Clinical Study With Blinatumomab in 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 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
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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).

Official Title
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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)

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: Blinatumomab


Participation Criteria
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Eligibility Criteria
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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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab<br>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. | 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 | Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR): bone marrow blasts ≤ 5% no evidence of disease full recovery of peripheral blood counts: platelets > 100,000/μL, and absolute neutrophil count (ANC) > 1,000/μL Complete Remission With Partial Hematological Recovery (CRh*): bone marrow blasts ≤ 5% no evidence of disease partial recovery of peripheral blood counts: platelets > 50,000/μL, and ANC > 500/μL. | Within the first 2 cycles of treatment, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Hematological Relapse (Duration of Response) | Time to hematological relapse was measured for participants in remission during the core study (the time from the first infusion through 30 days after the last infusion), from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without 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 date of death. Hematological relapse is defined as: proportion of blasts in bone marrow > 5% after documented CR/CRh* or blasts in peripheral blood after documented CR/CRh*. Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method. | Up to the data cut-off date of 10 October 2013; median observation time was 8.0 months. | 
| Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission | Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT. | Up to the data cut-off date of 10 October 2013. Maximum duration on study was 17.8 months. | 
| Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment | Complete Remission was defined by the following criteria: bone marrow blasts ≤ 5% no evidence of disease full recovery of peripheral blood counts: platelets > 100,000/μL, and absolute neutrophil count (ANC) > 1,000/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 | Complete Remission With Partial Hematological Recovery was defined by the following criteria: bone marrow blasts ≤ 5% no evidence of disease partial recovery of peripheral blood counts: platelets > 50,000/μL, and 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 | Partial Remission is defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline. | Within the first 2 cycles of treatment, 12 weeks | 
| Relapse-free Survival | Relapse-free survival was assessed for participants who achieved a complete remission or complete remission with partial hematological recovery 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 and the median observation time was calculated by the reverse Kaplan Meier method. | Up to the data cut-off date of 10 October 2013; median observation time was 8.9 months. | 
| Event-free Survival | Event-free survival was calculated from the start date of blinatumomab infusion until the date of bone marrow aspiration at which hematological relapse was first detected, or the date of diagnosis on which the hematological or extramedullary relapse was documented or the date of start of any new therapy for ALL (excluding HSCT), or the date of death, whichever was earlier. Participants who did not achieve complete remission or complete remission with partial hematological recovery during the core study were evaluated as having an event on Day 1. Participants in remission who did not experience hematological relapse, did not receive a new therapy for ALL (excluding HSCT), and did not die were censored on the date of the last available bone marrow aspiration or on the last date of survival follow-up visit, whichever was later. Event free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method. | Up to the data cut-off date of 10 October 2013; median observation time was 9.8 months. | 
| Overall Survival | Overall survival was measured for all participants from the time the participant received the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan Meier method. | Up to the data cut-off date of 10 October 2013; median observation time was 9.8 months. | 
| Number of Participants With Treatment-emergent Adverse Events | Adverse events (AEs) were evaluated for severity according to the 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, requires or prolongs inpatient hospitalization, results in persistent or significant incapacity or substantial disruption to conduct normal life functions, is a congenital anomaly or birth defect or is a medically important condition. Progressive disease was not an adverse event, per the protocol, unless it was more severe than expected for the patient. Therefore, many deaths due to progressive disease were not counted as adverse events. | 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. | 
| 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant | The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in remission (CR/CRh*) following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. Patients alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. The 100-day mortality rate after allogeneic HSCT was defined as the percentage of patients having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. | From the date of allogeneic HSCT until the data cut-off date of 10 October 2013; median observation time was 7.4 months. | 
| Serum Blinatumomab Concentration at Steady State | The steady state concentration of blinatumomab was summarized as the observed concentrations collected at least 10 hours after the start of the IV infusion or dose step for cycle 1 and cycle 2, respectively. Serum concentrations of blinatumomab were measured using a validated bioassay. The lower limit of quantitation (LLOQ) = 50.0 pg/mL. | Samples were taken before treatment start and on Days 3, 8, 10, 15, 22, and 29 after infusion start during Cycles 1 and 2. | 
| 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-4, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using enzyme-linked immunosorbent assays or cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the limit of quantification (LOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data < LOQ and > LOD were reported as measured. Serum IL-4 levels were below detection limit (< 20 pg/mL) at all time points in all participants studied. | 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. | 
| Percentage of Participants With a Best Response of Blast Free Hypoplastic or Aplastic Bone Marrow Within 2 Cycles of Treatment | Blast Free Hypoplastic or Aplastic Bone Marrow was defined as: bone marrow blasts ≤ 5% no evidence of disease insufficient recovery of peripheral counts: platelets ≤ 50,000/μL and/or absolute neutrophil count (ANC) ≤ 500/μL | Within the first 2 cycles of treatment, 12 weeks | 
| Best Response During the Core Study | Complete Remission (CR): bone marrow blasts ≤ 5% no evidence of disease full recovery of peripheral blood counts: platelets > 100,000/μL, and absolute neutrophil count (ANC) > 1,000/μL Complete Remission With Partial Hematological Recovery (CRh*): bone marrow blasts ≤ 5% no evidence of disease partial recovery of peripheral blood counts: platelets > 50,000/μL, and ANC > 500/μL Blast Free Hypoplastic or Aplastic Bone Marrow: bone marrow blasts ≤ 5% no evidence of disease insufficient recovery of peripheral counts: platelets ≤ 50,000/μL and/or ANC ≤ 500/μL Partial Remission: • bone marrow blasts 6% to 25% with at least a 50% reduction from Baseline. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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