Felzartamab in Late Antibody-Mediated Rejection
- Registration Number
- NCT05021484
- Lead Sponsor
- Farsad Eskandary
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 22
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo 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. Felzartamab Felzartamab 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.
- Primary Outcome Measures
Name Time Method Incidence of treatment-emergent adverse events 12 months (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).
- Secondary Outcome Measures
Name Time Method Graft loss 12 months Graft failure: time (months) to event (Kaplan Meier)
Death 12 months Patient death: time (months) to event (Kaplan Meier)
Felzartamab serum concentration At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52 Total felzartamab serum concentration (ELISA, ng/mL)
Leukocyte subsets in peripheral blood Week 0, 1, 4, 8, 12, 24, and 52 Counts of circulating plasma cells, natural killer cells, T and B cell subpopulations (flow cytometry, cell counts)
Serum immunoglobulin levels Week 0, 12, 24, and 52 Ig (sub)classes (ELISA, Nephelometry, mg/dL)
Proteinuria At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52 Urinary protein excretion in spot urine (protein/creatinine ratio in mg/g)
Transplant glomerulopathy score At week 24 and at week 52 Grading of renal transplant biopsies using a semiquantitative score (cg 0-3); higher = worse prognosis
C4d score At week 24 and at week 52 Grading of renal transplant biopsies using a semiquantitative score (c4d 0-3); higher = worse prognosis
Molecular ABMR score At week 24 and at week 52 ABMR score (0.0-1.0, dimensionless number) assessed via the Molecular Microscope Diagnostic Platform (MMDx); higher = worse prognosis
Morphologic ABMR categories At week 24 and at week 52 Phenotyping of renal transplant biopsies: active ABMR vs. chronic active ABMR vs. chronic inactive ABMR
Serum donor-specific antibody (DSA) levels Week 0, 12, 24, and 52 Mean fluorescence intensity (MFI) of the immunodominant DSA (Luminex)
eGFR At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52 Estimated GFR (CKD-EPI, mL/min/1.73m2)
Anti-Felzartamab antibodies At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52 Concentration of anti-felzartamab antibodies in serum (ELISA, ng/mL)
Torque Teno virus Week 0, 12, 24, and 52 Torque Teno virus (TTV) levels in plasma (quantitative PCR)
Immunologic biomarkers Week 0, 12, 24, and 52 CXCL9 and CXCL10 levels in blood and urine, BAFF levels in blood (ELISA, Luminex)
Glomerulitis plus peritubular capillaritis sum score At week 24 and at week 52 Grading of renal transplant biopsies using a semiquantitative score (g+ptc 0-6); higher = worse prognosis
Molecular ABMR categories At week 24 and at week 52 Molecular archetype analysis of rejection phenotypes using the Molecular Microscope Diagnostic Platform (MMDx). Phenotypes: early-stage ABMR; fully developed ABMR; late-stage ABMR
Trial Locations
- Locations (2)
Charité University
🇩🇪Berlin, Germany
Medical University of Vienna
🇦🇹Vienna, Austria