Phase II Study of the BiTE® Blinatumomab (MT103) in Patients With Minimal Residual Disease of 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 (BiTE®) Blinatumomab (MT103) is effective in the treatment of ALL patients with minimal residual disease.

Detailed Description
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The presence of leukemia cells below the cytological detection limit (5% leukemic cells) is defined as minimal residual disease (MRD). If no MRD is detectable (< 10^-4 = less than 1 leukemia cell per 10^4 bone marrow cells) a complete molecular remission is reached. In the last years a series of retrospective studies has shown that MRD in adult ALL is an independent prognostic factor as already demonstrated for childhood leukemia. Diagnostic tools for MRD are polymerase chain reaction (PCR) and/or flow cytometry. PCR analysis can detect fusion transcripts such as bcr/abl and individual clonal rearrangements of immunoglobulins (IgH) and/or T-cell receptor genes (TCR). About 25% of patients with MRD defined by rearrangement comprise a high-risk group with a 94% relapse rate within 3 years. In general for patients with MRD, who are not eligible for allogenic stem cell transplantation, curative treatment is not available. This accounts for MRD defined by the Philadelphia chromosome translocation as well as for MRD defined by rearrangement. The current study is set up to address the question of treating MRD positive ALL with the bispecific anti-cluster of differentiation (CD)19 x anti-CD3 antibody derivative blinatumomab (MT103).

Official Title
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Open-label, Multicenter Phase II Study to Investigate the Efficacy, Safety, and Tolerability of the Bispecific T-cell Engager (BiTE®) MT103 in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: Blinatumomab (MT103)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: B-precursor ALL patients in complete hematological remission with molecular failure or molecular relapse starting at any time after consolidation I of front-line therapy within German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia (GMALL) standards or at any time outside GMALL standards. Patients must have a molecular marker for evaluation of minimal residual disease which is either Breakpoint cluster region/gene on human chromosome #9 (Bcr/abl) at any detection level or individual rearrangements of immunoglobulin or T-cell receptor (TCR)-genes measured by an assay with a sensitivity of minimum 10^-4: At least one individual marker at a quantitative level ≥ 10^-4. Eastern Cooperative Oncology Group (ECOG) Performance Status < 2 Ability to understand and willingness to sign a written informed consent Signed and dated written informed consent is available Exclusion Criteria: Current extra medullar involvement History of or current relevant central nervous system (CNS) pathology (except migraine/headache and/or previous infiltration of cerebrospinal fluid (CSF) by ALL) Current infiltration of cerebrospinal fluid by ALL History of or current autoimmune disease Autologous stem cell transplantation within 6 weeks prior to study entry Any prior allogeneic stem cell transplantation Cancer chemotherapy within 4 weeks prior to study treatment (except for intrathecal prophylaxis and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, steroids) Radiotherapy within 4 weeks prior to study treatment Therapy with monoclonal antibodies (Rituximab, MabCampath) within 6 weeks prior to study treatment Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation Presence of human anti-murine antibodies (HAMA) Abnormal bone marrow, renal or hepatic function Indication for a hypercoagulative state History of malignancy other than ALL within 5 years prior to study entry, with the exception of basal cell carcinoma of the skin or cervix carcinoma in situ Active severe infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive) Pregnant or nursing women Women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter or male patients not willing to ensure effective contraception during participation in the study and at least three months thereafter

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 as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2 week treatment-free period (defined as one treatment cycle), for up to a maximum of 10 cycles. The initial dose was 15 μg/m^2/day. A dose increase to 30 μg/m^2/day was permitted with evidence for insufficient response to blinatumomab treatment. | Biological: Blinatumomab (MT103)<br>* Administered by continuous intravenous (CIV) over 4 weeks per 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 Minimal Residual Disease (MRD) Response Within 4 Cycles of Treatment | MRD Response is defined as: If Philadelphia Chromosome (Ph) positive (+) or translocation (t) (4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10^-4. If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10^-4. | Within 4 treatment cycles, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an MRD Response After Each Treatment Cycle | MRD Response is defined as: If Philadelphia Chromosome (Ph)+ or t(4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10^-4. If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10^-4. | At the end of each treatment cycle - Weeks 4, 10, 16, and 22. | 
| Time to Hematological Relapse | The time to hematological relapse is defined as the time between start of first infusion of blinatumomab and the first result of hematological relapse. Participants without an event of hematological relapse were censored on their last available date of bone marrow aspiration/biopsy. Hematological relapse is defined as > 5% leukemia cells in bone marrow. Time to hematological relapse was analyzed using Kaplan-Meier methods. | Up to the data cut-off date of 14 January 2010; maximum duration of follow-up was 564 days. | 
| Time to MRD Progression | Time to MRD progression is defined for participants who do not show MRD response at any time during the study as the time from start of first infusion until the first result of MRD progression or hematological relapse, if no MRD progression was diagnosed before hematological relapse. For participants who showed MRD response during the study the time to MRD progression is defined as the time from the date of the first MRD response to the date of MRD relapse. Participants without an event of MRD progression were censored on the day of their last bone marrow aspiration/biopsy. Participants who received a bone marrow transplant were censored on the last day of bone marrow aspiration/biopsy before transplantation. MRD progression is defined as the increase in the MRD level by 1 log as compared to the baseline level (equal to a 10-fold increase in the number of MRD cells), and had to be confirmed within 6 weeks. | Up to the data cut-off date of 14 January 2010; Median follow-up time was 155 days | 
| Time to MRD Relapse | Time to MRD relapse is defined only for participants with an MRD response during the study, defined as the time between the date of the first MRD response and the date of MRD relapse. If a participant experienced hematological relapse without having shown MRD positivity before then the time point of MRD relapse is defined as the time point of hematological relapse. Participants without an event of MRD relapse or hematological relapse were censored on the day of their last available bone marrow aspiration/biopsy. If a participant received a bone marrow transplant the last day of bone marrow aspiration/biopsy before transplantation was used as time point for censoring. MRD relapse is defined as reappearance of bcr/abl, and/or t(4;11) translocation at any detection level, and/or by individual rearrangements of immunoglobulin or T-cell receptor genes ≥10^-4 for at least 1 individual marker measured by an assay with a sensitivity of minimum 10^-4 and should be confirmed within 6 weeks. | Up to the data cut-off date of 14 January 2010; Median follow-up time was 116.5 days | 
| Number of Participants With Adverse Events | The severity (or intensity) of AEs was evaluated according to the grading scale provided in the Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, or according to the following: 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. A serious adverse event (SAE) is any untoward medical occurrence or effect that, at any dose results in death, is life-threatening, requires or prolongs hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. In addition, all laboratory abnormalities of grade four severity that occur during or after administration of the investigational drug, any overdose and a pregnancy or fathering were reported as SAEs. | From the start of study treatment until up to 4 weeks after the end of study treatment. The median treatment duration was 87.3 days. | 
| Change From Screening Value in B-cell Count During Cycle 1 | B-cells were measured by flow cytometry. | At Screening and in Cycle 1 at the start of infusion, 45 minutes, 2, 6, 12, 24 hours and at Days 2, 7, 14, 21, 28 and 35 after the start of infusion. | 
| Change From Screening Value in T-cell Count During Cycle 1 | T-cells were measured by flow cytometry. | At Screening and in Cycle 1 at the start of infusion, 45 minutes, 2, 6, 12, 24 hours and at Days 2, 7, 14, 21, 28 and 35 after the start of infusion. | 
| Serum Cytokine Peak Levels in Cycle 1 | 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-8, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using fluorescence-activated cell sorter (FACS)-based cytometric bead array (CBA) system.The limit of detection (LOD) for the cytokine determination was 20 pg/mL, the limit of quantification (LOQ) was 125 pg/mL. | Cycle 1 at pre-dose and at post infusion start at 45 minutes; 2, 6, 12, 24, and 48 hours; 7, 14, 21, and 28 days. | 
| Serum Blinatumomab Concentration at Steady State | The mean serum concentration of blinatumomab during cycle 1. The LOQ of the assay was 100 pg/mL, and the limit of detection (LOD) was 3 pg/mL. | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | 
| Area Under the Drug Concentration-time Curve From Time Zero to Infinity |  | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | 
| Apparent Volume of Distribution |  | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | 
| Clearance of Blinatumomab |  | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | 
| Terminal Half-life of Blinatumomab |  | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MT103, Minimal Residual Disease, adult ALL, immunotherapeutic treatment, anti-CD19 bispecific antibody derivative, Blinatumomab