Confirmatory Phase II Study of Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL)

B-cell Acute Lymphoblastic Leukemia Clinical Trial

— BLAST  

Official title:

A Confirmatory Multicenter, Single-arm Study to Assess the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (BLAST)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01207388
• Other study ID #: MT103-203
• Status: Completed
• Phase: Phase 2
• Start date: November 2010
• Est. completion date: January 7, 2019

Study information

• Verified date: January 2020
• Source: Amgen Research (Munich) GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to confirm whether the bispecific T cell engager blinatumomab (MT103) is effective, safe and tolerable in the treatment of ALL patients with minimal residual disease.

Description:

The detection of minimal residual disease (MRD) after induction therapy and/or consolidation therapy is an independent prognostic factor for poor outcome of adult ALL. No standard treatments are available for patients with MRD-positive B-precursor ALL. Blinatumomab (MT103) 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 cluster of differentiation (CD)19 expressing cells. The purpose of this study is to confirm whether the bispecific T-cell engager blinatumomab (MT103) is effective, safe and tolerable in the treatment of ALL patients with minimal residual disease.

Participants will receive up to four 4-week cycles of intravenous blinatumomab treatment followed by an infusion-free period of 14 days. A safety follow-up will be performed 30 days after the end of the last infusion and efficacy follow-ups will occur until 24 months after treatment start. Participants will be followed for up to 5 years after the start of treatment for survival.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 116
• Est. completion date: January 7, 2019
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with B-precursor ALL in complete hematological remission after at least 3 intense chemotherapy blocks

• Presence of minimal residual disease at a level of = 10^-3

• Availability of bone marrow specimen from primary diagnosis for clone-specific MRD assessment

• Negative human immunodeficiency virus (HIV) test, negative hepatitis B (HbsAg) test and hepatitis C virus (anti-HCV) test

• Negative pregnancy test in women of childbearing potential

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion Criteria:

• Presence of circulating blasts or current extra-medullary involvement by ALL

• History of relevant central nervous system (CNS) pathology or current CNS pathology

• Prior allogeneic hematopoietic stem cell transplant (HSCT)

• Eligibility for treatment with tyrosine-kinase inhibitors (TKI)

• Systemic cancer chemotherapy within 2 weeks prior to study treatment

• Therapy with monoclonal antibodies (rituximab, alemtuzumab) within 4 weeks prior to study treatment

• Previous treatment with blinatumomab

Related Conditions & MeSH terms

• B-cell Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Neoplasm, Residual
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Blinatumomab
Continuous intravenous infusion

Locations

Country	Name	City	State
Austria	1102 - LKH Graz	Graz
Austria	1107 - Krankenhaus der Elisabethinen	Linz
Austria	1106	Salzburg
Austria	1101 - AKH Wien	Vienna
Belgium	1504	Antwerpen
Belgium	1505	Brügge
Belgium	1502 - Cliniques Universitaires de Saint-Luc	Brussels
Belgium	1503	Gent
Belgium	1501 - Cliniques Universitaires UCL de Mont Godinne	Yvoir
France	1211 - CHU d'Angers	Angers
France	1210 - CHU de Besançon	Besançon
France	1206 - Hôpital de Pontoise	Cergy Pontoise
France	1205 - CHU Henri Mondor	Créteil
France	1209 - CHU de Lyon	Lyon
France	1212 - Hôpital de l'hôtel Dieu	Nantes
France	1213 - Centre Hospitalier Universitaire de Nice	Nice
France	1201 - Hôpital Saint Louis	Paris
France	1202 - CHU de Bordeaux - Hôpital Haut Lévêque	Pessac
France	1208 - CHU de Purpan	Toulouse
Germany	1011 - Charité Berlin	Berlin
Germany	1022 - Universitätsklinkum Carl Gustav Carus Dresden	Dresden
Germany	1009 - Universitätsklinikum Essen	Essen
Germany	1002 - Klinikum der Goethe Universität	Frankfurt
Germany	1014 - Asklepiosklinik St. Georg	Hamburg
Germany	1018 - Medizinische Hochschule Hannover	Hannover
Germany	1012 - Universitätsklinikum Heidelberg	Heidelberg
Germany	1003 - Universitätsklinikum Schleswig-Holstein	Kiel
Germany	1019 - Universitätsklinikum Leipzig	Leipzig
Germany	1010 - Klinikum der Universität München - Großhadern	Munich
Germany	1004 - Universitätsklinikum Münster	Münster
Germany	1016 - Universitätsklinikum Regensburg	Regensburg
Germany	1020 - Universitätsklinikum Rostock	Rostock
Germany	1007 - Robert-Bosch-Krankenhaus	Stuttgart
Germany	1015 - Universitätsklinikum Tübingen	Tübingen
Germany	1005 - Universitätsklinikum Ulm	Ulm
Germany	1001 - Julius-Maximilians-Universität Würzburg	Würzburg
Italy	1301 - Ospedali Riuniti di Bergamo	Bergamo
Italy	1303 - Istituto di Ematologia "L.& A.Seràgnoli" Azienda	Bologna
Italy	1314 - Azienda Ospedaliera Spedali Civili Brescia	Brescia
Italy	1313 - Universita di Catania	Catania
Italy	1312 - Azienda Ospedaliera Universitaria San Martino	Genoa
Italy	1305 - Ospedale San Gerardo	Monza
Italy	1309 - Azienda Ospedaliera Antonio Cardarelli	Napoli
Italy	1308 - Ospedali Riuniti "Villa Sofia-Cervello"	Palermo
Italy	1302 - Università La Sapienza di Roma	Rome
Italy	1310 - Fondazione Policlinico Tor Vergata	Rome
Italy	1315 - Azienda Ospedaliero-Universitaria S. Giovanni Battista (Le Molinette)	Torino
Italy	1311 - Azienda Ospedaliera di Verona	Verona
Netherlands	2204 - UMC Groningen	Groningen
Netherlands	2201 - Daniel Den Hoed Hospitaal	Rotterdam
Poland	1905 - Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok
Poland	1907 - Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	1908 - Swietokrzyskie Centrum Onkologii	Kielce
Poland	1902 - Uniwersytet Medyczny w Lublinie	Lublin
Poland	1901 - Klinika Hematologii - Instytut Hematologii i Transfuzjologii	Warsaw
Poland	1906 - MTZ Clinical Research Sp. z o.o.	Warsaw
Poland	1904 - Samodzielny Publiczny	Wroclaw
Romania	2101 - Institutul Clinic Fundeni, Hematologie II	Bucharest
Romania	2102 - Spitalul Clinic Coltea, Hematologie	Bucharest
Romania	2106 - Institutul Oncologic "Prof. Dr. I. Chiricuta"	Cluj-Napoca
Romania	2105 - Institutul Regional de Oncologie	Iasi
Russian Federation	2001 - Russian Hematology Research Center	Moscow
Russian Federation	2003 - Municipal Hospital No. 15	St. Petersburg
Spain	1401 - ICO Hospital Germans Trias I Pujol	Badalona
Spain	1404 - Hospital Clínic Servei d´Hematologia	Barcelona
Spain	1402 - Complexo Hospitalario Universitario A Coruña	La Coruña
Spain	1408 - Hospital 12 de Octubre	Madrid
Spain	1405 - Hospital Universitari Son Espases	Mallorca
Spain	1407 - Unidad de Citogenética Oncológica	Salamanca
Spain	1406 - Hospital Universitari i Politècnic La Fe de Valencia	Valencia
United Kingdom	1605 - Queen Elizabeth Hospital	Birmingham
United Kingdom	1602 - Bristol Royal Infirmary	Bristol
United Kingdom	1604 - University Hospital of Wales	Cardiff
United Kingdom	1601 - Royal Free Hospital	London
United Kingdom	1607 - Nottingham City Hospital NHS Trust	Nottingham

Sponsors (1)

Lead Sponsor	Collaborator
Amgen Research (Munich) GmbH

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Germany,  Italy,  Netherlands,  Poland,  Romania,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With a Minimal Residual Disease (MRD) Response Within the First Treatment Cycle	At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory.; Complete MRD response is defined as no polymerase chain reaction (PCR) amplification of individual rearrangements of immunoglobulin (Ig)- or T-cell receptor (TCR)-genes detected after completion of the first cycle.	During the first cycle (6 weeks)
Secondary	Hematological Relapse-free Survival (RFS)	Hematological RFS was measured from first dose of blinatumomab until the first assessment of documented relapse (either hematological or extramedullary), secondary leukemia, or death due to any cause. Participants without a documented relapse, or death due to any cause were censored at the time of their last hematological assessment. Participants who received chemotherapy for relapsed or persistent MRD or for any other reason after treatment with blinatumomab, or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse, or death occurred were censored at the start of chemotherapy or HSCT, respectively.; Hematological relapse was defined as unequivocal detection of > 5% leukemia cells in bone marrow as measured by cytological, microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia (whichever occurred first).; The 18-month Kaplan-Meier estimate of hematological RFS is reported.	18 months, up to the data cut-off date of 05 August 2015
Secondary	Overall Survival	Overall survival was measured from the first treatment with blinatumomab until death due to any cause. Participants who did not die were censored at their last contact date.	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.
Secondary	100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant	The mortality rate within 100 days after allogeneic HSCT was defined as the Kaplan-Meier estimate of the percentage of participants dying within 100 days after the day of the first allogeneic HSCT.	100 days after HSCT, as of the data cut-off date of 05 August 2015
Secondary	Time to Hematological Relapse	Time to hematological relapse was measured from the start of treatment with blinatumomab until hematological or extramedullary relapse. Participants who died or received HSCT or post-blinatumomab chemotherapy after treatment with blinatumomab were censored at their last hematological assessment prior to death or HSCT or post-blinatumomab chemotherapy (whichever occurred first).	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.
Secondary	Duration of Complete MRD Response	The duration of MRD response was analyzed as the time from onset of MRD negativity until MRD or hematological relapse or date of last confirmation of negative MRD status. Participants who received chemotherapy or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse were censored at the start of chemotherapy or HSCT, respectively.; MRD relapse is defined as the reappearance of individual rearrangements of Ig- or TCR-genes = lower limit of quantification (LLOQ) for at least 1 individual marker measured by an assay with a sensitivity of minimum 10^-4. Hematological relapse is defined as the unequivocal detection of > 5% leukemia cells in bone marrow as measured by cytological or microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia.	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.
Secondary	Change in MRD Level From Baseline to End of Cycle 1 in Non-MRD Responders	MRD level was measured by polymerase chain reaction (PCR) performed on bone marrow and assessed by the central laboratory. An MRD level of 10^-n corresponds to residual leukemia cells at a frequency of 1 per 10n bone marrow cells.	Baseline and end of cycle 1 (6 weeks)
Secondary	Number of Participants With Adverse Events	Adverse events (AEs) were evaluated for severity according to 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, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.	From the first dose of blinatumomab until 30 days after last dose; the median treatment duration was 55 days.
Secondary	Change From Baseline in EORTC-QLQ-C30 Scales	The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact).; For each of these scales, scores range from 0 to 100. For the GHS and 5 functional scales a high score indicates better global health status/functioning and a positive change from baseline indicates improvement. For the 9 symptom scales, a high score indicates a higher level of symptoms, and a negative change from Baseline indicates an improvement in symptoms.; The maximum changes from baseline to cycles 1 through 4 and the change from baseline to the end of the core study are reported.	Baseline and the end of each treatment cycle (day 29 of each cycle) and 30 days after end of the last infusion (end of the core study, a maximum of 26 weeks).
Secondary	Change From Baseline in EuroQoL 5-Dimension (EQ-5D) Scales	The EQ-5D is a self-administered questionnaire which captures 3 basic types of information: a descriptive profile (health state index) and the overall health rating using a visual analog scale. The health state index measures mobility, self-care, usual activities, pain/discomfort and anxiety/depression on scales from no problems (score = 1), some problems (score = 2), to extreme problems (score = 3). For each dimension the mean change from baseline was calculated at the end of each treatment cycle and at the end of the core study. The maximum observed change from baseline during cycles 1 to 4 and the change from baseline at the end of the core study are reported for each dimension.	Baseline and the end of each treatment cycle (day 29 of each cycle) and 30 days after end of the last infusion (end of the core study, a maximum of 26 weeks).
Secondary	Resource Utilization: Number of Participants Reporting Use of Transfusion of Blood Products		From first dose of study drug through the end of follow-up; median (minimum, maximum) time on study was 33.8 (1, 62) months
Secondary	Resource Utilization: Duration of Hospitalization		From first dose of study drug through the end of follow-up; median (minimum, maximum) time on study was 33.8 (1, 62) months.