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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: MOR00208 (formerly Xmab 5574)


Participation Criteria
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Eligibility Criteria
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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 Other indolent NHL (eg, MZL/MALT) DLBCL MCL 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 × 10^9/L Platelet count ≥ 75 × 10^9/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.

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: MOR00208 (formerly Xmab5574)<br>intravenous Infusion of MOR00208, Fc-Optimized Anti-CD19 Antibody | Drug: MOR00208 (formerly Xmab 5574)<br> <br> * Other names: MOR208;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Proportion of patients with Complete Remission (CR; disappearance of all evidence of disease) or Partial Remission (PR; regression of measurable disease and no new sites), assessed as per the 2007 International Working Group (IWG) response criteria by radiographic evaluations (CT, PET, MRI, or other). | From first dose until Follow-up Visit 12, up to 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stable Disease (SD) Rate | Proportion of patients with Stable Disease (failure to attain CR/PR with no progressive disease) | From first dose until Follow-up Visit 12, up to 4.5 years | 
| Duration of Response (DoR) | Time from first CR or PR to first documentation of relapse/progression (any new lesion or increase by ≥ 50% of previously identified site) | From first dose until Follow-up Visit 12, up to 4.5 years | 
| Time to Progression (TTP) | Time from first dosing until documentation of progression or death due to lymphoma | From first dose until Follow-up Visit 12, up to 4.5 years | 
| Progression-free Survival (PFS) | Time from first dosing until progression or death due to any case | From first dose until Follow-up Visit 12, up to 4.5 years | 
| Incidence and Severity of Adverse Events (AEs) | Number of patients with treatment-emergent AEs rated Mild, Moderate, and Severe | From first dose until 30 days after last dose of MOR00208, up to 8.5 years | 
| Number and Proportion of Patients Who Potentially Developed Anti-MOR00208 Antibodies and Semiquantitative Anti-MOR00208 Antibody Assessments | Number of patients with at least one positive (+ve) post-Baseline sample containing positive anti-MOR00208 antibodies; Baseline (pre-dose) sample has to be tested negative (-ve) | From first dose until Follow-up Visit 3, up to 7 months | 
| Pharmacokinetic (PK) Parameter: Maximum Serum Concentration Observed (Cmax) of MOR00208 | The highest concentration of MOR00208 measured in serum | 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: Time to Maximum Serum Concentration Observed (Tmax) of MOR00208 | The time to highest concentration of MOR00208 measured in serum | 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: Apparent Trough Serum Concentration Before Dosing (Clast) of MOR00208 | The last quantifiable concentration from the first dose of MOR00208 | 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]) | 
| PK Parameter: Apparent Terminal Rate Constant (λz) of MOR00208 | 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]) | 
| PK Parameter: Apparent Terminal Half-life (t[1/2]) of MOR00208 | Apparent terminal half-life calculated from ln(2)/λz | 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]) | 
| PK Parameter: Total Body Clearance (CL) of MOR00208 | Total body clearance calculated for single or multiple doses: dose(s)/AUC(0-inf) | 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]) | 
| PK Parameter: Apparent Volume of Distribution (Vz) of MOR00208 | Apparent volume of distribution during the terminal phase, calculated from dose/(AUC(0-inf)*λz) | 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]) | 
| Absolute Change From Baseline in Measurements of B-cell Populations | Actual change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: B-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 7.5 years) | 
| Percent Change From Baseline in Measurements of B-cell Populations | Relative change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: B-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 7.5 years) | 
| Absolute Change From Baseline in Measurements of T-cell Populations | Actual change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: T-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 7.5 years) | 
| Percent Change From Baseline in Measurements of T-cell Populations | Relative change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: T-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 7.5 years) | 
| Absolute Change From Baseline in Measurements of NK Cell Populations | Actual change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: 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 7.5 years) | 
| Percent Change From Baseline in Measurements of NK Cell Populations | Relative change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: 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 7.5 years) | 
| Evaluation of AEs Stratified by Baseline CD19 Expression on Malignant Lymphoma Cells | Incidence of AEs as stratified by presence of CD19 on malignant lymphoma cells detected by tumor biopsy/aspirate during Screening | From first dose until 30 days after last dose of MOR00208, up to 8.5 years | 
| Evaluation of ORR Stratified by Baseline CD19 Expression on Malignant Lymphoma Cells | 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 | From first dose until Follow-up Visit 12, up to 4.5 years | 
| Evaluation of AEs Stratified by FcγRIIa Polymorphism | Incidence of AEs as stratified by FcγRIIa polymorphism subgroups (genotypes HH, HR, or RR) | From first dose until 30 days after last dose of MOR00208, up to 8.5 years | 
| Evaluation of AEs Stratified by FcγRIIIa Polymorphism | Incidence of AEs as stratified by FcγRIIIa polymorphism subgroups (genotypes FF, FV, or VV) | From first dose until 30 days after last dose of MOR00208, up to 8.5 years | 
| Evaluation of ORR Stratified by FcγRIIa Polymorphism | The analysis of the primary endpoint (ORR) will additionally be stratified by FcγRIIa polymorphism subgroups (genotypes HH, HR, or RR) | From first dose until Follow-up Visit 12, up to 4.5 years | 
| Evaluation of ORR Stratified by FcγRIIIa Polymorphism | The analysis of the primary endpoint (ORR) will additionally be stratified by FcγRIIIa polymorphism subgroups (genotypes FF, FV, or VV) | From first dose until Follow-up Visit 12, up to 4.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, CD19, MOR208, MOR00208, Xmab5574, B-Cell Non-Hodgkin´s Lymphoma, Fc-optimized Anti-CD19 Antibody, Tafasitamab