, 49933
Hôpital de l'hôtel Dieu
Nantes, France, 44000
Hôpital Saint Louis
Paris, France, 75475
CHU de Purpan
Toulouse, France, 31059
Germany
Charité - Campus Benjamin Franklin
Berlin, Germany, 12200
Klinikum der Goethe Universität, Medizinische Klinik II
Frankfurt, Germany, 60590
Universitätsklinikum Freiburg
Freiburg, Germany, 79106
Medizinische Hochschule Hannover
Hannover, Germany, 30625
Universitätsklinikum Schleswig-Holstein
Kiel, Germany, 24116
Universitätsklinikum Münster
Münster, Germany, 48149
Universitätsklinikum Tübingen
Tübingen, Germany, 72076
Universitätsklinikum Ulm
Ulm, Germany, 89081
Julius-Maximilians-Universität, Medizinische Klinik und Poliklinik II
Würzburg, Germany, 97080
Italy
Ospedali Riuniti di Bergamo
Bergamo, Italy, 24128
Azienda Ospedaliera Antonio Cardarelli
Naples, Italy, 80131
Ospedali Riuniti "Villa Sofia-Cervello"
Palermo, Italy, 90146
Università La Sapienza di Roma
Rome, Italy, 00161
Azienda Ospedaliero-Universitaria
Turin, Italy, 10126
Azienda Ospedaliera di Verona
Verona, Italy, 37134
Spain
ICO Hospital Germans Trias I Pujol
Badalona, Spain, 08916
Hospital Clínic Servei d´Hematologia
Barcelona, Spain, 08036
Hospital 12 de Octubre
Madrid, Spain, 28041
Hospital universitario de Salamanca
Salamanca, Spain, 37007
Hospital Universitario Virgen Del Rocio
Sevilla, Spain, 41013
United Kingdom
University Hospitals Bristol NHS
Bristol, United Kingdom, BS2 8ED
Royal Free Hampstead NHS Trust
London, United Kingdom, NW3 2QG
The Christie NHS Foundation Trust
Manchester, United Kingdom, M20 4BX
Sponsors and Collaborators
Amgen Research (Munich) GmbH
Investigators
Principal Investigator: Nicola Gökbuget, MD Klinikum der Goethe Universität Frankfurt
Principal Investigator: Max Topp, MD Julius-Maximilians-Universität, Medizinische Klinik und Poliklinik II, Würzburg
Principal Investigator: Hagop Kantarjian, MD MD Anderson Cancer Center, Houston, Texas
  More Information

No publications provided

Responsible Party: Amgen Research (Munich) GmbH
ClinicalTrials.gov Identifier: NCT01466179     History of Changes
Other Study ID Numbers: MT103-211, 2011-002257-61
Study First Received: October 28, 2011
Results First Received: December 21, 2014
Last Updated: January 20, 2015
Health Authority: United States: Food and Drug Administration
Germany: Paul-Ehrlich-Institut
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: Ethics Committee
Spain: Agencia Española de Medicamentos y Productos Sanitarios
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Amgen Research (Munich) GmbH:
B-ALL
relapsed ALL
refractory ALL
adult ALL
Leukemia
Leukemia, Lymphoid
precursor cell lymphoblastic leukemia-lymphoma
Lymphatic diseases
Lymphoproliferative disorders
bispecific antibody
anti-CD19
Immunotherapeutic treatment
immunoproliferative disorders

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on March 02, 2015