Safety Study of the Bispecific T-cell Engager Blinatumomab (MT103) in Patients With Relapsed NHL

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a continuous infusion of Blinatumomab (MT103) is safe in the treatment of relapsed Non-Hodgkin's Lymphoma. Furthermore, the study is intended to provide pharmacokinetic and pharmacodynamic data of Blinatumomab as well as to get first indication of tumour activity.

Detailed Description
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Non-Hodgkin's Lymphoma (NHL) represents the 6th most common cancer. Globally, around 165,000 new cases are diagnosed each year, with approximately 90,000 deaths per year. The vast majority of NHLs are B-cell derived (90%) and express common B-cell antigens such as CD19, CD20 and CD22. NHL can be divided into indolent (low-grade) and aggressive (high-grade) lymphomas. Still almost all patients with advanced stage indolent disease will die from their disease. Therefore, a high medical need exists to develop novel agents that further improve the survival of NHL patients. Blinatumomab (MT103) is a bispecific antibody derivative, anti-CD19 x anti-CD3, designed to link B-cells and T-cells resulting in T-cell activation and a cytotoxic T-cell response against CD19+ cells. Data of prior phase I studies show evidence of biological activity in humans. In vitro and ex-vivo data suggest that a longterm presence of the drug in target tissues may provide antitumour activity. The study investigates the safety and tolerability of different doses of Blinatumomab administration in a continuous infusion regimen. Maximum tolerated dose (MTD) will be defined in a classical 3+3 dose escalation regimen.

Official Title
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An Open-label, Multi-center Phase I Study to Investigate the Tolerability and Safety of a Continuous Infusion of the Bispecific T-cell Engager MT103 in Patients With Relapsed Non-Hodgkin's Lymphoma (NHL)

Conditions
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Non-Hodgkin's Lymphoma, Relapsed

Intervention / Treatment
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* Biological: Blinatumomab (MT103)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with first or later relapse of histologically (World Health Organisation classification) confirmed: follicular lymphoma (grade I/II) marginal zone lymphoma lymphoplasmocytic lymphoma mantle cell lymphoma diffuse large B-cell lymphoma small lymphocytic lymphoma requiring therapy and not eligible for curative treatment Measurable disease (at least one lesion >= 1.5 cm) documented by computed tomography (CT) scan Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status <=2 Life expectancy of at least 6 months Ability to understand the patient information and informed consent form Signed and dated written informed consent is available B:T cell ratio (Fluorescence-Activated Cell Sorter [FACS] analysis results by central lab) available before study entry. Exclusion Criteria: Any other NHL not listed in inclusion criterion 1 Abnormal laboratory values as defined below: Peripheral lymphocyte count > 20 x 10^9/L Platelet counts ≤ 75,000/µL Hemoglobin level ≤ 9 g/dL Venous pH value out of normal range or oxygen saturation ≤ 90% Known or suspected central nervous system (CNS) involvement by NHL a)History of or current relevant CNS pathology as epilepsy, seizure, paresis,aphasia, apoplexia, severe brain injuries, cerebellar disease, organic brain syndrome, psychosis b)Evidence for presence of inflammatory lesions and/or vasculitis on cerebral MRI Autologous stem cell transplantation within 12 weeks prior to study entry Allogeneic stem cell transplantation Cancer chemotherapy within 4 weeks prior to study entry Radiotherapy within 4 weeks prior to study entry Treatment with rituximab within 4 weeks prior to study entry Prior treatment with alemtuzumab 12 weeks prior to study entry Treatment with any investigational agent within 12 weeks prior to study entry Contraindication for any of the concomitant medications Abnormal renal or hepatic function as defined below: Aspartate aminotransferase (AST; SGOT) and/or alanine aminotransferase (ALT; SGPT) >= 2 x upper limit of normal (ULN) total bilirubin >= 1.5 x ULN serum creatinine >= 2 x ULN creatinine clearance < 50mL/min Indication of hypercoagulative state as defined below: -antithrombin activity <LLN Presence of human anti-murine antibodies (HAMA) or known hypersensitivity to immunoglobulins History of malignancy other than B-cell lymphoma within 5 years prior to study entry, with the exception of basal cell carcinoma of the skin or carcinoma in situ of the cervix Active infection / not yet recovered from recent infection; known bacteriemia Any concurrent disease or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator Regular dose of corticosteroids during the four weeks prior to D1 of this study or anticipated need of corticosteroids exceeding prednisone 20 mg/day or equivalent, or any other immunosuppressive therapy within 4 weeks prior to study entry Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B or hepatitis C virus Pregnant or nursing women, or women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least three months thereafter. Male patients not willing to ensure that during the study and at least three months thereafter no fathering takes place.

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>Patients received blinatumomab as continuous intravenous infusion for 4 weeks. Participants with clinical benefit were permitted to continue for another 4 weeks for a total of 8 weeks. Participants with a clinical benefit 4 weeks after completion of the first cycle of treatment could also receive additional treatment approximately 3 months ater the end of infusion at the same dose level. | Biological: Blinatumomab (MT103)<br>* Doses from 0.5 to 120 µg/m^2/24hours by continuous intravenous infusion<br>* Other names: BLINCYTO™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Participants reporting at least one occurence of any adverse event including clinical symptoms, laboratory abnormalities, serious adverse events, and treatment-limiting adverse events | From the first infusion of blinatumomab until the safety follow-up visit 2 weeks after end of the treatment period, including the consolidation and relapse periods. The median treatment duration was 33.24 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentration of Blinatumomab | The steady state serum concentration (Css), summarized as the observed concentrations collected at least 10 hours after the start of continuous intravenous infusion or within the sampling window at the end of infusion. Concentrations below the lower limit of quantitation (100 pg/mL) were excluded from analysis. | Up to 24 hours after the end of infusion. | 
| Objective Tumor Response According to the Cheson Criteria (Without Minimal Response) | Tumor response was defined according to the Cheson criteria and assessed after 4 and 8 weeks of study treatment using computed tomography (CT) scan (neck, thorax and abdomen/pelvic to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Best clinical response is defined as the best response achieved during the course of the study, with response defined as: Complete Response, Complete Response Unconfirmed, Partial Response, Stable Disease, and Progressive Disease. In this analysis minimal response is set to stable disease as intended in the response categories according to the Cheson criteria. An independent external review by a radiologist (computed tomography scans) and a pathologist (biopsies) was performed to confirm response status. If no post-baseline tumor assessment was available, the overall clinical response was set to not available. | Assessed after 4 and 8 weeks of treatment | 
| Objective Tumor Response According to the Cheson Criteria (With Minimal Response) | Tumor response was defined according to the Cheson criteria and assessed after 4 and 8 weeks of study treatment using computed tomography (CT) scan (neck, thorax and abdomen/pelvic to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Minimal response was treated as a separate response category in this analysis. Best clinical response was defined as the best response achieved during the course of the study, whereby the following order was applied: Complete Response, Complete Response Unconfirmed, Partial Response, Minimal Response, Stable Disease, and Progressive Disease. If no post-baseline tumor assessment was available, the overall clinical response was set to not available. | Assessed after 4 and 8 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkin's Lymphoma, Cancer immunotherapy, Monoclonal antibody, anti-CD19, anti-CD3, BiTE, Blinatumomab