Clinical trial NCT01466179: Clinical Study With Blinatumomab in Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Keywords: 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
Lead sponsor: Amgen Research (Munich) GmbH
Sponsor class: INDUSTRY
First posted: 2011-11-06
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).

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 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

Primary outcomes:
measure: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
timeFrame: Within the first 2 cycles of treatment, 12 weeks
Secondary outcomes:
measure: Time to Hematological Relapse (Duration of Response)
timeFrame: Up to the data cut-off date of 10 October 2013; median observation time was 8.0 months.
measure: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission
timeFrame: Up to the data cut-off date of 10 October 2013. Maximum duration on study was 17.8 months.
measure: Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment
timeFrame: Within the first 2 cycles of treatment, 12 weeks
measure: Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
timeFrame: Within the first 2 cycles of treatment, 12 weeks
measure: Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment
timeFrame: Within the first 2 cycles of treatment, 12 weeks
measure: Relapse-free Survival
timeFrame: Up to the data cut-off date of 10 October 2013; median observation time was 8.9 months.
measure: Event-free Survival
timeFrame: Up to the data cut-off date of 10 October 2013; median observation time was 9.8 months.
measure: Overall Survival
timeFrame: Up to the data cut-off date of 10 October 2013; median observation time was 9.8 months.
measure: Number of Participants With Treatment-emergent Adverse Events
timeFrame: 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.
measure: 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant
timeFrame: From the date of allogeneic HSCT until the data cut-off date of 10 October 2013; median observation time was 7.4 months.
measure: Serum Blinatumomab Concentration at Steady State
timeFrame: Samples were taken before treatment start and on Days 3, 8, 10, 15, 22, and 29 after infusion start during Cycles 1 and 2.
measure: Serum Cytokine Peak Levels
timeFrame: 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.
measure: Percentage of Participants With a Best Response of Blast Free Hypoplastic or Aplastic Bone Marrow Within 2 Cycles of Treatment
timeFrame: Within the first 2 cycles of treatment, 12 weeks
measure: Best Response During the Core Study
timeFrame: 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.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Dana Farber Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Streets
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Angers
country: France
facility: CHU d'Angers
city: Nantes
country: France
facility: Hôpital de l'hôtel Dieu
city: Paris
country: France
facility: Hôpital Saint Louis
city: Toulouse
country: France
facility: CHU de Purpan
city: Berlin
country: Germany
facility: Charité - Campus Benjamin Franklin
city: Frankfurt
country: Germany
facility: Klinikum der Goethe Universität, Medizinische Klinik II
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Würzburg
country: Germany
facility: Julius-Maximilians-Universität, Medizinische Klinik und Poliklinik II
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Naples
country: Italy
facility: Azienda Ospedaliera Antonio Cardarelli
city: Palermo
country: Italy
facility: Ospedali Riuniti "Villa Sofia-Cervello"
city: Rome
country: Italy
facility: Università La Sapienza di Roma
city: Turin
country: Italy
facility: Azienda Ospedaliero-Universitaria
city: Verona
country: Italy
facility: Azienda Ospedaliera di Verona
city: Badalona
country: Spain
facility: ICO Hospital Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hospital Clínic Servei d´Hematologia
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Salamanca
country: Spain
facility: Hospital universitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Del Rocio
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS
city: London
country: United Kingdom
facility: Royal Free Hampstead NHS Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Klinikum der Goethe Universität Frankfurt
name: Nicola Gökbuget, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Julius-Maximilians-Universität, Medizinische Klinik und Poliklinik II, Würzburg
name: Max Topp, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MD Anderson Cancer Center, Houston, Texas
name: Hagop Kantarjian, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shi Z, Zhu Y, Zhang J, Chen B. Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia. Hematology. 2022 Dec;27(1):642-652. doi: 10.1080/16078454.2022.2074704.
citation: Gokbuget N, Kantarjian HM, Bruggemann M, Stein AS, Bargou RC, Dombret H, Fielding AK, Heffner L, Rigal-Huguet F, Litzow M, O'Brien S, Zugmaier G, Gao S, Nagorsen D, Forman SJ, Topp MS. Molecular response with blinatumomab in relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Adv. 2019 Oct 22;3(20):3033-3037. doi: 10.1182/bloodadvances.2019000457.
citation: Zhu M, Kratzer A, Johnson J, Holland C, Brandl C, Singh I, Wolf A, Doshi S. Blinatumomab Pharmacodynamics and Exposure-Response Relationships in Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Pharmacol. 2018 Feb;58(2):168-179. doi: 10.1002/jcph.1006. Epub 2017 Sep 18.
citation: Barlev A, Lin VW, Katz A, Hu K, Cong Z, Barber B. Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data. Adv Ther. 2017 Jan;34(1):148-155. doi: 10.1007/s12325-016-0447-x. Epub 2016 Nov 21.
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.
citation: Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foa R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Bruggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. doi: 10.1016/S1470-2045(14)71170-2. Epub 2014 Dec 16. Erratum In: Lancet Oncol. 2015 Apr;16(4):e158. doi: 10.1016/S1470-2045(15)70154-3.