Study of the BiTE® Blinatumomab (MT103) in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the bispecific T-cell engager blinatumomab is effective, safe and tolerable in the treatment of patients with relapsed/refractory B-precursor ALL.

Detailed Description
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Relapsed/refractory B-precursor ALL in adult patients is an aggressive malignant disease with dismal prognosis and unmet medical need. Additional therapeutic approaches are urgently needed. Blinatumomab 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 CD19 expressing cells. The purpose of this study is to investigate the efficacy, safety and tolerability of different doses of the bispecific T-cell engager blinatumomab in adult patients with relapsed/refractory B-precursor ALL. Patrticipants will receive up to five 4-week cycles of intravenous blinatumomab treatment.

Official Title
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An Open Label, Multicenter, Exploratory Phase II Study to Evaluate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab in Adult Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

Conditions
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B-ALL

Intervention / Treatment
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* Biological: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with B-precursor ALL relapsed after at least induction and consolidation or having refractory disease More than 5% blasts in bone marrow Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Life expectancy of ≥ 12 weeks Exclusion Criteria: History or presence of clinically relevant central nervous system (CNS) pathology Infiltration of cerebrospinal fluid (CSF) by ALL Autologous/allogeneic hematopoietic stem cell transplantation (HSCT) within six weeks/three months prior to start of blinatumomab treatment Active Graft-versus-Host Disease (GvHD) Patients with Philadelphia chromosome (Ph)+ ALL eligible for treatment with dasatinib or imatinib Cancer chemotherapy within two weeks prior to start of blinatumomab treatment Immunotherapy (e.g. rituximab) within four weeks prior to start of blinatumomab treatment Infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive) Pregnant or nursing women Previous treatment with blinatumomab

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab 15 μg<br>Participants received blinatumomab 15 μg/m²/day as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles. | Biological: Blinatumomab<br>* Continuous intravenous infusion over four weeks per treatment cycle<br>* Other names: BLINCYTO™;|
| Experimental: Blinatumomab 5/15 μg<br>Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, followed by 15 μg/m²/day starting from Week 2 of treatment. | Biological: Blinatumomab<br>* Continuous intravenous infusion over four weeks per treatment cycle<br>* Other names: BLINCYTO™;|
| Experimental: Blinatumomab 5/15/30 μg<br>Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, a dose of 15 μg/m²/day in the subsequent 7 days, followed by 30 μg/m²/day starting from Week 3 of treatment. | Biological: Blinatumomab<br>* Continuous intravenous infusion over four weeks per treatment cycle<br>* Other names: BLINCYTO™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment | At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Response/Remission (CR): Less than or equal to 5% blasts in the bone marrow No evidence of circulating blasts or extramedullar disease Full recovery of peripheral blood counts: Platelets > 100,000/μL Hemoglobin ≥ 11 g/dL Absolute neutrophil count (ANC) > 1,500/μL Complete Remission with only Partial Hematological Recovery (CRh*): Less than or equal to 5% blasts in the bone marrow No evidence of circulating blasts or extramedullar disease Partial recovery of peripheral blood counts: Platelets > 50,000/μL Hemoglobin ≥ 7 g/dL ANC > 500/μL. | Within the first 2 cycles of treatment, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment | At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Complete Response/Remission (CR) was defined by the following criteria: Less than or equal to 5% blasts in the bone marrow No evidence of circulating blasts or extramedullar disease Full recovery of peripheral blood counts: Platelets > 100,000/μL Hemoglobin ≥ 11 g/dL Absolute neutrophil count (ANC) > 1,500/μL | Within the first 2 cycles of treatment, 12 weeks | 
| Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment | At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Complete remission with only partial hematological recovery (CRh*) was defined by the following criteria: Less than or equal to 5% blasts in the bone marrow No evidence of circulating blasts or extramedullar disease Partial recovery of peripheral blood counts: Platelets > 50,000/μL Hemoglobin ≥ 7 g/dL ANC > 500/μL. | Within the first 2 cycles of treatment, 12 weeks | 
| Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment | At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Partial remission was defined by the following criteria: • Bone marrow blasts ≤ 25% | Within the first 2 cycles of treatment, 12 weeks | 
| Percentage of Participants With a Minimal Residual Disease (MRD) Response During the Core Study | A minimal residual disease (MRD) response is defined as MRD < 10^-4 blasts/nucleated cells based on polymerase chain reaction (PCR) evaluation of individual rearrangements of immunoglobulin or T cell receptor genes. | During the core study treatment period (up to 30 weeks). | 
| Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) After Treatment With Blinatumomab | The percentage of participants who underwent immediate allogeneic HSCT (defined as those in remission who undergo HSCT without receiving any other treatments) after having discontinued or completed the core study. | Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days | 
| Time to Hematological Relapse | Time to hematological relapse was measured for participants who achieved a CR or CRh* during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without a 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 day of death. Hematological Relapse was defined as: Proportion of blasts in bone marrow > 5% Extramedullary relapse. Time to hematological relapse was analyzed by Kaplan-Meier methods. | Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days. | 
| Relapse-free Survival | Relapse-free survival was measured only for participants who achieved a CR or CRh* 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. | Up to the data cut-off date of 15 October 2012; maximum follow up time was 459 days. | 
| Overall Survival | Overall survival was measured for all participants from the date of first infusion of blinatumomab until the date of death due to any cause. Participants who did not die were censored on the last documented visit date. Overall survival was estimated using Kaplan-Meier methods. | Up to the data cut-off date of 15 October 2012; maximum follow up time was 667 days. | 
| Number of Participants With Treatment-emergent Adverse Events | Adverse events were evaluated for severity according to the grading scale provided in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 and according to the following: Grade I (mild); Grade 2 (moderate); Grade 3 (severe - significantly limits the patient's ability to perform routine activities despite symptomatic therapy; Grade 4 (life-threatening); Grade 5 (death). The investigator used medical judgment to determine if there was a causal relationship (ie, certain, probable, possible, unlikely, not related) between an adverse event and blinatumomab. A serious adverse event is any untoward medical occurrence or effect, that at any dose: resulted in death, was life-threatening, required or prolonged hospitalization, resulted in persistent or significant disability or incapacity, is a congenital anomaly or birth defect or is a medically important condition. | 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 55.7 days. | 
| Steady State Blinatumomab Concentration | The steady state concentration of blinatumomab was summarized as the observed concentrations collected at least 10 hours after the intravenous infusion was started for cycle 1 and cycle 2, respectively. Actual doses administered were used in the analysis. Concentrations below the limit of detection (3 pg/mL) were set to zero before data analysis and concentrations below the lower limit of quantitation (50 pg/mL) were excluded from analysis. | Samples were collected at predose and at 48 hours following start of infusion, when dose is escalated and on Days 8, 15, 22, and 29 of the first 2 cycles. | 
| Clearance of Blinatumomab | Clearance was calculated as R0/Css; where R0 is the infusion rate (μg/m^2/hr) and Css is the steady state concentration. | Samples were collected at predose and at 48 hours following start of infusion, when dose is escalated and on Days 8, 15, 22, and 29 of the first 2 cycles. | 
| Serum Cytokine Peak Levels | The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) is 125 pg/mL and the limit of detection (LOD) is 20 pg/mL. | Samples were collected prior to treatment start (baseline), and at 2, 6, 24, and 48 hours after drug infusion start, and at these same time points when dose is escalated in each treatment cycle. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blinatumomab, B-ALL, adult ALL, relapsed ALL, refractory ALL, Leukemia, ALL, Lymphatic diseases, Lymphoproliferative disorders, bispecific antibody, anti-CD19, Immunotherapeutic treatment