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

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)

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.

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.

Inclusion Criteria:

1. 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

2. Measurable disease (at least one lesion >= 1.5 cm) documented by computed tomography (CT) scan

3. Age >= 18 years

4. Eastern Cooperative Oncology Group (ECOG) performance status <=2

5. Life expectancy of at least 6 months

6. Ability to understand the patient information and informed consent form

7. Signed and dated written informed consent is available

8. B:T cell ratio (Fluorescence-Activated Cell Sorter [FACS] analysis results by central lab) available before study entry.

Exclusion Criteria:

1. Any other NHL not listed in inclusion criterion 1

2. 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%

3. Known or suspected central nervous system (CNS) involvement by NHL

4. 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

5. Autologous stem cell transplantation within 12 weeks prior to study entry

6. Allogeneic stem cell transplantation

7. Cancer chemotherapy within 4 weeks prior to study entry

8. Radiotherapy within 4 weeks prior to study entry

9. Treatment with rituximab within 4 weeks prior to study entry

10. Prior treatment with alemtuzumab 12 weeks prior to study entry

11. Treatment with any investigational agent within 12 weeks prior to study entry

12. Contraindication for any of the concomitant medications

13. 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

14. Indication of hypercoagulative state as defined below:

    -antithrombin activity <LLN

15. Presence of human anti-murine antibodies (HAMA) or known hypersensitivity to immunoglobulins

16. 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

17. Active infection / not yet recovered from recent infection; known bacteriemia

18. Any concurrent disease or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator

19. 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

20. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B or hepatitis C virus

21. 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.