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Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

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B-cell Lymphoma

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Immunoglobulins

intravenous Infusion of MOR00208, Fc-Optimized Anti-CD19 Antibody

MOR00208 (formerly Xmab 5574)

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.

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

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).

Proportion of patients with Stable Disease (failure to attain CR/PR with no progressive disease)

Time from first CR or PR to first documentation of relapse/progression (any new lesion or increase by ≥ 50% of previously identified site)

Time from first dosing until documentation of progression or death due to lymphoma

Time from first dosing until progression or death due to any case

Number of patients with treatment-emergent AEs rated Mild, Moderate, and Severe

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)

The highest concentration of MOR00208 measured in serum

The time to highest concentration of MOR00208 measured in serum

The last quantifiable concentration from the first dose 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.

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.

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

Apparent terminal half-life calculated from ln(2)/λz

Total body clearance calculated for single or multiple doses: dose(s)/AUC(0-inf)

Apparent volume of distribution during the terminal phase, calculated from dose/(AUC(0-inf)\*λz)

Actual change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: B-cell populations

Relative change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: B-cell populations

Actual change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: T-cell populations

Relative change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: T-cell populations

Actual change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: NK cell populations

Relative change from baseline will be summarized descriptively by visit for the pharmacodynamic parameter: NK cell populations

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

Incidence of AEs as stratified by FcγRIIa polymorphism subgroups (genotypes HH, HR, or RR)

Incidence of AEs as stratified by FcγRIIIa polymorphism subgroups (genotypes FF, FV, or VV)

The analysis of the primary endpoint (ORR) will additionally be stratified by FcγRIIa polymorphism subgroups (genotypes HH, HR, or RR)

The analysis of the primary endpoint (ORR) will additionally be stratified by FcγRIIIa polymorphism subgroups (genotypes FF, FV, or VV)

MorphoSys AG

Patients were closely monitored for any kind of AE during the study. AEs were detected through physical examination, laboratory tests, or other assessments, or when volunteered by the patient in response to non-leading questioning during or between study visits. All SAEs are reported for the Safety Population, including events occurring prior to first dose of MOR00208. For non-serious AEs, only treatment-emergent events are reported (i.e., events occurring after first dose of MOR00208).

All patients received 12 mg/kg MOR00208 administered as an intravenous infusion.

Total

Patients with follicular lymphoma. All patients received 12 mg/kg MOR00208 administered as an intravenous infusion.

FL Subtype

Patients with diffuse large B-cell lymphoma. All patients received 12 mg/kg MOR00208 administered as an intravenous infusion.

DLBCL Subtype

Patients with mantle cell lymphoma. All patients received 12 mg/kg MOR00208 administered as an intravenous infusion.

MCL Subtype

Patients with other indolent non-Hodgkin's lymphoma. All patients received 12 mg/kg MOR00208 administered as an intravenous infusion.

Other iNHL

Combined group of patients with follicular lymphoma and patients with other indolent non-Hodgkin's lymphoma. All patients received 12 mg/kg MOR00208 administered as an intravenous infusion.

FL + Other iNHL

Age, Categorical

Age, Continuous

Sex: Female, Male

Asian

Black or African American

White

Other

Race/Ethnicity, Customized

Height was not collected at Screening for 2 patients (minor protocol noncompliance)

Height

Weight

Follicular lymphoma

Diffuse large B-cell lymphoma

Mantle cell lymphoma

Other indolent NHL

NHL Subtype

Per planned analyses, baseline characteristics are summarized by NHL subtype.

Medical Information

Complete remission

Partial remission

The Intent-to-treat (ITT) Population consisted of all patients who received at least one dose of study drug. Patients without any post-Baseline assessment of NHL response were included as non-responders. Per pre-specified analysis plan, efficacy analyses are summarized overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Overall Response Rate (ORR)

The ITT Population consisted of all patients who received at least one dose of study drug. Patients without any post-Baseline assessment of NHL response were included as non-responders. Per pre-specified analysis plan, efficacy analyses are summarized overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Stable Disease (SD) Rate

Patients in the ITT Population who had any response (CR or PR) during the study. Per pre-specified analysis plan, efficacy analyses are summarized overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Duration of Response (DoR)

Patients in the ITT Population with documented progression of disease. Per pre-specified analysis plan, efficacy analyses are summarized overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Time to Progression (TTP)

Patients in the ITT Population with documented progression of disease or death from any cause. Per pre-specified analysis plan, efficacy analyses are summarized overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Progression-free Survival (PFS)

Mild

Moderate

Severe

The Safety Population consisted of all patients who received at least one dose of study drug. Per pre-specified analysis plan, adverse event analyses are summarized overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Incidence and Severity of Adverse Events (AEs)

The Safety Population (all patients who received at least one dose of study drug). Per pre-specified analysis plan, statistical summaries are provided overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Number and Proportion of Patients Who Potentially Developed Anti-MOR00208 Antibodies and Semiquantitative Anti-MOR00208 Antibody Assessments

The PK Population included all patients who had at least one quantifiable serum MOR00208 concentration. PK parameters were calculated as data permitted. Per pre-specified analysis plan, statistical summaries are provided overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Pharmacokinetic (PK) Parameter: Maximum Serum Concentration Observed (Cmax) of MOR00208

PK Parameter: Time to Maximum Serum Concentration Observed (Tmax) of MOR00208

PK Parameter: Apparent Trough Serum Concentration Before Dosing (Clast) of MOR00208

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

PK Parameter: Area Under the Concentration Curve From Dose Time Zero to Infinity (AUC[0-inf]) of MOR00208

PK Parameter: Apparent Terminal Rate Constant (λz) of MOR00208

PK Parameter: Apparent Terminal Half-life (t[1/2]) of MOR00208

PK Parameter: Total Body Clearance (CL) of MOR00208

PK Parameter: Apparent Volume of Distribution (Vz) of MOR00208

Cycle 1 Day 8

Cycle 1 Day 15

Cycle 1 Day 22

Cycle 2 Day 1

Cycle 2 Day 15

Cycle 2 Day 28

Cycle 3 Day 1

Cycle 3 Day 15

Cycle 3 Day 28

Study Completion/Early Termination

Pharmacodynamic samples were collected at timepoints through the study where possible. Per pre-specified analysis plan, statistical summaries are provided overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Absolute Change From Baseline in Measurements of B-cell Populations

Percent Change From Baseline in Measurements of B-cell Populations

Absolute Change From Baseline in Measurements of T-cell Populations

Percent Change From Baseline in Measurements of T-cell Populations

Absolute Change From Baseline in Measurements of NK Cell Populations

Percent Change From Baseline in Measurements of NK Cell Populations

Per pre-specified analysis plan, if CD19 expression on tumor cells was able to be measured in less than 15% of the ITT population at screening, the stratification analyses by baseline CD19 expression (as planned in the protocol) would not be performed. It was not possible to measure CD19 expression in sufficient cases for such an analysis to be meaningful.

Evaluation of AEs Stratified by Baseline CD19 Expression on Malignant Lymphoma Cells

Evaluation of ORR Stratified by Baseline CD19 Expression on Malignant Lymphoma Cells

Genotype HH

Genotype HR

Genotype RR

Genotyping for FcγRIIa and FcγRIIIa polymorphisms was performed for patients who consented to an optional mucosal cheek swab. Per pre-specified analysis plan, statistical summaries are provided overall, by NHL subtype, and for the combined group comprising FL patients + other iNHL patients.

Spots Global Cancer Trial Database for Study of Fc-Optimized Anti-CD19 Antibody (MOR00208) to Treat Non-Hodgkin's Lymphoma (NHL)

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