Felzartamab in Late Antibody-Mediated Rejection

Study Overview
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Brief Summary
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This prospective trial will assess the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics and efficacy of the fully human CD38 monoclonal antibody felzartamab in kidney transplant recipients with late active or chronic-active ABMR. The study is designed as a randomized, controlled, double-blind pilot phase 2 trial. Participants will be randomized to receive either felzartamab or placebo for a period of six months, and then followed for another six months. After six and twelve months, study participants will be subjected to follow-up allograft biopsies.

Detailed Description
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This prospective bi-center study (University of Vienna, Charité Universitätsmedizin Berlin; Sponsor: Medical University of Vienna, Vienna, Austria; Funder: MorphoSys AG, Planegg, Germany) is an investigator-driven pilot trial designed to assess the safety&tolerability (primary endpoint), pharmacokinetics, immunogenicity, pharmacodynamics and efficacy (preliminary assessment) of the fully human CD38 monoclonal antibody felzartamab in kidney transplant recipients diagnosed with late active or chronic-active antibody-mediated rejection (ABMR) after kidney transplantation. Adult renal allograft recipients with anti-HLA donor-specific antibodies (DSA) and biopsy-proven ABMR (Banff 2019 classification) ≥180 days post-transplantation will be identified and recruited at the kidney transplantation outpatient services of the two center sites. The primary endpoint will be safety and tolerability. Participants will be randomized to receive either felzartamab (intravenous administration) or placebo (1:1 randomization stratified by study site and according to ABMR categories) for a period of 6 months (administration of felzartamab/placebo at day 0, 7, 14, 21, and thereafter in 4-weekly intervals. After six (week 24) and twelve months (week 52), study participants will be subjected to follow-up allograft biopsies. Primary goals of the trial are to assess the safety, pharmacokinetics and pharmacodynamics (peripheral blood plasma cell and natural killer cell depletion) of a 6-month course of treatment over a period of 12 months. The trial will in addition provide first data on efficacy (progression/activity of rejection, blood biomarkers) and potential associations of treatment with parameters reflecting clinical progression of allograft dysfunction, including the course of estimated glomerular filtration rate.

Official Title
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Safety, Tolerability and Efficacy of Monoclonal CD38 Antibody Felzartamab in Late Antibody-Mediated Renal Allograft Rejection - A Phase 2 Pilot Trial

Conditions
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Antibody-mediated Rejection

Intervention / Treatment
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* Drug: Felzartamab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written informed consent Age >18 years (maximum: 80 years) Functioning living or deceased donor allograft after ≥180 days post-transplantation eGFR ≥20 ml/min/1.73 m2 (CKD-EPI formula) HLA class I and/or II antigen-specific antibodies (preformed and/or de novo DSA). Active or chronic/active ABMR (±C4d in PTC) according to the Banff 2019 classification Molecular ABMR score (MMDx) ≥0.2 Exclusion Criteria: Patients actively participating in another clinical trial Age ≤18 years Female subject is pregnant or lactating or not on adequate contraceptive therapy ABO-incompatible transplant Index biopsy results: T-cell-mediated rejection classified Banff grade ≥I De novo or recurrent severe thrombotic microangiopathy Polyoma virus nephropathy De novo or recurrent glomerulonephritis Acute rejection treatment ≤3 month before screening Previous treatment with other CD38 monoclonal antibodies (e.g. daratumumab) Previous treatment with other immunomodulatory monoclonal/polyclonal antibodies (e.g. CD20 Ab rituximab, IL-6/IL-6R Ab) ≤3 months before study treatment Total bilirubin >2×the upper limit of normal [ULN], alanine transaminase and aspartate aminotransferase >2·5×ULN Haemoglobin <8 g/dL Thrombocytopenia: Platelets <100 G/L Leukopenia: Leukocytes <3 G/L Neutropenia: Neutrophils < 1.5 G/L Hypogammaglobulinemia: Serum IgG <400 mg/dL Active viral, bacterial or fungal infection precluding intensified immunosuppression Active malignant disease precluding intensified immunosuppressive therapy Latent or active tuberculosis (positive QuantiFERON-TB-Gold test) Administration of a live vaccine within 6 weeks of screening History of alcohol or illicit substance abuse Serious medical or psychiatric illness likely to interfere with participation in the study

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Felzartamab<br>9 doses of felzartamab as an intravenous infusion over 6 treatment cycles at 28 days each. Dosing occurs every week in cycle 1 and every four weeks in cycles 2-6. | Drug: Felzartamab<br>* Intravenous infusion in regular intervals over 6 months<br>* Other names: MOR202, CD38 monoclonal antibody;|
| Placebo Comparator: Placebo<br>9 doses of placebo as an intravenous infusion over 6 treatment cycles at 28 days each. Dosing occurs every week in cycle 1 and every four weeks in cycles 2-6. | Drug: Placebo<br>* Intravenous infusion in regular intervals over 6 months<br>* Other names: 0.9% Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events | (Serious) adverse events will be classified using the Medical Dictionary for Regulatory Activities (MedDRA). Documentation of an AE will include the assessment of its relationship with the study drug (unrelated, related) and the severity of AE will be graded on a three-point scale (mild, moderate, severe). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Felzartamab serum concentration | Total felzartamab serum concentration (ELISA, ng/mL) | At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52 | 
| Anti-Felzartamab antibodies | Concentration of anti-felzartamab antibodies in serum (ELISA, ng/mL) | At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52 | 
| Morphologic ABMR categories | Phenotyping of renal transplant biopsies: active ABMR vs. chronic active ABMR vs. chronic inactive ABMR | At week 24 and at week 52 | 
| Serum donor-specific antibody (DSA) levels | Mean fluorescence intensity (MFI) of the immunodominant DSA (Luminex) | Week 0, 12, 24, and 52 | 
| Serum immunoglobulin levels | Ig (sub)classes (ELISA, Nephelometry, mg/dL) | Week 0, 12, 24, and 52 | 
| Leukocyte subsets in peripheral blood | Counts of circulating plasma cells, natural killer cells, T and B cell subpopulations (flow cytometry, cell counts) | Week 0, 1, 4, 8, 12, 24, and 52 | 
| Immunologic biomarkers | CXCL9 and CXCL10 levels in blood and urine, BAFF levels in blood (ELISA, Luminex) | Week 0, 12, 24, and 52 | 
| Torque Teno virus | Torque Teno virus (TTV) levels in plasma (quantitative PCR) | Week 0, 12, 24, and 52 | 
| eGFR | Estimated GFR (CKD-EPI, mL/min/1.73m2) | At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52 | 
| Proteinuria | Urinary protein excretion in spot urine (protein/creatinine ratio in mg/g) | At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52 | 
| Graft loss | Graft failure: time (months) to event (Kaplan Meier) | 12 months | 
| Death | Patient death: time (months) to event (Kaplan Meier) | 12 months | 
| Glomerulitis plus peritubular capillaritis sum score | Grading of renal transplant biopsies using a semiquantitative score (g+ptc 0-6); higher = worse prognosis | At week 24 and at week 52 | 
| Transplant glomerulopathy score | Grading of renal transplant biopsies using a semiquantitative score (cg 0-3); higher = worse prognosis | At week 24 and at week 52 | 
| C4d score | Grading of renal transplant biopsies using a semiquantitative score (c4d 0-3); higher = worse prognosis | At week 24 and at week 52 | 
| Molecular ABMR score | ABMR score (0.0-1.0, dimensionless number) assessed via the Molecular Microscope Diagnostic Platform (MMDx); higher = worse prognosis | At week 24 and at week 52 | 
| Molecular ABMR categories | Molecular archetype analysis of rejection phenotypes using the Molecular Microscope Diagnostic Platform (MMDx). Phenotypes: early-stage ABMR; fully developed ABMR; late-stage ABMR | At week 24 and at week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD38, Kidney transplantation