Clinical Study With Blinatumomab in Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

NCT ID: NCT01466179

Last Updated: 2017-08-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 225 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-12-31
• Study Completion Date: 2017-01-31

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).

Conditions

Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Blinatumomab

Intervention Type: BIOLOGICAL

Continuous intravenous infusion over four weeks per treatment cycle

Interventions

Blinatumomab

Continuous intravenous infusion over four weeks per treatment cycle

Intervention Type: BIOLOGICAL

Other Intervention Names

AMG103; MT103; BLINCYTO™

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen Research (Munich) GmbH

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicola Gökbuget, MD

Role: PRINCIPAL_INVESTIGATOR

Klinikum der Goethe Universität Frankfurt

Max Topp, MD

Role: PRINCIPAL_INVESTIGATOR

Julius-Maximilians-Universität, Medizinische Klinik und Poliklinik II, Würzburg

Hagop Kantarjian, MD

Role: PRINCIPAL_INVESTIGATOR

MD Anderson Cancer Center, Houston, Texas

Locations

City of Hope

Duarte, California, United States

University of California Los Angeles

Los Angeles, California, United States

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States

Rush University Medical Center

Chicago, Illinois, United States

University of Chicago

Chicago, Illinois, United States

Dana Farber Institute

Boston, Massachusetts, United States

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Roswell Park Cancer Streets

Buffalo, New York, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

CHU d'Angers

Angers, , France

Hôpital de l'hôtel Dieu

Nantes, , France

Hôpital Saint Louis

Paris, , France

CHU de Purpan

Toulouse, , France

Charité - Campus Benjamin Franklin

Berlin, , Germany

Klinikum der Goethe Universität, Medizinische Klinik II

Frankfurt, , Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Universitätsklinikum Schleswig-Holstein

Kiel, , Germany

Universitätsklinikum Münster

Münster, , Germany

Universitätsklinikum Tübingen

Tübingen, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Julius-Maximilians-Universität, Medizinische Klinik und Poliklinik II

Würzburg, , Germany

Ospedali Riuniti di Bergamo

Bergamo, , Italy

Azienda Ospedaliera Antonio Cardarelli

Naples, , Italy

Ospedali Riuniti "Villa Sofia-Cervello"

Palermo, , Italy

Università La Sapienza di Roma

Rome, , Italy

Azienda Ospedaliero-Universitaria

Turin, , Italy

Azienda Ospedaliera di Verona

Verona, , Italy

ICO Hospital Germans Trias I Pujol

Badalona, , Spain

Hospital Clínic Servei d´Hematologia

Barcelona, , Spain

Hospital 12 de Octubre

Madrid, , Spain

Hospital universitario de Salamanca

Salamanca, , Spain

Hospital Universitario Virgen Del Rocio

Seville, , Spain

University Hospitals Bristol NHS

Bristol, , United Kingdom

Royal Free Hampstead NHS Trust

London, , United Kingdom

The Christie NHS Foundation Trust

Manchester, , United Kingdom

Countries

United States; France; Germany; Italy; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 35622074 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31648325 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28922466 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27873237 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27209293 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25524800 (View on PubMed)

Other Identifiers

2011-002257-61

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MT103-211

Identifier Type: -

Identifier Source: org_study_id