Antibody-mediated Rejection
Conditions
Keywords
CD38, Kidney transplantation
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.
Interventions
DRUGFelzartamab
Intravenous infusion in regular intervals over 6 months
DRUGPlacebo
Intravenous infusion in regular intervals over 6 months
Sponsors
Charite University, Berlin, Germany
University of Alberta
Biogen
Farsad Eskandary
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
19 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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) |
| Serum immunoglobulin levels | Week 0, 12, 24, and 52 | Ig (sub)classes (ELISA, Nephelometry, mg/dL) |
| 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) |
| Immunologic biomarkers | Week 0, 12, 24, and 52 | CXCL9 and CXCL10 levels in blood and urine, BAFF levels in blood (ELISA, Luminex) |
| Torque Teno virus | Week 0, 12, 24, and 52 | Torque Teno virus (TTV) levels in plasma (quantitative PCR) |
| 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) |
| 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) |
| Graft loss | 12 months | Graft failure: time (months) to event (Kaplan Meier) |
| Death | 12 months | Patient death: time (months) to event (Kaplan Meier) |
| 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 |
| 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 |
| 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 |
| 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) |
Countries
Austria, Germany
Outcome results
None listed