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

Phase 2

Completed

• Conditions: B-cell Acute Lymphoblastic Leukemia
• Interventions: Drug: Blinatumomab

• Registration Number: NCT01207388
• Lead Sponsor: Amgen Research (Munich) GmbH

Brief 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.

Detailed 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.

Study Timeline

• Study First Submitted: 2010-09-21
• Study First Submitted QC: 2010-09-21
• Study First Posted: 2010-09-22
• Study Start: 2010-11
• Primary Completion: 2014-02
• Results First Submitted: 2015-01-28
• Results First Submitted QC: 2015-01-28
• Results First Posted: 2015-02-12
• Study Completion: 2019-01-07
• Status Verified: 2020-01
• Last Update Submitted: 2020-01-31
• Last Update Posted: 2020-02-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 116

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Blinatumomab	Blinatumomab	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With a Minimal Residual Disease (MRD) Response Within the First Treatment Cycle	During the first cycle (6 weeks)	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.

Secondary Outcome Measures

Name	Time	Method
Hematological Relapse-free Survival (RFS)	18 months, up to the data cut-off date of 05 August 2015	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.
Overall Survival	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.	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.
100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant	100 days after HSCT, as of the data cut-off date of 05 August 2015	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.
Time to Hematological Relapse	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.	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).
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
Duration of Complete MRD Response	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.	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.
Change in MRD Level From Baseline to End of Cycle 1 in Non-MRD Responders	Baseline and end of cycle 1 (6 weeks)	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.
Number of Participants With Adverse Events	From the first dose of blinatumomab until 30 days after last dose; the median treatment duration was 55 days.	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.
Change From Baseline in EORTC-QLQ-C30 Scales	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).	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.
Change From Baseline in EuroQoL 5-Dimension (EQ-5D) Scales	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).	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.
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.

Trial Locations

Locations (75)

2105 - Institutul Regional de Oncologie; 🇷🇴 Iasi, Romania

1107 - Krankenhaus der Elisabethinen; 🇦🇹 Linz, Austria

1309 - Azienda Ospedaliera Antonio Cardarelli; 🇮🇹 Napoli, Italy

1310 - Fondazione Policlinico Tor Vergata; 🇮🇹 Rome, Italy

1907 - Uniwersyteckie Centrum Kliniczne; 🇵🇱 Gdansk, Poland

2003 - Municipal Hospital No. 15; 🇷🇺 St. Petersburg, Russian Federation

1407 - Unidad de Citogenética Oncológica; 🇪🇸 Salamanca, Spain

1009 - Universitätsklinikum Essen; 🇩🇪 Essen, Germany

1004 - Universitätsklinikum Münster; 🇩🇪 Münster, Germany

1020 - Universitätsklinikum Rostock; 🇩🇪 Rostock, Germany

1101 - AKH Wien; 🇦🇹 Vienna, Austria

1301 - Ospedali Riuniti di Bergamo; 🇮🇹 Bergamo, Italy

1504; 🇧🇪 Antwerpen, Belgium

1102 - LKH Graz; 🇦🇹 Graz, Austria

1502 - Cliniques Universitaires de Saint-Luc; 🇧🇪 Brussels, Belgium

1505; 🇧🇪 Brügge, Belgium

1211 - CHU d'Angers; 🇫🇷 Angers, France

1503; 🇧🇪 Gent, Belgium

1501 - Cliniques Universitaires UCL de Mont Godinne; 🇧🇪 Yvoir, Belgium

1210 - CHU de Besançon; 🇫🇷 Besançon, France

1206 - Hôpital de Pontoise; 🇫🇷 Cergy Pontoise, France

1205 - CHU Henri Mondor; 🇫🇷 Créteil, France

1212 - Hôpital de l'hôtel Dieu; 🇫🇷 Nantes, France

1209 - CHU de Lyon; 🇫🇷 Lyon, France

1201 - Hôpital Saint Louis; 🇫🇷 Paris, France

1202 - CHU de Bordeaux - Hôpital Haut Lévêque; 🇫🇷 Pessac, France

1213 - Centre Hospitalier Universitaire de Nice; 🇫🇷 Nice, France

1208 - CHU de Purpan; 🇫🇷 Toulouse, France

1011 - Charité Berlin; 🇩🇪 Berlin, Germany

1002 - Klinikum der Goethe Universität; 🇩🇪 Frankfurt, Germany

1022 - Universitätsklinkum Carl Gustav Carus Dresden; 🇩🇪 Dresden, Germany

1014 - Asklepiosklinik St. Georg; 🇩🇪 Hamburg, Germany

1018 - Medizinische Hochschule Hannover; 🇩🇪 Hannover, Germany

1012 - Universitätsklinikum Heidelberg; 🇩🇪 Heidelberg, Germany

1016 - Universitätsklinikum Regensburg; 🇩🇪 Regensburg, Germany

1010 - Klinikum der Universität München - Großhadern; 🇩🇪 Munich, Germany

1007 - Robert-Bosch-Krankenhaus; 🇩🇪 Stuttgart, Germany

1015 - Universitätsklinikum Tübingen; 🇩🇪 Tübingen, Germany

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

2204 - UMC Groningen; 🇳🇱 Groningen, Netherlands

1308 - Ospedali Riuniti "Villa Sofia-Cervello"; 🇮🇹 Palermo, Italy

1311 - Azienda Ospedaliera di Verona; 🇮🇹 Verona, Italy

1302 - Università La Sapienza di Roma; 🇮🇹 Rome, Italy

1315 - Azienda Ospedaliero-Universitaria S. Giovanni Battista (Le Molinette); 🇮🇹 Torino, Italy

2201 - Daniel Den Hoed Hospitaal; 🇳🇱 Rotterdam, Netherlands

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

2101 - Institutul Clinic Fundeni, Hematologie II; 🇷🇴 Bucharest, Romania

2102 - Spitalul Clinic Coltea, Hematologie; 🇷🇴 Bucharest, Romania

2001 - Russian Hematology Research Center; 🇷🇺 Moscow, Russian Federation

1404 - Hospital Clínic Servei d´Hematologia; 🇪🇸 Barcelona, Spain

1402 - Complexo Hospitalario Universitario A Coruña; 🇪🇸 La Coruña, Spain

1405 - Hospital Universitari Son Espases; 🇪🇸 Mallorca, Spain

1408 - Hospital 12 de Octubre; 🇪🇸 Madrid, Spain

1605 - Queen Elizabeth Hospital; 🇬🇧 Birmingham, United Kingdom

1604 - University Hospital of Wales; 🇬🇧 Cardiff, United Kingdom

1602 - Bristol Royal Infirmary; 🇬🇧 Bristol, United Kingdom

1607 - Nottingham City Hospital NHS Trust; 🇬🇧 Nottingham, United Kingdom

1401 - ICO Hospital Germans Trias I Pujol; 🇪🇸 Badalona, Spain

1003 - Universitätsklinikum Schleswig-Holstein; 🇩🇪 Kiel, Germany

1406 - Hospital Universitari i Politècnic La Fe de Valencia; 🇪🇸 Valencia, Spain

1001 - Julius-Maximilians-Universität Würzburg; 🇩🇪 Würzburg, Germany

1601 - Royal Free Hospital; 🇬🇧 London, United Kingdom

1019 - Universitätsklinikum Leipzig; 🇩🇪 Leipzig, Germany

1005 - Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

1106; 🇦🇹 Salzburg, Austria

1904 - Samodzielny Publiczny; 🇵🇱 Wrocław, Poland

1905 - Uniwersytecki Szpital Kliniczny w Białymstoku; 🇵🇱 Bialystok, Poland

2106 - Institutul Oncologic "Prof. Dr. I. Chiricuta"; 🇷🇴 Cluj-Napoca, Romania