Study of Fc-Optimized Anti-CD19 Antibody (MOR00208) to Treat Non-Hodgkin's Lymphoma (NHL)

A Phase IIa, Open-label, Multicenter Study of Single-agent MOR00208, an Fc-optimized Anti-CD19 Antibody, in Patients With Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

This is an open-label, multicenter study to characterize the safety and efficacy of the human anti-CD19 antibody MOR00208 in adult patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) who have received at least 1 prior therapy containing rituximab (at least once).

The study enrols patients from four different NHL subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and other indolent NHL (iNHL). The study will employ a two-stage design where the decision to further enrol any NHL subtype in stage 2 will depend on best responses after two or three cycles in stage 1.

NHL, CD19, MOR208, MOR00208, Xmab5574, B-Cell Non-Hodgkin´s Lymphoma, Fc-optimized Anti-CD19 Antibody, Tafasitamab

Proportion of Patients with Complete Response (CR) or Partial Response (PR), assessed as per the 2007 International Working Group (IWG) response criteria

Number and proportion of patients who potentially develop anti-MOR00208 antibodies and semiquantitative anti-MOR00208 antibody assessments

Estimated from first dose (samples taken on first day of dosing at pre-dose, end of infusion, after 1 hour, 4 hours, 24 hours, and pre-dose on Day 8)

Estimated from first dose (samples taken on first day of dosing at pre-dose, end of infusion, after 1 hour, 4 hours, 24 hours, and pre-dose on Day 8)

Estimated from first dose (samples taken on first day of dosing at pre-dose, end of infusion, after 1 hour, 4 hours, 24 hours, and pre-dose on Day 8)

PK parameter: Area under the concentration curve from dose time zero to the time the last quantifiable concentration is observed (AUC[0-t]) of MOR00208

Area under the concentration curve. The time curve from time zero (0) to the time that the last concentration above the lower limit of quantification (LLQ) is observed.

Estimated from first dose (samples taken on first day of dosing at pre-dose, end of infusion, after 1 hour, 4 hours, 24 hours, and pre-dose on Day 8)

PK parameter: Area under the concentration curve from dose time zero to infinity (AUC[0-inf]) of MOR00208

Area under the concentration curve. The time curve from time zero (0) to infinity (inf), where infinity is computed from AUC0-t + [Ct/λZ)]. Ct is calculated from the concentration at the last sampling time at which the sample is above LLQ.

Estimated from final dose (samples collected on the last day of Cycle 3 [C3D28; each cycle is 28 days long], and Follow-up Visits 1 [C3D28 + 4 weeks], 2 [C3D28 + 10 weeks], and 3 [C3D28 + 16 weeks])

Apparent terminal rate constant calculated from the regression analysis (slope) from the log-transformed measured concentrations on the terminal phase of the time-point concentration curve

Estimated from final dose (samples collected on the last day of Cycle 3 [C3D28; each cycle is 28 days long], and Follow-up Visits 1 [C3D28 + 4 weeks], 2 [C3D28 + 10 weeks], and 3 [C3D28 + 16 weeks])

Estimated from final dose (samples collected on the last day of Cycle 3 [C3D28; each cycle is 28 days long], and Follow-up Visits 1 [C3D28 + 4 weeks], 2 [C3D28 + 10 weeks], and 3 [C3D28 + 16 weeks])

Estimated from final dose (samples collected on the last day of Cycle 3 [C3D28; each cycle is 28 days long], and Follow-up Visits 1 [C3D28 + 4 weeks], 2 [C3D28 + 10 weeks], and 3 [C3D28 + 16 weeks])

Estimated from final dose (samples collected on the last day of Cycle 3 [C3D28; each cycle is 28 days long], and Follow-up Visits 1 [C3D28 + 4 weeks], 2 [C3D28 + 10 weeks], and 3 [C3D28 + 16 weeks])

Actual change from baseline will be summarized descriptively by visit for the pharmacodynamic parameters B-, T-, and NK cell populations.

Cycle 1 Day 1 (Baseline) to Cycle 1: Days 8, 15, and 22; Cycles 2 and 3: Days 1, 15, and 28 (each cycle is 28 days); End of Study (up to 4.5 years)

Percent change from baseline will be summarized descriptively by visit for the pharmacodynamic parameters B-, T-, and NK cell populations.

Cycle 1 Day 1 (Baseline) to Cycle 1: Days 8, 15, and 22; Cycles 2 and 3: Days 1, 15, and 28 (each cycle is 28 days); End of Study (up to 4.5 years)

Incidence of AEs as stratified by presence of CD19 on malignant lymphoma cells detected by tumor biopsy/aspirate during Screening

The analysis of the primary endpoint (ORR) will additionally be stratified by presence of CD19 on malignant lymphoma cells detected by tumor biopsy/aspirate during Screening

The analysis of the primary endpoint (ORR) will additionally be stratified by FcγRIIIa and FcγRIIa polymorphism subgroups

Inclusion Criteria: Male or female patients ≥ 18 years of age. Histologically-confirmed diagnosis according to Revised European American Lymphoma/World Health Organization classification, of the following B-cell lymphomas: FL MCL DLBCL Other indolent NHL (eg, MZL/MALT) Patients' NHL must have progressed after at least 1 prior rituximab containing regimen. One site of measurable disease by magnetic resonance imaging (MRI) or computed tomography (CT) scan defined as at least one lesion that measures at least 1.5 × 1.5 cm. Exception: For patients with MCL only, patients with nonmeasurable disease but evaluable sites (bone marrow, spleen, peripheral blood, gastrointestinal tract) can be enrolled. Patients who have previously received an autologous stem cell transplantation must be at least 4 weeks post-transplant before study drug administration and must have exhibited a full haematological recovery. Discontinued previous monoclonal antibody therapy (except rituximab) or radioimmunotherapy administration for at least 60 days before study drug administration. Off rituximab for at least 14 days before the screening visit and be confirmed to have either no response or have disease progression after rituximab treatment. Patients with DLBCL had a positive [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) scan at baseline (Cheson 2007 response criteria). Life expectancy of > 3 months. Eastern Cooperative Oncology Group (ECOG) performance status of < 3. Laboratory criteria at screening: Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L Platelet count ≥ 75 × 10⁹/L without previous transfusion within 10 days of first study drug administration Haemoglobin ≥ 8.0 g/dL (may have been transfused) Serum creatinine < 2.0 x upper limit of normal (ULN) Total bilirubin ≤ 2.0 × ULN Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN If a female of childbearing potential, a negative pregnancy test must be confirmed before enrolment and use of double-barrier contraception or oral contraceptive plus barrier contraceptive must be used during the study and for 3 months after the last dose, or confirmation of having undergone clinically documented total hysterectomy and/or oophorectomy, tubal ligation. If a male, an effective barrier method of contraception must be used during the study and for 3 months after the last dose if the patient is sexually active with a female of childbearing potential. Able to comply with all study-related procedures, medication use, and evaluations. Able to understand and give written informed consent and comply with the study protocol. Exclusion Criteria: Previous treatment with cytotoxic chemotherapy, immunotherapy, radiotherapy or other lymphoma specific therapy within 14 days before the screening visit or patient has not recovered from side effects of previous lymphoma-specific therapy. Treatment with a systemic investigational agent within 28 days before the screening visit. Previous treatment with an anti-CD19 antibody or fragments. Previous allogenic stem cell transplantation. Known or suspected hypersensitivity to the excipients contained in the study drug formulation. Clinically significant cardiovascular disease or cardiac insufficiency, cardiomyopathy, preexisting clinically significant arrhythmia, acute myocardial infarction within 3 months of enrolment, angina pectoris within 3 months of enrolment. Patients with positive hepatitis serology: Hepatitis B (HBV): Patients with positive serology for HBV defined as positivity for hepatitis B surface antigen (HBsAg) or total anti-hepatitis B core antibody (anti-HBc). Patients positive for anti-HBc may be included if HBV DNA is not detectable. Hepatitis C (HCV): Patients positive HCV serology (defined as positive for anti-HCV antibody [anti-HCV]) unless HCV-ribonucleic acid (RNA) is confirmed negative. History of HIV infection. Any active systemic infection (viral, fungal, or bacterial) requiring active parenteral antibiotic therapy within 4 weeks of study drug administration. Current treatment with immunosuppressive agents other than prescribed corticosteroids (not more than 10-mg prednisone equivalent). Major surgery or radiation therapy within 4 weeks before first study drug administration. Systemic diseases (cardiovascular, renal, hepatic, etc) that would prevent study treatment in the investigator's opinion. History or clinical evidence of central nervous system (CNS), meningeal, or epidural disease, including brain metastasis. Active treatment/chemotherapy for another primary malignancy within the past 5 years (except for ductal breast cancer in situ, non-melanoma skin cancer, prostate cancer not requiring treatment, and cervical carcinoma in situ). Pregnancy or breastfeeding in women and women of childbearing potential not using an acceptable method of birth control. History of noncompliance to medical regimens or patients who are considered potentially unreliable not cooperative.

Jurczak W, Zinzani PL, Gaidano G, Goy A, Provencio M, Nagy Z, Robak T, Maddocks K, Buske C, Ambarkhane S, Winderlich M, Dirnberger-Hertweck M, Korolkiewicz R, Blum KA. Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Ann Oncol. 2018 May 1;29(5):1266-1272. doi: 10.1093/annonc/mdy056.